Epidemiology

• Higher incidence (9 – 20/100,000 person years) and prevalence (156 – 291/100,000 people) in populations of North American and Northern European descent (Lancet 2012;380:1606)
• Incidence increased in industrialized countries and urban versus rural locations, suggestive of environmental triggers, such as improved sanitation, reduced exposure to childhood enteric infections and mucosal immune system maturation (Lancet 2012;380:1606)
• Bimodal age distribution with peaks at 15 – 30 years and 50 – 70 years (Lancet 2012;380:1606)
• Family history of inflammatory bowel disease, particularly that of a first degree relative (5.7 – 15.5%) and Ashkenazi Jewish descent (3 – 5x) show higher risk of disease development (Lancet 2012;380:1606)
• Gastrointestinal infections with Salmonella spp, Shigella spp and Campylobacter spp have twice the risk of developing ulcerative colitis postinfection (Lancet 2012;380:1606)
• M = F
• Former cigarette smoking is strong risk factor (Lancet 2017;389:1756)

• Almost always involves the rectum
  • Continuous pattern of involvement proximally to include up to the entire colon (pancolitis)
  • Rectal sparing can be seen, particularly after treatment (Lancet 2012;380:1606, Histopathology 2014;64:317, Am J Clin Pathol 2004;122:94)
• Patch of inflammation in the cecum, often involving the periappendiceal mucosa (cecal patch), can be present (Lancet 2012;380:1606, Histopathology 2014;64:317)
• Approximately 20% of patients will have inflammation in the terminal ileum (backwash ileitis)
  • Typically present in patients with pancolitis (Am J Surg Pathol 2005;29:1472)
• Focally enhanced gastritis can be seen in approximately 20% of pediatric patients (Pathology 2017;49:808)
• Extraintestinal manifestations:
  • Peripheral arthritis, seronegative
  • Ankylosing spondylitis or sacroiliitis
  • Erythema nodosum
  • Pyoderma granulosum
  • Primary sclerosing cholangitis (PSC)

Pathophysiology

• Not fully known but appears to be a complex multifactorial process involving an overwhelming T helper type 2-like immune response, leading to mucosal injury in response to gut microbial dysbiosis in genetically predisposed patients
• Proposed mechanisms include:
  • Damage to the colonic epithelial barrier due to dysregulation of epithelial tight junctions, which provide a physical barrier between the immune cells and the luminal microbes, leads to increased permeability (Lancet 2012;380:1606)
  • Colonic epithelium upregulation of antimicrobial peptides, known as beta defensins (Lancet 2012;380:1606)
  • Disruption in the homeostatic balance of the mucosal immunity and the enteric nonpathogenic bacteria, resulting in the patient’s aberrant immune response to the enteric commensal bacteria (Lancet 2012;380:1606, Front Microbiol 2018;9:2247)
  • Increased number of colonic epithelium activated and mature dendritic cells with increased stimulatory capacity (Lancet 2012;380:1606)
  • Increased expression of TLR4 by lamina propria cells and TLR4 polymorphism, which can alter susceptibility to enteric infections and tolerance to commensal bacteria (Lancet 2012;380:1606)
  • Disruption in the homeostatic balance between regulatory and effector T cells, leading to a nonclassic natural killer T cell production of IL5 and IL13, which have cytotoxic effects on epithelial cells, mediating an atypical Th2 response
    • IL13 can induce a positive feedback system on the natural killer T cells, leading to increased tissue injury (Lancet 2012;380:1606)
  • Increase in proinflammatory cytokines, chemoattractants such as CXCL8 and adhesion molecules such as MadCAM1 recruit increased leukocytes to the colonic mucosa (Lancet 2012;380:1606)
  • Other genetic risk loci include IL23 and IL10, JAK2 kinase pathway genes, hepatocyte nuclear factor 4α, CDH1 and laminin β1 (Lancet 2012;380:1606)

Etiology :

I propose a mechanism that involves the limbic system and that continuously maintains a state of stress equivalent to a situation of major stress (trauma) and therefore causes all the signs and symptoms of the disease. How does that happen?
Imagine the situation of this gazelle:

Its limbic system will use all means to save its life, by starting it will increase blood circulation in the muscles by dilating the arteries of the muscles (vasodilation), it will increase blood pressure to increase the pressure of perfusion, it will increase heart rate to increase blood flow per minute. This system will trigger other reactions at the level of other organs for example, in the liver and fat tissue it will cause an increase in the release of carbohydrates and fatty acids to bring the necessary energy to the muscles. It will give to this gazelle a deeper field of vision as well as many others possibilities with other systems (see physiopathology of stress) but this system will go further it will reduce the circulation in the internal organs to offer the muscles the blood flow necessary for survival (its survival is at stake the intestines and other organs can wait).

It will also stop the movement of the intestine  and the evacuation of the urinary system, because this is not the time to go to the bathroom!So no defecation and no urination. At the same time  for the same reason the appetite is inhibited  But while this gazelle is running it will see a lot of things it will see flowers, plants, streams, trees, the sun, as well as other animals…… in short it will see its usual environment in complete.Probably consciously it will record only the traumatic part of what happens to it, because it is concerned about its survival, but subconsciously all these elements will be recorded. As a result, it will consciously record a small portion of the information and a large portion of the information will be recorded subconsciously. If this gazelle succeeds in saving its life, it cannot help but record those moments of stress in his memories.

After this event this gazelle is condemned to live with the stress that is recorded and this state of stress will have a continuous effect because the environment of this gazelle’s life is filled with elements which unconsciously remind it of the stressful event and which trigger a major stress with all the resulting consequences. Inhibition of bowel motility will cause constipation. Abdominal and digestive artery vasoconstriction will result in functional ischemia whose intensity will determine the symptomatology. If the vasoconstriction is limited it will only cause slight clinical manifestations without a lesion visible macroscopically or microscopically at the level of the intestine it is the case of the irritable bowel syndrome.

If the vasoconstriction is more important, there will be ischemia creating a minor cellular suffering and especially in the segments where the intestine is in the remote areas of the irrigation network and especially without anastomosis ie in the areas vulnerable. 

This explains the frequency with which the rectum gets affected…

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The limbic system is a group of gray matter and white matter structures lodged deep within the cerebrum that are involved in four functions: olfaction, emotional responses, behavioral activities and memories.

Anatomical structures:

–Limbic lobe: has two main components that are cingulate gyrus (involved in memory and emotional processing and autonomic nervous system) and Para hippocampal gyrus (primarily involved in memory processing).

– Hippocampal formation: composed of three parts: dentate gyrus (afferent information, subiculum (efferent information) hippocampus proper (efferent information)

– Amygdala: which is involved in emotions and emotional behaviors and emotional responses to smell. The Amygdala has two components: cortico medial nuclear group (involved in olfaction) and basolateral nuclear group (all other emotions and behaviors not related to olfaction).

– Hypothalamus: the most important nuclei of hypothalamus in relation with limbic system are mammillary bodies, and autonomic nervous system nuclei (posterior sympathetic anterior parasympathetic)

– Thalamus: there are two main nuclei involved in the limbic system (anterior nucleus of the thalamus which is involved in papez circuit and the other one is called the mediodorsal nucleus which is involved in the circuit connecting the amygdala to prefrontal cortex “emotions and behaviors)

Septal area:

Habenula (part of epithalamus)

Habenula and septal area are connected via a structure called stria medullaris and are involved, particularly in reward pathway and emotional responses as well.

Pathways connecting different structures of the limbic system:

Fornix:

Connects hippocampus to hypothalamus (mammillary bodies) and the septal area.

Striae terminalis: connects the amygdala to the hypothalamus and septal area.

Ventral amygdalofugal pathway : connects the amygdala to the hypothalamus and septal area and also to the mediodorsal nucleus of the thalamus

Striae Medullaris thalami: connects septal area to habenula.

Mamillo-thalamic tract: connects mammillary bodies to the anterior nucleus of the thalamus.

Medial forebrain bundle:  two-way connection that connects the prefrontal cortex to the reticular formation in the brain stem running through the hypothalamus.

Mamillo tegmental tract: connects mammillary bodies of hypothalamus to ventral tegmental area

Mamillary peduncles: connects the ventral tegmental area to the hypothalamus

Functions of limbic system:

-Olfaction: Olfactory epithelial cells, olfactory bulb, action potential in the olfactory tracts, the olfactory tracts bifurcate in medial olfactory striate and lateral olfactory striate which goes into the Para hippocampal gyrus (memory) and to the amygdala (emotions of smell).

-Memory (learning): papez circuit:

Subiculum → Fornix → Mamillary bodies → Mamillo thalamic tract → anterior nucleus of the thalamus → cingulate gyrus →Para hippocampal gyrus → entorhinal cortex → dentate gyrus → subiculum.

Hippocampus (dentate gyrus, which is the receiving portion and subiculum and hippocampus proper which are the leaving portion),

Cingulate gyrus sends also the information to the prefrontal cortex and the purpose of communicating with the prefrontal cortex is to have our memory be involved with our thought and decision making.

-Emotions: particularly the emotional responses, and it’s also involved in behaviors and there are three types of behaviors that the limbic system is involved in :

a) Emotional responses: that means (fear, rage, anger, sadness)

b) Behaviors (feeding behaviors, sexual behaviors, motivational behaviors)

The Amygdala is the center (epicenter) for emotions and behaviors in the limbic system. How does it basically know that we are fearful, angry, or sad? In fact, the limbic system is in communication with our cerebral cortex.

Prefrontal cortex: is involved in thought processing (reasoning, judgment, decision making, personality

Temporal lobe: is involved in multiple functions (smell, taste, visceral sensations, and other areas which are involved in auditory association areas and all are in communication with the amygdala)

Posterior association area: receives information from three different areas: somatosensory association cortex, visual association cortex, and auditory association cortex, and then communicates that with the amygdala, so the amygdala receives informations from all of these structures. And from the cerebral cortex communicating with the amygdala, it will be possible to have enough information to send information to two regions via striae terminalis to septal area and hypothalamus.

The feeding is also controlled by amygdala imagine the sadness amygdala will send information to the nuclei of hypothalamus the ventro-medial nucleus is involved in satiety and the other nucleus is called lateral hypothalamus nucleus and is involved in hunger so the amygdala is responsible for feeding aspect of the organism.

The sexual behavior is also controlled by amygdala:

Depending your psychological situation amygdala feel if you are in sexual mood or not and if yes it will intervene by two nucleus the first one is paraventricular nucleus which releases oxytocin which is commonly secreted in females for uterine contraction and milk ejection, in males it is engaged in sexual orgasm and sexual drives itself. And the other one is Medial Preoptic nucleus which releases Gonadotropin releasing Hormone and GNRH releases in male testosterone which is also responsible for increased sex drive.

Motivational behavior:

We know that amygdala connects with septal area and hypothalamus via the striae terminalis or Ventral medio amygdalo fugal pathway and from the septal area or from the hypothalamus they both can communicate with the ventral tegmental area located in the brainstem, in the ventral tegmental area there is a lot of dopamine (many dopaminergic neurons are located there) and ventral tegmental area sends neurons to Nucleus Accumbens and prefrontal cortex so the amygdala in some conditions (drug abuse for example)  will sends the information to the septal area and to hypothalamus and these in turn will send informations to the ventral tegmental area and from the ventral tegmental area the dopaminergic neurons will connect with nucleus Accumbens and prefrontal cortex. The pathway from the ventral tegmental area to the prefrontal cortex is called the meso cortical pathway and the pathway from the ventral tegmental area to the nucleus Accumbens is called the mesolimbic pathway. The areas receiving the dopaminergic neurons are engaged in reward sensation

Fear:

In fear induced (as emotion) the amygdala will connect via the stria terminalis and ventral amygdalofugal pathway with hypothalamus (posterior hypothalamic nucleus) and the posterior hypothalamic nucleus sends its descending axons downwards via what is called the hypothalamospinal tract and innervates the preganglionic neurons(sympathetic) located within the thoraco lumbar region of the spinal cord  and from there the sympathetic motor neurons will go to the target organs and the final result will be:

Sympathetic activation: cf autonomic nervous system

And the Paraventricular nucleus of hypothalamus which will secrete the cortico-tropine releasing hormone (CRH) which will stimulate the secretion of ACTH by pituitary gland, which in turn will activate the cortisol secretion in adrenal gland (cortisol is called the stress hormone)

Corticotropin-releasing hormone (CRH), a 41 amino acid neuropeptide, discovered in 1981 by Wiley Vale is likely involved in all three types of stress-response. Behavioral responses may involve CRH present in the cerebral cortex and amygdala. Autonomic responses are controlled in part by brainstem fibers descending from the locus coeruleus, which receives CRH-containing fibers from the amygdala and paraventricular nucleus. Hormonal responses center on activation of the hypothalamic–pituitary–adrenal (HPA) axis, which is initiated by CRH present in the paraventricular nucleus of the hypothalamus (PVH).

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                  Fig. 1: Illustration of a Stressful Situation

The image above clearly illustrates a stressful situation triggered by two types of factors:

• The physical stressor

This refers to pain caused by a mechanical injury and detected by mechanical and polymodal nociceptors, as well as free nerve endings.

Within the skin and underlying tissues, there are numerous free nerve endings. Some respond primarily to intense mechanical pressure (mechanical nociceptors), whereas others respond to multiple types of noxious stimuli, including mechanical pressure, extreme heat, and chemical irritation (polymodal nociceptors). These sensory receptors detect tissue injury or potentially damaging stimuli.

Once the alarm signal has been triggered, the electrical signal must travel along the sensory neuron. It is transmitted through two main types of nerve fibers:

• Aδ fibers: relatively large and rapidly conducting fibers that transmit sharp, well-localized, and immediate pain.
• C fibers: thin, slowly conducting fibers that transmit secondary, dull, burning, and more diffuse pain, which may persist after the initial injury.

The signal then travels toward the cell body of the primary sensory neuron, which is located in the dorsal root ganglion (spinal ganglion) (see Fig. 2).

The nociceptive information subsequently enters the spinal cord through the dorsal root, where the primary sensory afferent neurons synapse with second-order neurons, particularly within Rexed laminae I, II, and V. These laminae are anatomically defined layers of the spinal dorsal horn.

Rexed laminae I, II, and V are key regions involved in the reception, processing, and integration of nociceptive signals.               Fig. 2: Neural Mechanisms Underlying the Physical Stress Circuit

The second-order sensory neuron, following synaptic relay within the Rexed laminae of the spinal cord, conveys the nociceptive signal toward higher-order centers. After decussating to the contralateral side of the spinal cord, its axon ascends via the contralateral spinothalamic tract toward supraspinal structures.

                                    Fig. 3: The Spinothalamic Tract

The spinothalamic tract in the medulla is located in the lateral region, in a dorsolateral position, close to the spinal trigeminal nucleus. It is part of the anterolateral system.

    Fig. 4: The Spinothalamic Tract and the Anterolateral System in the Medulla

Bulbar Connections

1. Collateral projections to the reticular formation
   These projections contribute to the spinoreticular pathway, which is involved in the affective and emotional dimensions of pain, with subsequent projections to the intralaminar nuclei of the thalamus.
2. Connections with the spinal trigeminal nucleus
   These connections contribute to the integration of somatic and facial pain.
3. Contribution to the spinoparabrachial pathway (indirect)
   This pathway provides relay connections to autonomic control centers.

The Spinothalamic Tract in the Pons:

                                 Fig. 5: The Spinothalamic Tract in the Pons

Connections at the pontine level

1. Pontine reticular formation: modulation of arousal and participation in autonomic responses to pain.
2. Periaqueductal gray (PAG): via ascending projections; an indirect connection that contributes to the initiation of descending pain-modulatory mechanisms.
3. Parabrachial complex: projections to the hypothalamus, contributing to autonomic responses and the affective component of pain.

The Spinothalamic Tract in the Midbrain

Major Midbrain Connections

1. Periaqueductal gray (PAG)
   A major center for pain modulation; initiates descending inhibitory pathways and activates the nucleus raphe magnus, leading to spinal inhibition.
2. Superior colliculus (minor collateral projections)
   Involved in orienting reflexes toward nociceptive stimuli.
3. Midbrain reticular formation
   Contributes to arousal and alertness in response to nociceptive stimuli.

Thalamus (Major Relay)

Thalamic Nuclei

• VPL (ventral posterolateral nucleus) → conveys nociceptive information from the body.
• Intralaminar nuclei → involved in the affective and emotional components of pain.

Cerebral Cortex – Conscious Pain Perception

At the cortical level, the primary somatosensory cortex (S1) receives nociceptive information and contributes to the conscious perception of pain, particularly its location and intensity.

Other activated regions:

• Secondary somatosensory cortex (S2) → higher-order processing and integration of somatosensory information.
• Insular cortex → contributes to the subjective awareness of bodily states and the sensory-affective experience of pain.
• Anterior cingulate cortex (ACC) → emotional and affective dimensions of pain, including suffering and distress.
• Amygdala → emotional processing of threat, including fear and defensive responses such as escape or avoidance.

Psychological Stressor: Fear

Fear is a primary survival emotion whose function is to detect potential threats and trigger rapid defensive responses, such as flight, fight, or freezing. In animals such as the gazelle, this response is essential for survival.

Rapid Detection of Threat

Threat detection begins through sensory systems, including:

• Visual system
• Auditory system
• Olfactory system
• Somatosensory system (touch)

The sensory information is then transmitted to the thalamus, which acts as an important relay.

From the thalamus, information can reach the amygdala through two functionally distinct processing routes, as described in the LeDoux model:

1. The fast pathway (“low road”)
   Thalamus → Amygdala

   This pathway provides rapid but relatively coarse processing of potential threats. It bypasses detailed cortical analysis and can operate largely outside conscious awareness. Because of its limited sensory resolution, it may generate a false alarm—for example, interpreting a coiled rope as a snake.

2. The slow cortical pathway (“high road”)
   Thalamus → Sensory cortex → Amygdala

   This pathway involves more detailed cortical processing before the information reaches the amygdala. It is slower but more precise, allowing conscious evaluation and discrimination of the stimulus—for example, determining whether the apparent “snake” is actually a rope.

Fig. 7: Fear Pathways to the Amygdala

 Stress Responses of the Organism

1) Response to a Physical Stressor

The information reaches the hypothalamus through the parabrachial nuclei and/or the amygdala, which initiates the fight-or-flight response.

a) Immediate autonomic response (via the hypothalamus and brainstem)

Activation of the sympathetic nervous system:

tachycardia, Increased blood pressure, vasoconstriction of the abdominal and peripheral arteries, vasodilation of the skeletal muscle arteries, mydriasis (pupillary dilation), bronchodilation, sweating, inhibition of gastrointestinal motility, temporary reduction in urine production, as the body prioritizes vital functions such as the heart and skeletal muscles. Reduced renal blood flow leads to decreased glomerular filtration and, consequently, reduced urine output in the short term. In some cases, an urgent need to urinate may occur as a paradoxical response. This constitutes the “fight-or-flight” response.

Fig. 8: Stimulation of Bone Marrow Stem Cells

   Fig. 9: The Hypothalamic–Pituitary–Adrenal (HPA) Axis

The HPA axis induces the release of cortisol, which exerts an anti-inflammatory effect during the acute stress response.

2) Response to a Psychological Stressor (Fear)

Fear is a primary survival emotion whose function is to detect danger and trigger rapid defensive responses, such as flight, fight, or freezing. In animals such as gazelles, this response is essential for survival.

Rapid detection of danger:
Danger is detected through the sensory systems, including the visual, auditory, olfactory, and somatosensory systems.

The sensory information reaches the thalamus, which acts as a sensory relay and processing center.

Between the thalamus and the amygdala, there are two transmission pathways, as described in the LeDoux model:

Fig. 10: The Two Fear-Transmission Pathways

En 1937, dans son article scientifique intitulé “A Proposed Mechanism of Emotion”,Papez cherchait à expliquer le fonctionnement des émotions dans le cerveau. Il a proposé un circuit neuronal fermé, aujourd’hui appelé circuit de Papez, reliant plusieurs structures cérébrales.

Fig. 11: Papez circuit

Although Papez’s model was subsequently modified, particularly with the introduction of the concept of the limbic system, it remains a major historical foundation in neuroscience. We later realized that this system is far more complex and involves numerous nuclei and interconnected structures, allowing us to experience the extraordinary diversity of human emotions and pleasures.

Fig. 12: The Amygdala and Hippocampal Network in the Papez Circuit

In summary, the information reaches all of these nuclei within their respective networks, with the amygdala and hippocampus playing important roles: the amygdala is involved in encoding the emotional value of an experience, whereas the hippocampus records the context and environmental setting associated with the traumatic event. For example, in the case of this gazelle, the entire surrounding environment is unconsciously encoded, whereas the predator itself is consciously perceived and encoded.

The BLA (basolateral amygdala) then stimulates the BNST (bed nucleus of the stria terminalis), which in turn activates the DMH (dorsomedial hypothalamus) and the PVN (paraventricular nucleus of the hypothalamus). The PVN subsequently acts on the sympathetic nervous system and the HPA axis (see above).

The amygdala is also closely interconnected with the prefrontal cortex (PFC), which normally exerts an inhibitory regulatory influence on the amygdala. Under certain conditions, the amygdala becomes hyperactive and is no longer adequately controlled by the PFC. In such circumstances, the stress response becomes dominant, and the patient may experience severe anxiety.

Fig. 13: The Limbic System

2.1 When and How Fear Becomes Traumatic

What is trauma? Trauma occurs when the threat is extreme, pain and fear are intense, a sense of helplessness is present, and the situation overwhelms the individual’s adaptive capacities. In this context, the attack involving claws and the perception of imminent death could potentially be considered traumatic.

In such situations:

1. Abnormal encoding of the traumatic memory
2. The amygdala becomes hyperactive and over-encodes fear, strongly associating stimuli with danger.
3. The hippocampus is inhibited by cortisol, resulting in impaired encoding of the context (time and place), and producing a fragmented, poorly dated memory.

Result: The brain does not properly categorize the event as something that belongs to the past.

1. Failure of prefrontal cortex regulation

Under normal conditions, the prefrontal cortex (PFC) inhibits the amygdala and provides cognitive reassurance, essentially signaling: “It is over; you are safe; calm down.”

Following trauma, prefrontal activity may decrease, leading to a loss of top-down control, while the amygdala remains hyperactive.

Possible manifestations in the gazelle

a) Hypervigilance

• Excessive reactions to the slightest noise
• Inappropriate or disproportionate flight responses

b) Re-experiencing (animal equivalent)

• Reactivation of fear in response to similar stimuli
• Automatic and maladaptive responses

c) Avoidance

• Abandonment of areas that are actually safe
• Changes in feeding behavior

d) Possible freezing response

• Immobility (freeze)
• Failure or inability to initiate an escape response

Key Difference to Remember

Fundamental Message

PTSD is not simply an excess of fear; it is a survival memory that fails to switch off.

Trauma as Pavlovian Conditioning

Recap: Classical Pavlovian Conditioning

Simple model:
Neutral stimulus (NS) + aversive stimulus (US) → fear response

After repeated pairings or an extremely intense aversive experience, the previously neutral stimulus becomes capable of triggering a fear response on its own.

 PKA (Protein Kinase A)

Final Outcome

• Increased number and efficacy of AMPA receptors
• Structural changes, including dendritic spine remodeling
• Long-lasting strengthening of the synapse

Logical Chain Summary

Intense stimulation → AMPA activation → NMDA activation → ↑ Ca²⁺ → activation of CaMKII / PKA / MAPK → ↑ AMPA receptors + structural modifications → LTP (memory)

The Relationship Between Stress and Inflammation

Stress-induced immune responses in the periphery and their underlying mechanisms

Stress-Induced Leukocyte Mobilization from the Bone Marrow

Studies in rodents, primarily using repeated social defeat stress, have shown that stress alters the number, distribution, and properties of leukocytes. In general, chronic stress decreases lymphocytes, such as T cells and B cells, while increasing myeloid cells, such as neutrophils and monocytes, in the blood and bone marrow.

These changes may result from altered leukocyte differentiation and proliferation in the bone marrow, as well as changes in their release into the circulation.

These leukocyte populations do not respond in the same way after cessation of stress. The increase in neutrophils and decrease in B cells persist for several days after the last stress exposure, whereas other leukocyte changes disappear.

Acute stress may induce changes in leukocytes similar to those observed with chronic stress, as a decrease in lymphocytes and an increase in myeloid cells can be detected immediately after a single 2-hour exposure to social defeat stress. However, the effects of acute stress may be less persistent. Twelve hours after a single 2-hour exposure to social defeat stress, only an increase in neutrophils, but not in monocytes, was observed.

These findings indicate that chronic stress induces more persistent leukocyte changes than acute stress, and that the increase in neutrophils persists longer than changes affecting other leukocyte subsets.

Roles of the Autonomic and Neuroendocrine Systems

Stress-induced leukocyte mobilization from the bone marrow is mediated primarily by the autonomic and neuroendocrine systems.

Activation of the sympathetic nervous system (SNS) during stress induces the release of norepinephrine and epinephrine into the blood and tissues. These neurotransmitters activate adrenergic receptors on leukocytes and surrounding cells, such as mesenchymal stem cells in the bone marrow, thereby promoting stress-induced leukocyte mobilization.

Sympathetic activation may be sufficient to produce these effects, as systemic administration of isoproterenol, a non-selective β-adrenergic agonist, decreases lymphocytes and increases monocytes and granulocytes in the bone marrow.

These adrenergic receptors may promote myeloid cell differentiation and proliferation. They may also reduce the expression of C-X-C motif chemokine ligand 12 (CXCL12) by osteoblasts and mesenchymal stem cells. CXCL12 normally contributes to the retention of myeloid cells in the bone marrow through the C-X-C motif chemokine receptor 4 (CXCR4).

In addition, stress activates the hypothalamic–pituitary–adrenal (HPA) axis, increasing circulating glucocorticoid levels.

Glucocorticoids act directly on myeloid and lymphoid cells to suppress inflammatory responses. They also promote the apoptosis of T cells, macrophages, and dendritic cells, thereby inhibiting immune responses.

However, following chronic stress, monocytes and macrophages develop glucocorticoid resistance, or reduced glucocorticoid sensitivity, in both mice and humans. This glucocorticoid resistance can consequently disinhibit inflammatory responses.

At the same time, glucocorticoids can promote innate immune responses to stress by suppressing the CXCL12–CXCR4 pathway, which normally retains myeloid cells in the bone marrow, and by increasing cytokine release from these cells. These effects were prevented by metyrapone, an inhibitor of glucocorticoid synthesis.

Roles of Cytokines and Chemokines

Stress affects the expression of various cytokines and chemokines in the bone marrow and circulation, likely contributing to stress-induced immune responses. Distinct but overlapping cytokine pathways regulate the proliferation and mobilization of neutrophils and monocytes.

G-CSF (Granulocyte Colony-Stimulating Factor) generally promotes neutrophil proliferation and mobilization, although its effects are not exclusively restricted to neutrophils. G-CSF is thought to locally activate the sympathetic nervous system within the bone marrow, thereby promoting neutrophil mobilization. CXCL1/2 and their receptor CXCR2 also stimulate neutrophil mobilization.

M-CSF (Macrophage Colony-Stimulating Factor) and GM-CSF (Granulocyte-Macrophage Colony-Stimulating Factor) promote monocyte proliferation and mobilization. Similarly, CCL2 (C-C motif chemokine ligand 2), also known as monocyte chemoattractant protein-1 (MCP-1), and its receptor CCR2 (C-C chemokine receptor type 2) stimulate monocyte mobilization.

Stress increases circulating levels of G-CSF. Because IL-17 promotes neutrophil mobilization through G-CSF secretion, restraint stress has been shown to increase the number of aged neutrophils through an IL-17A-dependent mechanism, presumably involving intestinal T helper 17 (Th17) cells. Because this neutrophil mobilization depends on segmented filamentous bacteria (SFB) in the gut, IL-17A may provide a mechanistic link between the gut microbiota and the innate immune response to stress.

Indeed, stress alters the gut microbiota, which is associated with both stress susceptibility and stress-related responses. Although the underlying mechanisms remain incompletely understood, the gut microbiota is regulated by multiple pathways, including the vagus nerve, glucocorticoids, leukocytes, and secreted cytokines.

However, the effects of stress on circulating IL-17 levels vary across studies, and it remains to be established whether IL-17A directly mediates stress-induced neutrophil mobilization.

In addition, stress increases circulating and brain levels of CXCL2 and CCL2. The increase in CCL2 is not essential for stress-induced monocyte mobilization into the circulation, since CCR2 deficiency does not prevent this mobilization. In contrast, the increase in CCL2 within the brain is critical for stress-induced monocyte infiltration into the central nervous system.

Effects of Stress on the Immune System Through Multiple Organs

Stress can affect the spleen and lymph nodes, at least in part through sympathetic nervous system projections. Acute stress is thought to induce norepinephrine release from sympathetic nerve terminals in the spleen, which acts on choline acetyltransferase-positive (ChAT⁺) T lymphocytes via β2-adrenergic receptors. These splenic T cells subsequently release acetylcholine, thereby inhibiting the production of pro-inflammatory cytokines by macrophages. This anti-inflammatory pathway is beneficial in various models of inflammatory disease, including ischemic acute kidney injury, and can be activated by vagal pathways connected to the splenic sympathetic nerves.

Chronic stress, such as repeated foot-shock stress or restraint stress, increases the proportion of CD4⁺ T cells exhibiting reduced glycolysis and oxidative phosphorylation, together with increased mitochondrial fission, in the spleen and lymph nodes. This metabolic remodeling appears to contribute to stress-induced anxiety-like behavior.

Chronic stress can also increase splenic plasma cells and enhance antibody-dependent immune responses by activating stress-related brain regions, including the central nucleus of the amygdala (CeA) and the paraventricular nucleus of the hypothalamus (PVN), as well as the splenic nerves. However, this enhancement of humoral responses occurs only under mild stress conditions that do not trigger glucocorticoid release. It therefore does not occur during restraint stress accompanied by substantial glucocorticoid secretion. Thus, humoral immunity is differentially regulated depending on the nature and intensity of the stressor.

Stress can also affect non-immune peripheral organs. Acute stress, for example, may increase IL-6 release from brown adipocytes through direct sympathetic signaling.

Collectively, the interactions among multiple organs—including the bone marrow, spleen, gut, and brown adipose tissue—shape stress-induced innate and adaptive immune responses in a manner that depends strongly on the specific conditions and intensity of stress.

Roles of Bone Marrow-Derived Myeloid Cells

The stress-induced immune responses described above can influence neuronal function and contribute to stress-induced behavioral changes. Multiple barriers separate the brain from the peripheral immune system, and leukocytes are rarely present within the healthy brain parenchyma. Nevertheless, myeloid cells, particularly monocytes, are thought to infiltrate the perivascular spaces of the brain, especially during chronic stress.

Circulating monocytes can adhere to brain vascular endothelial cells and subsequently migrate into the perivascular space. In parallel, an elegant skull transplantation study demonstrated a direct pathway by which bone marrow-derived myeloid cells can migrate from the skull bone marrow to the dura mater, thereby bypassing entry into the circulation.

However, dural myeloid cells would still have to cross additional anatomical barriers—the arachnoid and pia mater—to reach the brain parenchyma.

Repeated social defeat stress increases the number of perivascular monocytes in a CCR2-dependent manner. CCL2, a ligand for CCR2, has been reported to increase in microglia following repeated social defeat stress, suggesting that microglia-derived CCL2 recruits circulating monocytes into the perivascular compartment through CCR2 signaling.

In CCR2-deficient mice, both stress-induced anxiety-like behavior and the associated infiltration of monocytes into the brain are attenuated. These findings suggest that blood-borne monocytes may contribute to the anxiogenic effects of chronic stress.

Repeated social defeat stress also mobilizes neutrophils into the circulation, and this increase persists for a longer period after cessation of stress than the corresponding increase in monocytes. Notably, stress-induced neutrophil mobilization is more pronounced in BALB/c mice than in C57BL/6N mice.

Because BALB/c mice are generally more susceptible to stress than C57BL/6N mice, stress-induced neutrophil mobilization may contribute to genetically determined differences in stress susceptibility.

Role of Calcium (Ca²⁺)

Ca²⁺ binds to calmodulin, leading to the activation of myosin light-chain kinase (MLCK).

Final outcome:

 Activation and increased expression of MLCK

3. Function of MLCK

Key reaction:

MLCK catalyzes the phosphorylation of the myosin light chain (MLC):

MLC + ATP → phosphorylated MLC (MLC-P)

Mechanical consequence

Under basal conditions / without stress:

• Low MLC phosphorylation
• Stable actin cytoskeleton
• Intact tight junctions

Under stress conditions:

• ↑ MLC phosphorylation
• Increased contraction of the actin–myosin cytoskeleton
• Mechanical tension is exerted on the tight junctions
• This cytoskeletal contraction pulls on the tight junctions, contributing to their disruption and increased intestinal permeability.

4. Disorganization of Tight Junctions

Normal structure

Key proteins include:

• Claudins
• Occludin
• ZO-1 / ZO-2

These proteins maintain the integrity and sealing of the intestinal epithelial barrier between adjacent cells.

Following MLCK activation

Four major effects:

1. Actomyosin contraction
2. Dissociation of ZO-1 from the junctional complex
3. Internalization of occludin
4. Reorganization of claudins

Result:

Opening of the paracellular spaces between epithelial cells
↑ Paracellular permeability

5. Immunological Consequences

Once the intestinal barrier becomes compromised, several luminal molecules can cross the epithelial barrier, including:

• LPS (lipopolysaccharide)
• Peptidoglycans
• Dietary antigens

Immune activation

These microbial products can be recognized by immune cells, including macrophages, through pattern-recognition receptors such as: TLR4 (Toll-like receptor 4)

Cytokine production

This can promote the production of pro-inflammatory cytokines, including:

• TNF-α
• IL-6
• IL-1β

Consequences

Inflammation, which may be:

• Local, within the intestine
• Systemic, when inflammatory mediators enter the circulation

6. Self-Sustaining Feedback Loop — The Vicious Cycle

The system can become self-amplifying:

1. Stress
↓
2. Mast-cell activation
↓
3. ↑ Pro-inflammatory cytokines

4. ↑ MLCK activation/expression
↓
5. ↑ Intestinal permeability
↓
6. Increased translocation of microbial products and luminal antigens
↓
7. ↑ Inflammation

This inflammatory state can further enhance stress responsiveness and perpetuate the cycle.

Contribution of the gut microbiota

• Dysbiosis → disruption of the microbial ecosystem
• ↓ Butyrate → loss of an important intestinal barrier–supporting metabolite

These changes may further aggravate barrier dysfunction and inflammation.

7. Fine Regulation of MLCK

Transcriptional regulation

Transcription factors implicated in the regulation of MLCK expression include:

• NF-κB
• AP-1
• C/EBPβ

Post-translational regulation

MLCK activity can also be modulated through:

• Phosphorylation by protein kinases, including PKC and MAPK-related pathways
• Interactions with the cytoskeleton and junctional complexes

Modulators

Potential protective/modulatory factors:

• Butyrate
• Probiotics
• AMPK activation
• Antioxidants, such as N-acetylcysteine

Factors promoting MLCK activation or barrier dysfunction:

• TNF-α
• LPS
• Oxidative stress
• Dysbiosis

8. Experimental Evidence

MLCK inhibition

The MLCK inhibitor ML-7 has been used experimentally to inhibit MLCK activity and can reduce stress- or inflammation-associated increases in intestinal permeability.

Genetic models

Experimental models indicate that:

• MLCK deficiency or inhibition → increased resistance to epithelial hyperpermeability
• MLCK overexpression/activation → increased intestinal permeability

Stress models

Experimental stress paradigms have been associated with:

• ↑ MLCK
• ↑ MLC phosphorylation
• ↑ Intestinal permeability

These effects can be attenuated when MLCK activity is inhibited, supporting a causal role for the MLCK–MLC pathway in epithelial barrier regulation.

Overall Conclusion

MLCK acts as a key biomechanical switch linking extracellular signals to changes in intestinal epithelial barrier function.

It translates:

Psychological and inflammatory signals
↓
Ca²⁺/calmodulin signaling

↓
MLCK activation
↓
MLC phosphorylation
↓
Actomyosin contraction
↓
Tight-junction remodeling
↓
Increased intestinal permeability

Ultra-Synthetic Summary

Stress → CRH + inflammatory signals → ↑ Ca²⁺ → calmodulin → MLCK → MLC phosphorylation → actomyosin contraction → tight-junction opening/remodeling → ↑ intestinal permeability → immune activation/inflammation → vicious cycle

Clinical relevance

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In addition, renin release is stimulated by the sympathetic nervous system.

High concentrations of angiotensin II suppress renin secretion via a negative feedback loop. Angiotensin II acts on specific angiotensin receptors AT1 and AT2, causing a contraction of the smooth muscles and the release of aldosterone, prostacyclins and catecholamines. The renin – angiotensin – aldosterone system plays an important role in controlling blood pressure, including sodium balance.

ADH ( vasopressin):

Vasopressin is a small hormone, synthesized in the hypothalamus and released into the circulation from the posterior lob of hypophysis. Although historically named as a result of its potent vasopressor actions, these actions only occur when plasma vasopressin is present in the plasma in supraphysiological concentrations. The most important action of vasopressin is its antidiuretic action on the collecting ducts of the kidney. This leads to a decrease in renal free water clearance, concentration of urine, and a reduction in urine volume. The net effect is the reabsorption of water into the blood, which, along with thirst-generated water intake, leads to normalization of plasma osmolality.Regulation of vasopressin secretion and action thus represents a key homeostatic process which protects the osmotic milieu of the body, allowing normal cellular function.

Synthesis :

Vasopressin is most abundantly produced in magnocellular neurosecretory neurons in the supraoptic and paraventricular (PVN) nuclei, transported to terminals in the neurohypophysis, and released into the general circulation. Vasopressin production is also found in parvocellular neurons in the PVN and vasopressinn produced in these neurons is transported to terminals in the external layer of the median eminence, from which it is released into the hypophysial portal system.

Release and feedback controle :

Vasopressin release is regulated by osmoreceptors in the hypothalamus (OVLT, SFO), which are exquisitely sensitive to changes in plasma osmolality of as little as 1% to 2%. Under hyperosmolar conditions, osmoreceptor stimulation leads to vasopressin release and stimulation of thirst. These two mechanisms result in increased water intake and retention. Vasopressin release is also regulated by baroreceptors in the carotid sinus and aortic arch, under conditions of hypovolemia, these receptors stimulate vasopressin release to increase plasma volume. At very high concentrations, vasopressin also causes vascular smooth muscle constriction through the V1 receptor, increasing vascular tone and therefore the blood pressure. Accordingly, vasopressin is often administered parenterally as a vasopressor agent in patients with hypotension that is refractory to volume restriction.

Vasopressin has effects on the immune system independent of its effect in stimulating the HPA axis. When given intraventricularly to rats, vasopressin decreases the T-cell response to mitogen independently of the HPA axis, probably via the sympathetic nervous system. Like CRH, vasopressin stimulates immune responses in peripheral tissues. Circulating or local vasopressin enhances lymphocyte reactions and potentiates primary antibody. Elevated vasopressin levels are found in a mouse model of autoimmune disease, and antibody neutralization ameliorates the inflammatory response in these mice. Vasopressin can potentiate the release of prolactin, a proinflammatory  peptide hormone.

Because vasopressin has immunosuppressive effects when present in the central nervous system and immunosupportive effects when present in peripheral tissues, predicting which effect would predominate during vasopressin infusion in the ICU is difficult.

Vasopressin is a hormone of the posterior pituitary, that is secreted in response to high serum osmolarity. Excitation of atrial stretch receptors inhibits vasopressin secretion. Vasopressin is also released in response to stress, inflammatory signals, and some medications. Hypotension, morphine, nicotine, angiotensin II, glucocorticoids, and IL-6 all stimulate release of vasopressin. Circulating vasopressin levels are usually high in the early phase of septic shock,  but vasopressin deficiency has been described in vasodilatory shock states in both adults and children. The level of vasopressin that is normal in the late phase of sepsis is unclear.

Vasopressin selectively raises free water reabsorption through the upregulation of aquaporin-2  water channels in the collecting duct, resulting in blood pressure elevation (Elliot et al., 1996; Linshaw 2011). Although it appears that the developing kidney is less sensitive to circulating vasopressin, plasma levels of vasopressin are markedly elevated in the neonate, especially after vaginal delivery, and its cardiovascular actions facilitate neonatal adaptation (Pohjavuori et al., 1985; Linshaw, 2011). The high vasopressin levels are in part also responsible for the diminished urine output of the healthy term neonate during the first day after birth. Under certain pathologic conditions, the dysregulated release of, or the end-organ unresponsiveness to, vasopressin significantly affects renal and cardiovascular functions and electrolyte and fluid status in the sick preterm and term neonate (Svenningsen et al., 1974). In the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), an uncontrolled release of vasopressin occurs in sick preterm and term neonates, with resulting water retention, hyponatremia, and oligouria. In the syndrome of diabetes insipidus, the lack of pituitary production of vasopressin or renal unresponsiveness to vasopressin results in polyuria and hypernatremia.

Le Peptide natriurétique auriculaire :
Le peptide natriurétique auriculaire (ANP) est libéré des granules auriculaires. Il produit une natriurèse, une diurèse et une baisse modeste de la pression artérielle, tout en diminuant la rénine et l’aldostérone plasmatiques. Les peptides natriurétiques modifient également la transmission synaptique des osmorécepteurs. Le (PNA) est libéré à la suite de la stimulation de l’oreillette par distension et étirement des récepteurs. Les concentrations de (PNA) sont augmentées par des pressions de remplissage élevées et chez les patients souffrant d’hypertension artérielle et d’hypertrophie ventriculaire gauche comme la paroi du ventricule gauche est épaissie participe à la sécrétion d’ANP.
Eicosanoïdes :
Les métabolites de l’acide arachidonique modifient la pression artérielle par des effets directs sur le tonus musculaire lisse vasculaire et les interactions avec d’autres systèmes vasorégulateurs: système nerveux autonome, le système rénine-angiotensine – aldostérone et autres voies humorales. Chez les patients hypertendus, un dysfonctionnement des cellules endothéliales vasculaires pourrait entraîner une réduction des facteurs de relaxation dérivés de l’endothélium tels que l’oxyde nitrique, la prostacycline et le facteur hyperpolarisant dérivé de l’endothélium, ou une augmentation de la production de facteurs de contraction tels que l’endothéline-1 et le thromboxane A2. Systèmes kallikréine-kinine Les kallikréines tissulaires agissent sur le kininogène pour former des peptides vasoactifs. Le plus important est le bradykinin vasodilatateur. Les kinines jouent un rôle dans la régulation du débit sanguin rénal et de l’excrétion d’eau et de sodium. Les inhibiteurs de l’ECA diminuent la dégradation de la bradykinine en peptides inactifs. Mécanismes endothéliaux L’oxyde nitrique (NO) intervient dans la vasodilatation produite par l’acétylcholine, la bradykinine, le nitroprussiate de sodium et les nitrates. Chez les patients hypertendus, la relaxation dérivée de l’endothélium est inhibée. L’endothélium synthétise les endothélines, les vasoconstricteurs les plus puissants. La génération ou la sensibilité à l’endothéline-1 n’est pas plus élevée chez les sujets hypertendus que chez les sujets normotendus. Néanmoins, les effets vasculaires délétères de l’endothéline-1 endogène peuvent être accentués par une génération réduite d’oxyde nitrique causée par une dysfonction endothéliale hypertensive.
Stéroïdes surrénales :
Les minéraux et glucocorticoïdes augmentent la pression artérielle. Cet effet est médié par la rétention de sodium et d’eau (minéralocorticoïdes) ou une réactivité vasculaire accrue (glucocorticoïdes). De plus, les glucocorticoïdes et les minéralocorticoïdes augmentent le tonus vasculaire en régulant les récepteurs des hormones pressives telles que l’angiotensine II. Vasodépression rénomédullaire Les cellules interstitielles rénomédullaires, situées principalement dans la papille rénale, sécrètent une substance inactive la médullipine I. Ce lipide est transformé dans le foie en médullipine II. Cette substance exerce un effet hypotenseur prolongé, éventuellement par vasodilatation directe, inhibition de la pulsion sympathique en réponse à l’hypotension et une action diurétique. On suppose que l’activité du système rénomédullaire est contrôlée par le flux sanguin médullaire rénal. Excrétion de sodium et d’eau La rétention de sodium et d’eau est associée à une augmentation de la pression artérielle. Il est postulé que le sodium, via le mécanisme d’échange sodium-calcium, provoque une augmentation du calcium intracellulaire dans le muscle lisse vasculaire entraînant une augmentation du tonus vasculaire. La principale cause de rétention de sodium et d’eau peut être une relation anormale entre la pression et l’excrétion de sodium résultant d’une diminution du débit sanguin rénal, d’une masse néphronique réduite et d’une augmentation de l’angiotensine ou des minéralocorticoïdes. Physiopathologie L’hypertension est une élévation chronique de la pression artérielle qui, à long terme, cause des dommages aux organes terminaux et entraîne une augmentation de la morbidité et de la mortalité. La pression artérielle est le produit du débit cardiaque et de la résistance vasculaire systémique. Il s’ensuit que les patients souffrant d’hypertension artérielle peuvent avoir une augmentation du débit cardiaque, une augmentation de la résistance vasculaire systémique, ou les deux. Dans le groupe d’âge plus jeune, le débit cardiaque est souvent élevé, tandis que chez les patients plus âgés, une résistance vasculaire systémique accrue et une rigidité accrue du système vasculaire jouent un rôle dominant. Le tonus vasculaire peut être élevé en raison d’une stimulation accrue des récepteurs a-adrénergiques ou d’une libération accrue de peptides tels que l’angiotensine ou les endothélines. La dernière voie est une augmentation du calcium cytosolique dans le muscle lisse vasculaire provoquant une vasoconstriction. Plusieurs facteurs de croissance, dont l’angiotensine et les endothélines, provoquent une augmentation de la masse musculaire vasculaire lisse appelée remodelage vasculaire. A la fois une augmentation de la résistance vasculaire systémique et une augmentation de la résistance vasculaire
la rigidité augmente la charge imposée au ventricule gauche; cela induit une hypertrophie ventriculaire gauche et un dysfonctionnement diastolique ventriculaire gauche. Chez les jeunes, la pression du pouls générée par le ventricule gauche est
relativement faible et les ondes reflétées par le système vasculaire périphérique se produit principalement après la fin de la systole, augmentant ainsi la pression au début partie de la diastole et l’amélioration de la perfusion coronaire. Avec vieillissement, raidissement de l’aorte et des artères élastiques,augmente la pression du pouls. Les ondes réfléchies passent de la diastole précoce à la systole tardive. Il en résulte une augmentation de la postcharge ventriculaire gauche et contribue à l’hypertrophie ventriculaire gauche. L’élargissement de la pression du pouls avec le vieillissement est un puissant prédicteur des maladies coronariennes. Le système nerveux autonome joue un rôle important dans le contrôle de la pression artérielle. Chez les patients hypertendus, une libération accrue et une sensibilité périphérique accrue à la noradrénaline peuvent être trouvées. De plus, il y a une réactivité accrue aux stimuli stressants. Une autre caractéristique de l’hypertension artérielle est la réinitialisation des baroréflexes diminution de la sensibilité des barorécepteurs. Le système rénine-angiotensine est impliqué au moins dans certaines formes d’hypertension (par exemple l’hypertension rénovasculaire) et est supprimé en présence d’hyperaldostéronisme primaire. Les patients âgés ou noirs ont tendance à souffrir d’hypertension à faible rénine. D’autres ont une hypertension à rénine élevée et ceux-ci sont plus susceptibles de développer un infarctus myocardique et d’autres complications cardiovasculaires. Dans l’hypertension essentielle humaine et expérimentale,l’hypertension, la régulation du volume et la relation entre la pression artérielle et l’excrétion de sodium (natriurèse sous pression) sont anormales. Des preuves considérables indiquent que la réinitialisation de la natriurèse sous pression joue un rôle clé dans la cause de l’hypertension. Chez les patients souffrant d’hypertension essentielle, la réinitialisation de la natriurèse sous pression se caractérise soit par un déplacement parallèle vers des pressions sanguines plus élevées et une hypertension insensible au sel, soit par une diminution de la pente de la natriurèse sous pression et de l’hypertension sensible au sel. Conséquences et complications de l’hypertension Les conséquences cardiaques de l’hypertension sont l’hypertrophie ventriculaire gauche et la maladie coronarienne. L’hypertrophie ventriculaire gauche est causée par une surcharge de pression et est concentrique. Il y a une augmentation de la masse musculaire et de l’épaisseur de la paroi mais pas du volume ventriculaire. L’hypertrophie ventriculaire gauche altère la fonction diastolique, ralentit la relaxation ventriculaire et retarde le remplissage. L’hypertrophie ventriculaire gauche est un facteur de risque indépendant de maladie cardiovasculaire, en particulier de mort subite. Les conséquences de l’hypertension sont fonction de sa gravité. Il n’y a pas de seuil de complications, car l’élévation de la pression artérielle est associée à une morbidité accrue dans toute la plage de pression artérielle (tableau 1).
La maladie coronarienne est associée à, et accélérée par, l’hypertension artérielle chronique, entraînant une ischémie myocardique et un infarctus du myocarde. En effet, l’ischémie myocardique est beaucoup plus fréquente chez les patients hypertendus non traités ou mal contrôlés que chez les patients normotendus. Deux principaux facteurs contribuent à l’ischémie myocardique: une augmentation de la demande en oxygène liée à la pression et une diminution de l’apport coronarien en oxygène résultant des lésions athéromateuses associées. L’hypertension est un facteur de risque important de décès par maladie coronarienne. L’insuffisance cardiaque est une conséquence d’une surcharge de pression chronique. Il peut commencer par un dysfonctionnement diastolique et évoluer vers une insuffisance systolique manifeste avec congestion cardiaque. Les AVC sont des complications majeures de l’hypertension; ils résultent d’une thrombose, d’une thrombo-embolie ou d’une hémorragie intracrânienne. La maladie rénale, initialement révélée par une micro albuminaémie, peut évoluer lentement et se manifester au cours des années suivantes. Traitement à long terme de l’hypertension Tous les antihypertenseurs doivent agir en diminuant le débit cardiaque, la résistance vasculaire périphérique ou les deux. Les classes de médicaments les plus couramment utilisées comprennent les diurétiques thiazidiques, les bbloquants, les inhibiteurs de l’ECA, les antagonistes des récepteurs de l’angiotensine II, les bloqueurs des canaux calciques, les bloqueurs des récepteurs adrénergiques, les bloqueurs combinés des a et b, les vasodilatateurs directs et certains médicaments à action centrale tels que les a2- agonistes des récepteurs adrénergiques et agonistes des récepteurs de l’imidazoline I1. La modification du style de vie est la première étape du traitement de l’hypertension; il comprend une restriction modérée en sodium, une réduction de poids chez les obèses, une diminution de la consommation d’alcool et une augmentation de l’exercice. Un traitement médicamenteux est nécessaire lorsque les mesures ci-dessus n’ont pas réussi ou lorsque l’hypertension est déjà à un stade dangereux (stade 3) lors de sa première reconnaissance.
Thérapie médicamenteuse
Diurétiques:
Le traitement diurétique à faible dose est efficace et réduit le risque d’accident vasculaire cérébral, de maladie coronarienne, d’insuffisance cardiaque congestive et de mortalité totale. Alors que les thiazides sont les plus couramment utilisés, les diurétiques de l’anse
sont également utilisés avec succès et l’association avec un diurétique d’épargne potassique réduit le risque d’hypokaliémie et d’hypomagnésémie. Même à petites doses, les diurétiques potentialisent d’autres antihypertenseurs. Le risque de mort subite est réduit lorsque des diurétiques épargneurs de potassium sont utilisés. À long terme, les spironolactones réduisent la morbidité et la mortalité chez les patients souffrant d’insuffisance cardiaque
c’est une complication typique de l’hypertension de longue date.
Bêta-bloquants:
Un tonus sympathique élevé, l’angine de poitrine et un infarctus du myocarde antérieur sont de bonnes raisons d’utiliser des bêtabloquants. Étant donné qu’une faible dose minimise le risque de fatigue (un effet désagréable du blocage b

l’ajout d’un diurétique ou d’un inhibiteur calcique est souvent bénéfique. Cependant, le traitement par blocage b estassociée à des symptômes de dépression, de fatigue et de dysfonction sexuelle. Ces effets secondaires
doivent être pris en considération dans l’évaluation des avantages du traitement. Au cours des dernières années, les b-bloquants ont été utilisés de plus en plus fréquemment dans la prise en charge de l’insuffisance cardiaque, complication connue de l’hypertension artérielle. Ils sont efficaces mais leur introduction en présence d’insuffisance cardiaque doit être très prudente, à commencer par des doses très faibles pour éviter une aggravation initiale de l’insuffisance cardiaque. Bloqueurs des canaux calciques Les bloqueurs des canaux calciques peuvent être divisés en dihydropyridines (par exemple nifédipine, nimodipine, amlodipine) et non-dihydropyridines (vérapamil, diltiazem). Les deux groupes diminuent la résistance vasculaire périphérique mais le vérapamil et le diltiazem ont des effets inotropes et chronotropes négatifs. Les dihydropyridines à courte durée d’action telles que la nifédipine provoquent une activation sympathique réflexe et une tachycardie, tandis que les médicaments à longue durée d’action tels que l’amlodipine et les préparations à libération lente de nifédipine provoquent moins d’activation sympathique. Les dihydropyridines à courte durée d’action semblent augmenter le risque de mort subite. Cependant, l’essai sur l’hypertension systolique en Europe (SYST-EUR) qui comparait la nitrendipine au placebo a dû être arrêté tôt en raison des avantages significatifs
thérapie. Les inhibiteurs calciques sont efficaces chez les personnes âgées et peuvent être sélectionnés en monothérapie pour les patients atteints du phénomène de Raynaud, de maladie vasculaire périphérique ou d’asthme, car ces patients ne tolèrent pas les b-bloquants. Le diltiazem et le vérapamil sont contre-indiqués dans l’insuffisance cardiaque. La nifédipine est efficace dans l’hypertension sévère et peut être utilisée par voie sublinguale; il faut faire preuve de prudence en raison du risque d’hypotension excessive. Les bloqueurs des canaux calciques sont souvent associés aux b-bloquants, aux diurétiques et / ou aux inhibiteurs de l’ECA.
Inhibiteurs de l’enzyme de conversion de l’angiotensine:
Les inhibiteurs de l’ECA sont de plus en plus utilisés comme traitement de première intention. Ils ont relativement peu d’effets secondaires et de contre-indications, à l’exception des sténoses bilatérales de l’artère rénale. Bien que les inhibiteurs de l’ECA soient efficaces dans l’hypertension rénovasculaire unilatérale, il existe un risque d’atrophie ischémique. Par conséquent, l’angioplastie ou la reconstruction chirurgicale de l’artère rénale sont préférables à une thérapie purement médicale à long terme. Les inhibiteurs de l’ECA sont des agents de premier choix chez les patients hypertendus diabétiques car ils ralentissent la progression de la dysfonction rénale. Dans l’hypertension avec insuffisance cardiaque, les inhibiteurs de l’ECA sont également des médicaments de premier choix. L’essai HOPE a montré que le ramipril réduisait le risque d’événements cardiovasculaires même en l’absence d’hypertension. Ainsi, cet inhibiteur de l’ECA peut exercer un effet protecteur par des mécanismes autres que la réduction de la pression artérielle. Bloqueurs des récepteurs de l’angiotensine II Comme l’angiotensine II stimule les récepteurs AT1 qui provoquent la vasoconstriction, les antagonistes des récepteurs de l’angiotensine AT1 sont des antihypertenseurs efficaces. Le losartan, le valsartan et le candésartan sont efficaces et provoquent moins de toux que les inhibiteurs de l’ECA. L’étude LIFE est le plus récent essai historique sur l’hypertension. Plus de 9000 patients ont été randomisés pour recevoir soit le losartan, un antagoniste des récepteurs de l’angiotensine, soit un b-bloquant
(aténolol). Les patients du bras losartan ont présenté une meilleure réduction de la mortalité et de la morbidité, en raison d’une plus grande réduction des AVC. Le losartan a également été plus efficace pour réduire l’hypertrophie ventriculaire gauche, un puissant facteur de risque indépendant d’effets indésirables. Chez les patients souffrant d’hypertension systolique isolée, la supériorité du losartan sur l’aténolol était encore plus prononcée que chez ceux souffrant d’hypertension systolique et diastolique. Ces résultats favorables ont conduit à un éditorial intitulé: «Blocus de l’angiotensine dans l’hypertension: une promesse tenue». Il convient de noter que le comparateur de l’étude LIFE était un b-bloquant et que, dans le passé, les b-bloquants n’étaient pas meilleurs que le placebo chez les personnes âgées.
Bloqueurs a1-adrénergiques Exempts d’effets secondaires métaboliques, ces médicaments réduisent le cholestérol sanguin et la résistance vasculaire périphérique. La prazosine a une action plus courte que la doxazosine, l’indoramine et la térazosine. Ces médicaments sont hautement sélectifs pour les récepteurs adrénergiques a1. La somnolence, l’hypotension orthostatique et parfois la tachycardie peuvent être gênantes. La rétention d’eau peut nécessiter l’ajout d’un diurétique. La phénoxybenzamine est un agoniste des récepteurs a-adrénergiques non compétitif utilisé (en association avec un b-bloquant) dans la prise en charge des patients atteints de phaéochromocytome, bien que récemment la doxazosine ait été utilisée avec succès. Vasodilatateurs directs:
L’hydralazine et le minoxidil sont des vasodilatateurs à action directe. Leur utilisation a diminué en raison du potentiel d’effets secondaires graves (syndrome du lupus avec l’hydralazine, hirsutisme avec le minoxidil). Inhibiteurs adrénergiques centraux La méthyldopa est à la fois un faux neurotransmetteur et un agoniste des récepteurs adrénergiques a2. La clonidine et la dexmédétomidine sont des agonistes des récepteurs a2-adrénergiques situés au centre. La sélectivité pour les adrénorécepteurs a2 vs a1 est la plus élevée pour la dexmédétomidine (1620: 1), suivie par la clonidine (220: 1), et la moins pour l’a-méthyldopa (10: 1). La clonidine et la dexmédétomidine rendent la circulation plus stable,
réduire la libération de catécholamines en réponse au stress, et
provoquer une sédation telle que la dexmédétomidine est maintenant utilisée pour la sédation dans les unités de soins intensifs.
La moxonidine est représentative d’une nouvelle classe d’agents antihypertenseurs agissant sur les récepteurs de l’imidazoline1 (I1). La moxonidine réduit l’activité sympathique en agissant sur les centres de la rostrale ventrale
médullaire latérale, réduisant ainsi la résistance vasculaire périphérique.
Peptides natriurétiques:
Les peptides natriurétiques jouent un rôle dans le contrôle du tonus vasculaire et interagissent avec le système rénine-angiotensine-aldostérone. En inhibant leur dégradation, les inhibiteurs de la peptidase rendent ces peptides naturels plus efficaces, réduisant ainsi la résistance vasculaire. Cependant, il n’y a que des essais à petite échelle de leur efficacité. Dans l’ensemble, des études récentes n’ont pas réussi à démontrer la supériorité des agents modernes sur les médicaments plus traditionnels, sauf dans des circonstances particulières, comme l’a démontré une méta-analyse basée sur 15 essais et 75 000 patients. Chez de nombreux patients, un traitement efficace est obtenu par l’association de deux agents ou plus, avec un gain d’efficacité et une réduction des effets secondaires.
Gestion des risques
En plus des mesures pharmacologiques pour le contrôle de la pression artérielle, il devrait y avoir un traitement actif des facteurs connus pour augmenter le risque d’hypertension. Il existe deux mesures distinctes. Premièrement, ceux qui abaissent la tension artérielle, par exemple la réduction de poids, la réduction de la consommation de sel, la limitation de la consommation d’alcool, l’exercice physique, l’augmentation de la consommation de fruits et légumes et la réduction de la consommation totale et de graisses saturées. Deuxièmement, ceux qui réduisent le risque cardiovasculaire, par exemple arrêter de fumer; remplacer les graisses saturées par des graisses polyinsaturées et monoinsaturées; augmentation de la consommation de poisson gras; et réduit l’apport total en graisses. Étant donné que les patients hypertendus courent un risque très élevé de maladie coronarienne, d’autres mesures thérapeutiques comprennent les thérapies par l’aspirine et les statines. L’aspirine à faible dose est efficace dans la prévention des événements thrombotiques tels que les accidents vasculaires cérébraux et l’infarctus du myocarde;
cela est également vrai chez les patients hypertendus dont la pression artérielle est bien contrôlée. Le risque de saignement sévère est très faible à condition que la pression artérielle soit réduite à moins de 150 / 90mmHg. Les avantages du traitement médicamenteux hypolipidémiant avec des statines sont bien établis dans les maladies coronariennes et les maladies cérébrovasculaires, deux conditions fréquemment associées à l’hypertension artérielle.

Références clés
Cain AE, Khalil RA. Physiopathologie de l’hypertension essentielle: rôle de la pompe, du vaisseau et du rein. Semin Nephrol 2002; 22: 3-16

Franklin SS, Khan SA, Wong ND, Larson MG, Levy D. La pression du pouls est-elle utile pour prédire le risque de maladie coronarienne? L’étude cardiaque de

Framingham. Circulation 1999; 100: 354–60

Hansson L, Zanchetti A, Carruthers SG, et al. Effets de la pression artérielle intensive diminution et faible dose d’aspirine chez les patients souffrant d’hypertension: principaux résultats de l’essai randomisé sur le traitement optimal de l’hypertension (HOT). Groupe d’étude HOT. Lancet 1998; 351: 1755–62

Haynes WG, Webb DJ. L’endothéline en tant que régulateur de la fonction cardiovasculaire dans la santé et la maladie. J Hypertension 1998; 16: 1081–98

Howell SJ, Hemming AE, Allman KG, Glover L, Sear JW, Foe¨x P. Prédicteurs de l’ischémie myocardique postopératoire. Le rôle de l’hypertension artérielle intercurrente et d’autres facteurs de risque cardiovasculaire. Anesthésie 1997; 52: 107-11
Prys-Roberts C. Phaeochromocytoma — progrès récents dans sa gestion. Br J Anaesth 2000; 85: 44 57

Weinberger MH. Sensibilité au sel de la pression artérielle chez l’homme. Hypertension 1996; 27: 481–90

Williams B, Poulter NR, Brown MJ. Directive de la British Hypertension Society pour la gestion de l’hypertension. Br J Med 2004; 328: 634–40

Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effets d’un inhibiteur de l’enzyme de conversion de l’angiotensine, le ramipril, sur les événements cardiovasculaires chez les patients à haut risque. Les chercheurs de l’étude d’évaluation de la prévention des résultats cardiaques. New Engl J Med 2000; 342: 145–53

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«MacLean, says that three brains operate like “three interconnected biological computers, [each] with its own special intelligence, its own subjectivity, its own sense of time and space and its own memory”. He refers to these three brains as the neocortex or neo-mammalian brain, the limbic or paleo-mammalian system, and the reptilian brain, the brainstem and cerebellum. Each of the three brains is connected by nerves to the other two, but each seems to operate as its own brain system with distinct capacities. This hypothesis has become a very influential paradigm, which has forced a rethink of how the brain functions. It had previously been assumed that the highest level of the brain, the neocortex, dominates the other, lower levels. MacLean has shown that this is not the case, and that the physically lower limbic system, which rules emotions, can hijack the higher mental functions when it needs to.
Reptilian brain:
This brain controls all reflexes, which are automatic and purely regulatory: body temperature, hormonal secretion, blood glucose level, blood pressure, spontaneous respiration…
Ondin’s curse ( lesion or abnormality to the midbrain region: Ondine’s curse—more appropriately known as congenital central hypoventilation syndrome or CCHS—is a rare, severe form of sleep apnea in which an individual completely stops breathing when falling asleep. It is usually congenital, meaning that it is present from birth. It may be noted in the neonatal unit after delivery.  Central sleep apnea is characterized by the brainstem failing to prompt normal breathing. This seems to be due to a decreased responsiveness to high levels of carbon dioxide and low oxygen levels within the blood. This becomes especially dangerous during sleep.
Ondine’s curse is named after a mythical tale in which a heartbroken water nymph curses her unfaithful husband to stop breathing should he ever fall asleep. In medical terms, Ondine’s curse represents an extreme form of sleep apnea.
Limbic system (paleo mammalian brain):
Anatomy:

        Fig 1: in this mid sagittal dissection the hypothalamus and thalamus are                                         delineated by the hypo thalamic sulcus
Anteriorly the hypothalamus extends to the anterior commissure and the optic chiasm. Inferiorly it includes the mammillary bodies and extends to the infundibular stuck where it communicates with the pituitary gland. The hypothalamus is structurally part of the diencephalon but it functions as part of the limbic system through the reciprocal connections. It helps to maintain homeostasis in the entire body through influences on the endocrine system and importantly through its primary influence on both the sympathetic and parasympathetic systems.
-The limbic system is extremely old from an evolutionary perspective and in its connections; it is interposed between the hypothalamus and the neocortex. Limbic lob is not a true lobe rather it spans the frontal, parietal and temporal lobes, it comprises a ring of cortex in the in the medial surface in the brain (the cingulate gyrus and the para hippocampal gyrus)

Fig 2 : cingulate gyrus ( left) Parahippocampale gyrus(right)

-The Hippocampus: is primarily involved in memory and it lies in the inferior horn of … And from its posterior ends fibers emerge to form the fornix which swings over the thalamus to rich the mammillary bodies of the hypothalamus by column of the fornix

Fig 3 : Hippocampus 
– The mammillary bodies are primarily responsible for emotional processing.

    Fig 4 : connection between fornix and mammillary bodies

-The mammillo-thalamic tract connects the mammillary bodies with the anterior nucleus and dorso-medial nucleus of the thalamus and from the thalamus the information travels to the limbic lob (this is the classic papez circuit involved in learning, memory and emotions).
We now know that other structures are involved this circuit including (amygdala…
The amygdala is located in the roof of the inferior horn of lateral ventricle directly underneath the uncus, it lies superior and anterior to the hippocampus (delineated by green dashed cycle)

Fig 5 Amygdala (green dashed)
The structure delineated by red is the uncus.The amygdala is a key structure in the expression of emotions, emotional memory and basic drives.

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1) The Hypothalamus: which is regarded as the highest control system over the autonomic motor neurons that affect the activity of our visceral organs so the hypothalamus is the center of homeostasis (continuously and unconsciously adjusting the activity of our visceral effectors to match the person’s physical activity and energy requirements).

For example, the heart rate will be adjusted when we are sleeping and or when we are running and this will be done automatically or the heart rate will increase if we are frightened. We can see that hypothalamus is influenced by our emotions that means the hypothalamus is connected to our limbic system. The hypo thalamus is in the area of the brain right above the pituitary gland and we can see that the hypothalamus is connected to the limbic system which is associated with emotions and there are various descending tracts that effects autonomic motor neurons.

Branching of the brain and spinal cord these autonomic motor neurons innervate various internal organs.

There are two types of autonomic motor neurons that innervate each visceral organ of the body (Dual innervation):

1) the parasympathetic autonomic motor neurons that exerts the predominant influence on the visceral organs during the state of relaxation (low energy requirement): rest and digest

2) the sympathetic autonomic motor neurons that exerts the predominant influence on the visceral organs during states of stress (high energy requirement): fight, fright, flight

                       General patterns of autonomic outflow from the C.N.S

1. A) Parasympathetic motor neurons:

The parasympathetic motor neurons are present only in certain cranial nerves and in the sacral spinal nerves: (cranio-sacral)

Cranial nerves III (oculomotor), VII ( Facial), IX ( Glossopharyngeal), X (Vagus) and sacral S2, S3, S4 contains parasympathetic motor neurons.

Some of the cranial nerves contain parasympathetic motor neurons and some of the spinal nerves coming out of the sacral level of the spinal cord contains parasympathetic motor neurons. ………

1. B) Sympathetic (thoraco-lumbar) division of the Autonomic nervous system:

The only nerves that contain inside them sympathetic motor neurons are those spinal nerves coming of at thoracic and lumbar levels. That’s why the sympathetic nervous system is also known as thoraco-lumbar division. So, there is clear difference anatomically.

Now what’s interesting is that there are many sympathetic motor neurons that innervate all internal organs instead there is only vagal nerve for parasympathetic nervous system. In other words, all internal organs are innervated by two types of autonomic motor neurons: Dual innervation

“somatic muscles have nicotinic acetylcholine receptors and are totally dependent of their innervation: they are called neurogenic”

To study the ANS we will take the heart as a simple model (but it could be any other organ)

We know that sympathetic as well as parasympathetic innervation takes two motor neurons to go from the C.N.S to the internal organ. The first neuron is myelinated and the second one is not myelinated (it is the same for Para and sympathetic)

                  dual innervation of the heart

The acetylcholine is liberated by parasympathetic nerve at the heart (! Acetylcholine receptor at the heart is muscarinic and not nicotinic like the somatic muscles)

Acetylcholine is also released from preganglionic fiber of sympathetic motor neuron as in the preganglionic motor neurons of parasympathetic system but at the level of target organ there is  epinephrine release ( we say that post ganglionic fiber is adrenergic)

So in the heart there are two types of receptors ( adrenergic receptors and acetycholine muscarinic receptors)

Somatic muscles havent nicotinic receptors of acetyl choline and if their motor neurons are cut the muscle will be paralysed that means they are totally dependant of the motor neuron ( they are neurogenic) .

Here the dual innervation of the heart is  discussed (schematized) but this system can be applied to all of the internal organs of the body .

The adrenergic receptors on the heart are B1 and

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Keilin (1925) was studying the mosquitoes responsible of the malaria. With a spectromicroscope he looked at the legs of one mosquito and saw that they change of colour. At rest the muscles are oxidised but when they are excited the muscles consume the oxygen and are thus less oxidised. The colour is given by the cytochrome, a molecule that changes of colour in function of the oxidation.

This molecule belongs to the mitochondrion. The mitochondrion is a kind of bacteria hosted by eukaryotes.

They have their own membrane, composed of an inner membrane and of a porous outer membrane. The matrix is inside the inner membrane and the intermembrane space is also called cristae where the membrane is protruding. Similarly to the haemoglobin, the cytochrome is a protein that possesses a haem the iron of which can change of oxidation state. This property is used in the respiratory chain. Cytochrome belongs to the inner membrane of the mitochondrion along which it can move and it separate the glycolysis from the citric acid cycle. The cycle of the citric acid takes place in the matrix of the mitochondrion while glycolysis takes place outside of the mitochondrion.

Respiratory chain

The respiratory chain can be summarised by the following figure and table:

 In the inner membrane we find 4 complexes – NADH-ubiquinone reductase, succinate-ubiquinone reductase, ubiquinol-cytochrome c reductase and cytochrome oxidase – that make redox reactions and transfer electrons from one side of the membrane to the other side (sometimes protons instead of electrons). One reaction at one side of the membrane (matrix or intermembrane space) is always coupled with one reaction at the other side of the membrane. One reaction of reduction is coupled with a reduction of oxidation and vice-versa. The whole phenomenon involves transfers of electrons inside the membrane and transfers of protons from one side of the membrane to the other side. Note that some complexes belong to the membrane but only face one of its sides.

Q is the ubiquinone, a cofactor that belongs to the membrane. It interacts with the cytochrome c in a loop of oxidoreduction. One can see that the oxygen is involved by the complex IV. To resume the loop, we can write two reactions of oxidoreduction, one with the NAD and one with the FAD.

However O₂ cannot directly interact with FADH₂ and NADH+H⁺ and this loop is thus necessary. For redox, the free energy of Gibbs is

To determine the difference of potential ∆E°, we look at the couples involved in the reaction:

For FAD we have 43.3kcal/mol. There is a transfer of protons involved in the process but there must be an equilibrium between the concentrations of charge inside the cell and outside the cell. The protons can move out of the matrix of the mitochondrion through some protein complexes that generate ATP from the flow of protons (bottom of the figure). The F₁-ATPase protein is composed of two parts, F₀ in the membrane and F₁ in the matrix of the mitochondrion. F₀ pumps the protons from the intermembrane space towards the matrix. F₁ receives the energy from the transport and transforms ADP into ATP. Those species are charged negatively and require a transport through the membrane (top of the figure). One ADP can go in the matrix only if one ATP is moving out of the matrix. The inorganic phosphates P_i are also transported through the membrane.

The energy to form the ATP comes from the gradient of pH. It generates a proton motive force.

Where the indexes mat and ext respectively matrix and its exterior (the intermembrane space). The gradient of pH generates a difference of electric potential ΔV.

Combining the two effects, we have

Dividing this expression by nF, we obtain the expression of a variation of free energy ∆p associated to the transfer of one mole of protons (in volt).

The coefficient 2.303RT/nF of the gradient of pH has a value of 59mV at 25°C.

We can measure the pH and the difference of potential: ∆V=0.14V and ∆pH=-1.4.

It corresponds to a variation of free energy equal to

To form one mole of ATP, we need 7.3kcal. In the respiratory chain, there are 4 complexes that oxidise the NADH and the FAD.  They respectively form the equivalent of 11 and 8 protons by loop.

We can write a global equation of the “combustion” of a pyruvate during the citric acid cycle and the respiratory chain:To summarise, the oxidation of one NADH generates ~3 ATP and the oxidation of FAD generates ~2ATP.

The 15 ATP come from

• 4 NADH (one before the citric acid cycle and 3 during the cycle) à12ATP,
• from 1 FADH₂ à 2ATP
• and from 1 GTP»1 ATP.

To form one pyruvate, glycolysis forms 2 ATP and uses 2 NAD that are reduced into NADH+H⁺.

So considering 3 ATP by NADH, it corresponds to the production of 8 ATP. Added to the 15 ATP of each pyruvate (x2), we obtain 38ATP by glucose. In comparison to the combustion of the glucose (∆G°’=-686kcal/mol), it represents about 40% of the potential energy (38×7.3kcal/mol=277kcal/mol).

The NAD involved in the glycolysis and that produces a NADH is not at the same place (cytosol) that the NADH required in the cellular respiration (matrix of the mitochondrion). The NADH cannot enter freely into the mitochondrion because it is charged. There is a system of shuttle that may differ for different cells and that will modify the NADH to allow its passage through the membrane, then modify it again so it can be used there. In the brain and in muscles, it is a shuttle of glycophosphate that we will next explain. The shuttle is basically composed of two reactions: one in the cytosol and one in the matrix of the mitochondrion:

The shuttle can be represented like this:

If you remember, dihydroxyacetone-3P was part of the glycolysis (red rectangle in the following figure): it is one of the two trioses phosphate produced from fructose -1,6-diphosphate. The fact that this triose is involved in the shuttle does not really decrease the yield of the glycolysis significantly: the cell needs a given quantity of dihydroxyacetone for the shuttle but the molecules are regenerated in the matrix of mitochondria and can then return to the cytosol. So they just have to be produced once. The rest of the production is turned into glyceraldehyde 3P for the glycolysis.

The FADH₂ is oxidised during the respiration and the dihydroxyacetone can move back to the cytosol. The shuttle has a small cost: it oxidises one NADH into NAD in the cytosol while the reaction in the matrix involves FAD/FADH₂. In term of energy, it represents one ATP used because all the processes don’t take place at the same place.

The malate-aspartate shuttle

The same cofactors (NADH+H⁺/NAD⁺) are used so the yield does not change with this shuttle (38 ATP). The mechanism is based on the reducing power of the oxaloacetate.

Reduced into malate (1), it is transported in the matrix of the mitochondrion (2) through the malate-α-ketoglutarate transporter if one α-ketoglutarate is available to make the displacement in the opposite direction. The reverse reaction, the oxidation of the malate into the oxaloacetate is made in the matrix (3). Yet, the oxaloacetate cannot goes back out of the membrane. To do so, it is transformed into an amino acid, the aspartate, by a reaction of transamination (4):

It is done here by the aspartate transaminase with the use of the glutamate as amino acid. As a result, the oxaloacetate is transformed into aspartate that can move through the membrane through a transporter requiring the passage in the opposite direction of a glutamate (5). In the cytosol, it is turned back into the oxaloacetate with the exact same reaction (6) than at the other side of the membrane.

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The cycle of Krebs: cycle of the citric acid

Szent Fuorgue studied the cellular respiration from an extract of muscle. He analysed the absorption of O₂ in presence of various molecules. He observed that some of them considerably increase the absorption of oxygen by the tissues. It is the case for the succinate and the fumarate.

These molecule are stable to variations of temperature. The combustion of one succinate normally consumes 3 O₂ but during the experiments they observed that the absorption of oxygen was above this value. They also showed that the absorption can be decreased if we add malate to the system. The malate is an inhibitor that affects the oxaloacetate, one catalyst of the cycle of Kerbs that is regenerated at each cycle except in presence of malate.

The cycle can be resumed by the following figure.

Citrate is the product of the first reaction of the cycle. Before explanations on the cycle, we will explain the formation of the acetyl CoA. It is made from pyruvate. The first step is the substitution of one CO₂ by the CoASH through a thioester liaison.

The reaction is irreversible (release of CO₂) and is catalysed by a big enzyme: the pyruvate dehydrogenase. Inside the enzyme we find the B₁ vitamin. Simultaneously, there is an oxidation made by the NAD⁺. The product is the acetyl coenzyme A, or acetyl-coA.

The first step forms the citrate by the condensation between the acetyl-coA and the oxaloacetate. The reaction is helped by the citrate synthase that take a proton from the methyl group of the acetylCoA. It releases the coenzyme that can be used again.

The citrate is symmetrical but it is considered as prochiral by the enzyme of the next reaction. To pursue to cycle, the aconitase changes the conformation of the citrate to obtain the isocitrate.

The equilibrium is heavily in favour of the left but the right species is consumed by the next reactions so the reaction is displaced towards the right. Step 3 is subdivided into one reaction of oxidation and one decarboxylation.

The step 4 is similar to the formation of the acetyl-CoA and leads to the formation of the succinyl-coA.

The cleavage of the thioester liaison gives enough energy to form, not an ATP but a GTP.

The succinate is next oxidised to for the fumarate. The cofactor is the FAD: Flavin adenine dinucleotide, a derivate of the riboflavin (vitamin B2).

The reduction of the FAD is done at the orange area.

Step 7 needs one molecule of water to form the malate. Malate is a chiral molecule, the chirality given by the structure of the active site of the enzyme. As a result, only the l-malate is obtained.

Finally, the oxaloacetate is regenerated from the malate.

Now, you may say that there is none of the 38 ATP promised at the beginning of the section. Only one GTP was formed during the cycle but several CO₂ were rejected and 3 NAD⁺ and one FAD were reduced. These molecules represent the energy of the ATP. Moreover, it is the process that occurs in aerobic cells but no O₂ was ever involved in the cycle. We will see the source of the ATP in the next section: the respiratory chain.

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To facilitate the study of genes, they must be isolated and amplified. One method of isolation and amplification of a gene of interest is to clone the gene by inserting it into another DNA molecule that serves as a vehicle or vector that can be replicated in living cells. When these two DNAs of different origin are combined, the result is a recombinant DNA molecule. The recombinant DNA molecule is placed in a host cell, either prokaryotic or eukaryotic. The host cell then replicates (producing a clone), and the vector with its foreign piece of DNA also replicates. The foreign DNA thus becomes amplified in number, and following its amplification can be purified for further analysis.

In 1962, Allan Campbell noted that the linear genome of bacteriophage λ forms a circle upon entering the host bacterial cell, and a recombination (breaking and rejoining) event inserts the phage DNA into the host chromosome. Reversal of the recombination event leads to normal excision of the phage DNA. Further analysis revealed that phage λ had short regions of single-stranded DNA whose base sequences were complementary to each other at each end of its linear genome. These single-stranded regions were called “cohesive” (cos) sites. Complementary base pairing of the cos sites allowed the linear genome to become a circle within the host bacterium. The idea of joining DNA segments by “cohesive sites” became the guiding principle for the development of genetic engineering. With the molecular characterization of restriction and modification systems in bacteria, it soon became apparent that the ideal engineering tools for making cohesive sites on specific DNA pieces were already available in the form of restriction endonucleases.

Early on, Salvador Luria and other phage workers were intrigued by a phenomenon termed “restriction and modification.” Phages grown in one bacterial host often failed to grow in different bacterial strains (“restriction”). However, some rare progeny phages were able to escape this restriction. Once produced in the restrictive host they had become “modified” in some way so that they now grew normally in this host. The entire cycle could be repeated, indicating that the modification was not an irreversible change. For example, phage λ grown on the C strain of Escherichia coli (λ·C) were restricted in the K-12 strain (the standard strain for most molecular work). However, the rare phage λ that managed to grow in the K-12 strain now had “K” modification (λ·K). These phages grew normally on both C and K-12; however, after growth on C, the phage λ with “C” modification (λ·C) was again restricted in K-12. Thus, the K-12 strain was able to mark its own resident DNA for preservation, but could eliminate invading DNA from another distantly related strain. In 1962, the molecular basis of restriction and modification was defined by Werner Arber and co-workers.

Restriction system :

After demonstrating that phage λ DNA was degraded in a restricting host bacterium, Arber and co-workers hypothesized that the restrictive agent was a nuclease with the ability to distinguish whether DNA was resident or foreign. Six years later, such a nuclease was biochemically characterized in E. coli K-12 by Matt.

Meselson and Bob Yuan. The purified enzyme cleaved λ·C-modified DNA into about five pieces but did not attack λ·K-modified DNA. Restriction endonucleases (also referred to simply as restriction enzymes) thus received their name because they restrict or prevent viral infection by degrading the invading nucleic acid.

Modification system

At the time, it was known that methyl groups were added to bacterial DNA at a limited number of sites. Most importantly, the location of methyl groups varied among bacterial species. Arber and colleagues were able to demonstrate that modification consisted of the addition of methyl groups to protect those sites in DNA sensitive to attack by a restriction endonuclease. In E. coli, adenine methylation (6-methyl adenine) is more common than cytosine methylation (5-methyl cytosine)

Methyl-modified target sites are no longer recognized by restriction endonucleases and the DNA is no longer degraded. Once established, methylation patterns are maintained during replication. When resident DNA replicates, the old strand remains methylated and the new strand is unmethylated. In this hemimethylated state, the new strand is quickly methylated by specific methylases. In contrast, foreign DNA that is unmethylated or has a different pattern of methylation than the host cell DNA is degraded by restriction endonucleases.

The first cloning experiments

Hamilton Smith and co-workers demonstrated unequivocally that restriction endonucleases cleave a specific DNA sequence. Later, Daniel Nathans used restriction endonucleases to map the simian virus 40 (SV40) genome and to locate the origin of replication. These major breakthroughs underscored the great potential of restriction endonucleases for DNA work. Building on their discoveries, the cloning experiments of Herbert Boyer, Stanley Cohen, Paul Berg, and their colleagues in the early 1970s ushered in the era of recombinant DNA technology. One of the first recombinant DNA molecules to be engineered was a hybrid of phage λ and the SV40 mammalian DNA virus genome. In 1974 the first eukaryotic gene was cloned. Amplified ribosomal RNA (rRNA) genes or “ribosomal DNA” (rDNA) from the South African clawed frog Xenopus laevis were digested with a restriction endonuclease and linked to a bacterial plasmid. Amplified rDNA was used as the source of eukaryotic DNA since it was well characterized at the time and could be isolated in quantity by CsCl-gradient centrifugation. Within oocytes of the frog, rDNA is selectively amplified by a rolling circle mechanism from an extrachromosomal nucleolar circle . The number of rRNA genes in the oocyte is about 100- to 1000-fold greater than within somatic cells of the same organism. To the great excitement of the scientific community, the cloned frog genes were actively transcribed into rRNA in E. coli. This showed that recombinant plasmids containing both eukaryotic and prokaryotic DNA replicate stably in E. coli. Thus, genetic engineering could produce new combinations of genes that had never appeared in the natural environment, a feat which led to widespread concern about the safety of recombinant DNA work

Cutting and joining DNA

Two major categories of enzymes are important tools in the isolation of DNA and the preparation of recombinant DNA: restriction endonucleases and DNA ligases. Restriction endonucleases recognize a specific, short, nucleotide sequence on a double-stranded DNA molecule, called a restriction site, and cleave the DNA at this recognition site, depending on the type of enzyme. DNA ligase joins two pieces of DNA by forming phosphodiester bonds.

Major classes of restriction endonucleases

There are three major classes of restriction endonucleases. Their grouping is based on the types of sequences recognized, the nature of the cut made in the DNA, and the enzyme structure:

– Type I and III restriction endonucleases are not generally  used for gene cloning because they cleave DNA at sites other than the recognition sites and thus cause random cleavage patterns.

– type II endonucleases are widely used for mapping and reconstructing DNA in vitro because they recognize specific sites and cleave just at these sites . In addition, the type II endonuclease and methylase activities are usually separate, single subunit enzymes. Although the two enzymes recognize the same target sequence, they can be purified separately from each other

Nomenclature :

Restriction endonucleases are named for the organism in which they were discovered, using a system of letters and numbers. For example, HindIII  was discovered in Haemophilus influenza strain d and III is for the third enzayme of that type. Sma I is from serratia marcescens ,  Eco RI is Escherichia coli( strain R) and BamHI is from Bacillus amyloliquefaciens ( strain H ). Over 3000 type II esrtriction endonucleases have been isolated and characterised to date.

Recognition sequences for type II restriction endonucleases :

Each orthodox type II restriction endonuclease is composed of two identical polypeptide subunits that join together to form a homodimer. These homodimers recognize short symmetric DNA sequences of 4–8 bp. Six base pair cutters are the most commonly used in molecular biology research. Usually, the sequence read in the 5′ → 3′ direction on one strand is the same as the sequence read in the 5′ → 3′ direction on the complementary strand. Sequences that read the same in both directions are called palindromes . Figure 8.3 shows some common restriction endonucleases and their recognition sequences. Some enzymes, such as EcoR1, generate a staggered cut, in which the single-stranded complementary tails are called “sticky” or cohesive ends because they can hydrogen bond to the singlestranded complementary tails of other DNA fragments. If DNA molecules from different sources share the same palindromic recognition sites, both will contain complementary sticky ends (single-stranded tails) when digested with the same restriction endonuclease. Other type II enzymes, such as SmaI, cut both strands of the DNA at the same position and generate blunt ends with no unpaired nucleotides when they cleave the DNA.

Restriction endonucleases exhibit a much greater degree of sequence specificity in the enzymatic reaction than is exhibited in the binding of regulatory proteins, such as the Lac repressor to DNA . For example, a single base pair change in a critical operator sequence usually reduces the affinity of the Lac repressor by 10- to 100-fold, whereas a single base pair change in the recognition site of a restriction endonuclease essentially eliminates all enzymatic activity.

Like other DNA-binding proteins, the first contact of a restriction endonuclease with DNA is nonspecific. Nonspecific binding usually does not involve interactions with the bases but only with the DNA sugar–phosphate backbone. The restriction endonuclease is loosely bound and its catalytic center is kept at a safe distance from the phosphodiester backbone. Nonspecific binding is a prerequisite for efficient target site location. For example, BamHI moves along the DNA in a linear fashion by a process called “sliding.” Sliding involves helical movement due to tracking along a groove of the DNA over short distances (< 30–50 bp). This reduces the volume of space through which the protein needs to search to one dimension. However, the “random walk” nature of linear diffusion gives equal probabilities for forward and reverse steps, so if the distances between the nonspecific binding site and the recognition site are large (> 30–50 bp), the protein

would return repeatedly to its start point. The main mode of translocation over long distances is thus by “hopping” or “jumping.” In this process, the protein moves between binding sites through three-dimensional space, by dissociating from its initial site before reassociating elsewhere in the same DNA chain. Because of relatively small diffusion constants of proteins, most rebinding events will be short range “hops” back to or near the initial binding site. In the example of BamHI, once the target restriction site is located, the recognition process triggers large conformational changes of the enzyme and the DNA (called coupling), which leads to the activation of the catalytic center. In addition to indirect interaction with the DNA backbone, specific binding is characterized by direct interaction of the enzyme with the nitrogenous bases.

All structures of orthodox type II restriction endonucleases characterized by X-ray crystallography so far show a common structural core composed of four conserved β-strands and one α-helix . In the presence of the essential cofactor Mg²⁺, the enzyme cleaves the DNA on both strands at the same time within or in close proximity to the recognition sequence (restriction site). The enzyme cuts the duplex by breaking the covalent, phosphodiester bond between the phosphate of one nucleotide and the sugar of an adjacent nucleotide, to give free 5′-phosphate and 3′-OH ends. Type II restriction endonucleases do not require ATP hydrolysis for their nucleolytic activity. Although there are a number of models for how this nucleophilic attack on the phosphodiester bond occurs, the exact mechanism by which restriction endonucleases achieve DNA cleavage has not yet been proven experimentally for any type II restriction endonuclease.

DNA ligase :

The study of DNA replication and repair processes led to the discovery of the DNA-joining enzyme called DNA ligase. DNA ligases catalyze formation of a phosphodiester bond between the 5′-phosphate of a nucleotide on one fragment of DNA and the 3′-hydroxyl of another . This joining of linear DNA fragments together with covalent bonds is called ligation. Unlike the type II restriction endonucleases, DNA ligase requires ATP as a cofactor.

Because it can join two pieces of DNA, DNA ligase became a key enzyme in genetic engineering. If restriction-digested fragments of DNA are placed together under appropriate conditions, the DNA fragments from two sources can anneal to form recombinant molecules by hydrogen bonding between the complementary base pairs of the sticky ends. However, the two strands are not covalently bonded by phosphodiester bonds. DNA ligase is required to seal the gaps, covalently bonding the two strands and regenerating a circular molecule. The DNA ligase most widely used in the lab is derived from the bacteriophage T4. T4 DNA ligase will also ligate fragments with blunt ends, but the reaction is less efficient and higher concentrations of the enzyme are usually required in vitro. To increase the efficiency of the reaction, researchers often use the enyzme terminal deoxynucleotidyl transferase to modify the blunt ends. For example, if a single-stranded poly(dA) tail is added to DNA fragments from one source, and a singlestranded poly(dT) tail is added to DNA from another source, the complementary tails can hydrogen bond. Recombinant DNA molecules can then be created by ligation.

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The first step is the phosphorylation of the glucose. The phosphate is added on 6’. For this reaction, as for the others of the glycolysis, an enzyme (the hexokinase/glucokinase) to form the ester and to cleave the anhydride of the ATP.

The second reaction involves the transformation of a pyranose into a furanose.

The third step is dependant of the needs of the cell in energy.

When the cell absolutely needs energy, its consume ADP and forms AMP. If the concentration of AMP in the cell increases then a signal is sent to the phosphofructokinase to increase the rate of the reaction. On the contrary, if the cell is full of ATP, then there is no need to make more of them and the reaction is slowed.

In the next step, the fructose is cleaved into two chains of 3 carbons, an aldose and a ketone that can be transformed into each other by the triose phosphate isomerase.

Because the reaction 5 is reversible, if the C₁ of the glyceraldehyde was marked, we would find the fructose marked on 3’ or in 4’.

The next steps involve chains of 3 carbons. From one glucose, they are thus occurring twice.

The enzyme of the step 6 is the GAPDH (glyceraldehyde 3-phosphate dehydrogenase) and the NAD (nicotinamide adenine dinucleotide) is its cofactor and has to be in the active site of the enzyme for it to work. NAD⁺ is its oxidised form and NADH+H⁺ its reduced form.

The presence of the reduced form can be confirmed by a new peak of absorbance at 340nm. The reduction generates some energy to allow the formation of a phosphoanhydride, what is a liaison high in energy. It will thus generate a lot of energy when it is cleaved.

The seventh step uses the energy of this liaison to regenerate one ATP.

The eighth reaction displaces one phosphate. It is done by an enzyme called mutase.

The ninth step is an intramolecular reaction of oxidation. C₂ is oxidised while C₃ is reduced. We have now a phosphoenol the cleavage of which restores one ATP in the following reaction of tautomerization.

In total, two ATP were used during the glycolysis to form the trioses. These steps are thus using the reserve of energy of the cell. However two reactions form one ATP by triose. As there are two trioses by glucose and the isomerase can turn the ketone into the glyceraldehyde, so we form 4 ATP from the trioses. During the complete glycolysis, 2 ATP are thus formed that can be used by the cell. For anaerobic cells, it is the only way to produce ATP.

The NAD⁺ has to be regenerated by fermentation.

Lactic acid fermentation

The pyruvate, the final product of the glycolysis, is used to oxidise the NADH+H⁺ and form lactate that is next released in the middle.

Ethanol fermentation

Also called alcoholic fermentation, this process also uses the pyruvate but is made in two steps. One first that involves the rejection of CO₂ and the second that oxidises the NADH+H⁺ and frees some ethanol.

Comments on the glycolysis

• In the case of a lack of NAD⁺, or a too large quantity of glucose, more NAD⁺ can be formed from the “unused” triose, the dihydroxyacetone phosphate

The reaction is in equilibrium and is only made in case of need. If the triose was essentially used to do this, the whole process of the glycolysis would be pointless: it would consume 2 ATP to form 2 ATP.

• Coupling of reactions

Some steps of the glycolysis have a positive ∆G⁰’. It is the case of the steps that form rich liaisons. In this way, the step 6 is coupled to the step 7 that cleaves the rich liaison to form an ATP.

If we consider the two reactions at once, i.e. a reaction of oxidation of the aldehyde into a carboxylic acid, we find a ∆G⁰’=-10kcal (7.3kcal are equivalent to one ATP). The two-steps reaction is favoured because we can store the energy as ATP.

The same is true for the steps 8, 9, 10.

The two first steps cost energy but the third is very favourable. In total, we have a ∆G⁰’=-6kcal/mol and the formation of an ATP.

• Uncoupling agent

There are some molecules that can block the formation of the ATP. It is for instance the case of the arsenate ion which is a poison for us. In the step 6 and 7, the ion takes the place of an inorganic phosphate.

We still obtain the product of the step 7 but without the formation of ATP.

• energetic balance

The combustion of one glucose is an exothermic reaction:

The combustion of the products of the glycolysis (two pyruvates) gives

It is about 7% of the energy of one glucose. To that we can add the energy of the phosphoester bond of the 2ATP: 2×7.3kcal/mol.

It is still a very small quantity of energy that was recovered from the glucose. This method was used when there was almost no oxygen available and is used in anaerobic environments.

• Other monosaccharides can make the glycolysis after being transformed by enzymes into glucose or one intermediate of the glycolysis.

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