Role of Corticotropin-releasing Factor in Gastrointestinal Permeability (original) (raw)
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AJP: Gastrointestinal and Liver Physiology, 2008
7 other HighWire-hosted articles: This article has been cited by http://ajpgi.physiology.org/content/295/3/G452#cited-by including high resolution figures, can be found at: Updated information and services http://ajpgi.physiology.org/content/295/3/G452.full can be found at: AJP -Gastrointestinal and Liver Physiology about Additional material and information http://www.the-aps.org/publications/ajpgi This information is current as of July 9, 2013. website at http://www.the-aps.org/. 20814-3991.
Brain, Behavior, and Immunity, 2010
The interaction between gut inflammatory processes and stress is gaining increasing recognition. Corticotropin releasing factor (CRF)-receptor activation in the brain is well established as a key signaling pathway initiating the various components of the stress response including in the viscera. In addition, a local CRF signaling system has been recently established in the gut. This review summarize the present knowledge on mechanisms through which both brain and gut CRF receptors modulate intestinal inflammatory processes and its relevance towards increased inflammatory bowel disease (IBD) activity and post-infectious irritable bowel syndrome (IBS) susceptibility induced by stress.
Corticotropin-Releasing Factor and the Brain-Gut Motor Response to Stress
Canadian Journal of Gastroenterology, 1999
The characterization of corticotropin-releasing factor (CRF) and CRF receptors, and the development of specific CRF receptor antagonists selective for the receptor subtypes have paved the way to the understanding of the biochemical coding of stress-related alterations of gut motor function. Reports have consistently established that central administration of CRF acts in the brain to inhibit gastric emptying while stimulating colonic motor function through modulation of the vagal and sacral parasympathetic outflow in rodents. Endogenous CRF in the brain plays a role in mediating various forms of stressor-induced gastric stasis, including postoperative gastric ileus, and activates colonic transit and fecal excretion elicited by psychologically aversive or fearful stimuli. It is known that brain CRF is involved in the cross-talk between the immune and gastrointestinal systems because systemic or central administration of interleukin-1-beta delays gastric emptying while stimulating colo...
Current Neuropharmacology, 2016
Background: Stress of different origin is known to alter so called "braingut axis" and contributes to a broad array of gastrointestinal disorders including inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and other functional gastrointestinal diseases. The stressful situations and various stressors including psychosocial events, heat, hypo-and hyperthermia may worsen the course of IBD via unknown mechanism. The aims of this paper were to provide an overview of experimental and clinical evidences that stress activates the brain-gut axis which results in a mucosal mast cells activation and an increase in the production of proinflammatory cytokines and other endocrine and humoral mediators. Methods: Research and online content related to effects of stress on lower bowel disorders are reviewed and most important mechanisms are delineated. Results: Brain conveys the neural, endocrine and circulatory messages to the gut via brain-gut axis reflecting changes in corticotrophin releasing hormone, mast cells activity, neurotransmission at the autonomic nerves system and intestinal barrier function all affecting the pathogenesis of animal colitis and human IBD. Stress triggers the hypothalamus-pituitary axis and the activation of the autonomic nervous system, an increase in cortisol levels and proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin-8, interleukin-1beta and interleukin-6. Conclusion: The acute or chronic stress enhances the intestinal permeability weakening of the tight junctions and increasing bacterial translocation into the intestinal wall. An increased microbial load in the colonic tissue, excessive cytokine release and a partially blunted immune reactivity in response to stress result in its negative impact on IBD.
Visceral Inflammation and Immune Activation Stress the Brain
Frontiers in immunology, 2017
Stress refers to a dynamic process in which the homeostasis of an organism is challenged, the outcome depending on the type, severity, and duration of stressors involved, the stress responses triggered, and the stress resilience of the organism. Importantly, the relationship between stress and the immune system is bidirectional, as not only stressors have an impact on immune function, but alterations in immune function themselves can elicit stress responses. Such bidirectional interactions have been prominently identified to occur in the gastrointestinal tract in which there is a close cross-talk between the gut microbiota and the local immune system, governed by the permeability of the intestinal mucosa. External stressors disturb the homeostasis between microbiota and gut, these disturbances being signaled to the brain via multiple communication pathways constituting the gut-brain axis, ultimately eliciting stress responses and perturbations of brain function. In view of these rel...
Corticosterone mediates stress-related increased intestinal permeability in a region-specific manner
Neurogastroenterology & Motility, 2013
Background-Chronic psychological stress (CPS) is associated with increased intestinal epithelial permeability and visceral hyperalgesia. It is unknown whether corticosterone (CORT) plays a role in mediating alterations of epithelial permeability in response to CPS. Methods-Male rats were subjected to 1-hour water avoidance (WA) stress or subcutaneous CORT injection daily for 10 consecutive days in the presence or absence of corticoid-receptor antagonist RU-486. The visceromotor response (VMR) to colorectal distension (CRD) was measured. The in situ single-pass intestinal perfusion was used to measure intestinal permeability in jejunum and colon simultaneously. Key Results-We observed significant decreases in the levels of glucocorticoid receptor (GR) and tight junction proteins in the colon but not the jejunum in stressed rats. These changes were largely reproduced by serial CORT injections in control rats and were significantly reversed by RU-486. Stressed and CORT-injected rats demonstrated a 3-fold increase in permeability for PEG-400 (MW) in colon but not jejunum and significant increase in VMR to CRD, which was significantly reversed by RU-486. In addition, no differences in permeability to PEG-4,000 and PEG-35,000 were detected between control and WA groups. Conclusions & Inferences-Our findings indicate that CPS was associated with regionspecific decrease in epithelial tight junction protein levels in the colon, increased colon epithelial permeability to low-molecular weight macromolecules which were largely reproduced by CORT treatment in control rats and prevented by RU-486. These observations implicate a novel, regionspecific role for CORT as a mediator of CPS-induced increased permeability to macromolecules across the colon epithelium.
The FASEB Journal, 2012
Psychological stress is gaining recognition as an important predisposing or inciting factor in the development of gastrointestinal disease. The shift from a protective response intended to maintain homeostasis to one that results in profound consequences and the development of disease is unclear. The stress response is mediated by corticotropin-releasing factor (CRF) that may be released both centrally and peripherally. The bi-directional communication between the brain and gut serves as the link between stress perception and gastrointestinal function. Mast cells have been identified as important mediators of the braingut axis, and previous research has demonstrated that intestinal mast cells play a critical role in mediating stress-induced gastrointestinal dysfunction although the mechanism remains unclear. Mast cells have been shown to express both CRF receptor subtypes, CRF 1 and CRF 2 , and can be activated through binding of either receptor. However, the influence of CRF 1 and CRF 2 on mast cell function during the stress response is yet to be elucidated. Here we demonstrate a dichotomous role of CRF receptor subtypes in mast cell activation in response to psychological stress. Furthermore, we have identified a novel protective role for mast cell CRF 2 in modulating stress-induced intestinal permeability. Mast cell-deficient mice repleted with CRF 1-/-bone marrow-derived mast cells (BMMCs) were completely protected from stress-induced increases in intestinal permeability; whereas, mice repleted with CRF 2-/v TABLE OF CONTENTS LIST OF FIGURES .
The Journal of Physiology, 2007
Neonatal maternal deprivation (NMD) increases gut paracellular permeability (GPP) through mast cells and nerve growth factor (NGF), and modifies corticotrophin-releasing factor (CRF) and corticosterone levels. CRF, corticosterone and mast cells are involved in stress-induced mucosal barrier impairment. Consequently, this study aimed to specify whether corticosteronaemia and colonic expression of both preproCRF and CRF are modified by NMD, and to determine if altered expression may participate in the elevated GPP in connection with NGF and mast cells. Male Wistar rat pups were either separated from postnatal days 2-14, or left undisturbed with their dam. At 12 weeks of age, adult rats were treated with mifepristone (an antagonist of corticoid receptors), α-helical CRF (9-41) (a non-specific CRF receptor antagonist), or SSR-125543 (CRF-R 1 receptor antagonist). We also determined corticosteronaemia and both colonic preproCRF and CRF expression. Then, control rats were treated by CRF, doxantrazole (mast cell stabilizer), BRX-537A (a mast cell activator) and anti-NGF antibody. NMD did not modify colonic CRF level but increased colonic preproCRF expression and corticosteronaemia. Peripheral CRF, via CRF-R 1 receptor, but not corticosterone, was involved in the elevated GPP observed in these rats, through a mast-cell-mediated mechanism, since the increase of GPP induced by exogenous CRF was abolished by doxantrazole. Anti-NGF antibody treatment also reduced the elevated GPP induced by CRF or BRX-537A. CRF acts through CRF-R 1 receptors to stimulate NGF release from mast cells, which participates in the elevated GPP observed in NMD adult rats. This suggests that early traumatic experience induced neuro-endocrine dysfunction, involved in alterations of gut mucosal barrier.
Intestinal Homeostasis under Stress Siege
International Journal of Molecular Sciences
Intestinal homeostasis encompasses a complex and balanced interplay among a wide array of components that collaborate to maintain gut barrier integrity. The appropriate function of the gut barrier requires the mucus layer, a sticky cushion of mucopolysaccharides that overlays the epithelial cell surface. Mucus plays a critical anti-inflammatory role by preventing direct contact between luminal microbiota and the surface of the epithelial cell monolayer. Moreover, mucus is enriched with pivotal effectors of intestinal immunity, such as immunoglobulin A (IgA). A fragile and delicate equilibrium that supports proper barrier function can be disturbed by stress. The impact of stress upon intestinal homeostasis results from neuroendocrine mediators of the brain-gut axis (BGA), which comprises a nervous branch that includes the enteric nervous system (ENS) and the sympathetic and parasympathetic nervous systems, as well as an endocrine branch of the hypothalamic-pituitary-adrenal axis. Thi...
A role for corticotropin-releasing factor in functional gastrointestinal disorders
Current Gastroenterology Reports, 2009
Functional gastrointestinal disorders (FGIDs), which include irritable bowel syndrome (IBS), encompass a heterogeneous group of diseases identified by chronic or recurrent symptom-based diagnostic criteria. Psychosocial factors are key components in the outcome of clinical manifestations of IBS symptoms. Anxiogenic and endocrine responses to stress are mediated by the corticotropin-releasing factor (CRF)-CRF 1 receptor pathway. Preclinical studies show that activation of the CRF 1 receptor by exogenous CRF or stress recapitulates many functional symptoms of IBS diarrhea-predominant patients as related to anxiogenic/hypervigilant behavior, autonomic nervous system alterations, induction of diarrhea, visceral hyperalgesia, enhanced colonic motility, mucus secretion, increased permeability, bacterial translocation, and mast cell activation, which are all alleviated by selective CRF 1 receptor antagonists. Clinical studies also support that CRF administration can induce IBS-like symptoms in healthy subjects and heighten colonic sensitivity in IBS patients. Yet to be ascertained is whether CRF 1 receptor antagonists hold promise as a new therapy in IBS treatment.