Direct evidence of mast cell involvement in Clostridium difficile toxin a—induced enteritis in mice☆☆☆

Wershil, Barry K.; Castagliuolo, Ignazio; Pothoulakis, Charalabos

doi:10.1016/s0016-5085(98)70315-4

Cited by 114 publications

(70 citation statements)

References 44 publications

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“…After 2 h, some animals (n ϭ 6 per group) were killed by CO 2 inhalation, and loops were collected and washed in Hanks' Balanced Salt Solution containing 0.35 g͞liter NaHCO 3 for SP measurements. At 4 h the remaining animals (n ϭ 6 per group) were killed, and fluid secretion was estimated as the loop weight-to-length ratio as described (34,35). Tissues were then washed in saline, cut into 5 ϫ 5-mm pieces, and snap-frozen for myeloperoxidase (MPO) measurements.…”

Section: Methodsmentioning

confidence: 99%

Corticotropin-releasing hormone (CRH) requirement inClostridium difficiletoxin A-mediated intestinal inflammation

Anton

Mykoniatis²,

Pan³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Clostridium difficile, the causative agent of antibiotic-associated colitis, mediates inflammatory diarrhea by releasing toxin A, a potent 308-kDa enterotoxin. Toxin A-induced inflammatory diarrhea involves many steps, including mucosal release of substance P (SP) corticotropin-releasing hormone (CRH) and neutrophil transmigration. Here we demonstrate that, compared with wild type, mice genetically deficient in CRH (Crh ؊/؊ ) have dramatically reduced ileal fluid secretion, epithelial cell damage, and neutrophil transmigration 4 h after intraluminal toxin A administration. This response is associated with diminished mucosal activity of the neutrophil enzyme myeloperoxidase compared with that of wildtype mice. In wild-type mice, toxin A stimulates an increase in intestinal SP content compared with buffer administration. In contrast, toxin A administration in Crh ؊/؊ mice fails to result in an increased SP content. Moreover, immunohistochemical experiments showed that CRH and SP are colocalized in some enteric nerves of wild-type mice, and this colocalization is more evident after toxin A administration. These results provide direct evidence for a major proinflammatory role for CRH in the pathophysiology of enterotoxin-mediated inflammatory diarrhea and indicate a SP-linked pathway.C orticotropin-releasing hormone (CRH), a 41-aa peptide, is a major peptide hormone that modulates the activity of the hypothalamic-pituitary-adrenal axis during stress, including inflammation (1-3). CRH mediates its effects by binding to its G protein-coupled receptor subtypes, CRH1 and CRH2 (4-6). CRH plays a dual role in the pathophysiology of inflammation. CRH secreted from the hypothalamus has indirect antiinflammatory effects via stimulation of glucocorticoid release, but CRH is also expressed peripherally, and its expression is increased in leukocytes, nerve fibers, and other cells involved in inflammatory reactions (7-12). Moreover, in vivo and in vitro studies indicate that CRH is a potent proinflammatory peptide (7,(12)(13)(14)(15).A limited number of studies indicate that CRH and its receptors play a role in the pathophysiology of intestinal inflammation. Thus, Van Tol et al. (11) found increased CRH expression in the rat cecum in colitis induced by injection of peptidoglycan-polysaccharide polymers. Increased expression of CRH-immunoreactive cells was also evident in the colonic mucosa of patients with inflammatory bowel disease (16). CRH gene expression is increased in hypothalamic neurons during colitis after intracolonic administration of 2,4,6-trinitrobenzenesulfonic acid (17) and appears to play a protective role in the worsening of experimental colitis induced by stress (18). We have recently shown that expression of CRH as well as CRH1 and CRH2 was dramatically increased in mouse ileum shortly after intraluminal administration of Clostridium difficile toxin A (19). Moreover, experiments with CRH receptor antagonists indicate that CRH plays a proinflammatory role in toxin A-induced intestinal secretion and inflammatio...

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Section: Methodsmentioning

confidence: 99%

Corticotropin-releasing hormone (CRH) requirement inClostridium difficiletoxin A-mediated intestinal inflammation

Anton

Mykoniatis²,

Pan³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…26 Mast cell-deficient mice have reduced infiltration of neutrophils and intestinal secretion in response to TcdA challenge, but reconstitution of the mice fully restores their susceptibility. 163 The disease and lesions of CDAD have a neural component, as well. Release of substance P apparently results from direct stimulation of primary sensory neurons by TcdA; this, in turn, stimulates mast cell degranulation.…”

Section: Pathogenesis Of Cdadmentioning

confidence: 99%

The Comparative Pathology ofClostridium difficile-associated Disease

2006

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Abstract. Clostridium difficile is a confirmed pathogen in a wide variety of mammals, but the incidence of disease varies greatly in relation to host species, age, environmental density of spores, administration of antibiotics, and possibly, other factors. Lesions vary as well, in severity and distribution within individuals, and in some instances, age groups, of a given species. The cecum and colon are principally affected in most species, but foals and rabbits develop severe jejunal lesions. Explanations for variable susceptibility of species, and age groups within a species, are largely speculative. Differences in colonization rates and toxin-receptor densities have been proposed. Clostridium difficile-associated disease is most commonly diagnosed in Syrian hamsters, horses, and neonatal pigs, but it is reported sporadically in many other species. The essential virulence factors of C. difficile are large exotoxins, toxin A (TcdA) and toxin B (TcdB). Receptor-mediated endocytosis of the toxins is followed by endosomal acidification, a necessary step for conversion of the toxin to its active form in the cytosol. Cell-surface receptors have been characterized for TcdA, but remain to be identified for TcdB. Both TcdA and TcdB disrupt the actin cytoskeleton by disrupting Rho-subtype, intracellular signaling molecules. Disruption of the actin cytoskeleton is catastrophic for cellular function, but inflammation and neurogenic stimuli are also involved in the pathogenesis of the disease.

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“…We (23,24) and others (25) have provided evidence that primary sensory neurons containing substance P (SP) are involved in the early stages of toxin A enteritis. Furthermore, activation of mast cells (26) and macrophages (24) and recruitment of circulating PMNs (27) are important steps in toxin A-induced intestinal inflammation.…”

Section: Introductionmentioning

confidence: 99%

Neurotensin is a proinflammatory neuropeptide in colonic inflammation

Castagliuolo¹,

Wang²,

Valenick³

et al. 1999

J. Clin. Invest.

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129

130

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A growing body of evidence suggests that interaction of epithelial and immune cells via neuropeptides, hormones, and cytokines participate in the pathophysiology of diarrhea and intestinal inflammation (reviewed in ref. 1). Neurotensin (NT), a bioactive peptide (2) with a primary distribution in the brain and the gastrointestinal tract, has been localized by immunohistochemistry to endocrine cells (N cells) and neurons in the intestinal mucosa, submucosa, and muscularis of animals and humans (3). A wide range of biological activities has been described for NT with actions on the cardiovascular, gastrointestinal, reproductive, and central nervous systems (3). The known intestinal effects of this peptide include trophic effects on small and large bowel, pancreas, and stomach; inhibition of small bowel and gastric motility; and stimulation of colonic motor activity (3). Studies in animals (3, 4, 5) and humans (3, 6) also demonstrate that NT may modulate fluid secretion in the intestinal tract and that its secretory effects in the ileum may be mediated through a nervous reflex in the enteric nervous system (5).Several lines of evidence indicate that NT may also participate in inflammatory reactions. Intravenous administration of NT to rats causes mast cell degranulation (7) and increases vascular permeability and levels of histamine and leukotriene C4 in the plasma (8); these effects can be inhibited by a specific NT receptor antagonist (9).NT also interacts in vitro with immune and inflammatory cells, including leukocytes (10), peritoneal mast cells (7), and macrophages (11,12). Although these studies point to a role for NT in inflammatory reactions, the possibility that this peptide participates in the pathogenesis of colonic inflammation has not been examined.NT exerts its effects by interacting with specific receptors (NTR) on cell surfaces. Two specific receptors for NT (NTR1 and NTR2), which belong to the seven transmembrane G protein-linked superfamily, have been identified and cloned (13,14). NTR1-mRNA and NT binding sites have been identified in the brain (15), small and large intestine of animals and humans (13, 15), human colonic epithelial cell lines (16,17), human blood mononuclear cells (11), and endothelial cells (18). Recently, we demonstrated the presence of NTR1 mRNA in the rat colonic mucosa, including colonic epithelial cells (19). We also showed that administration of the specific NT receptor nonpeptide antagonist SR-48,692 to rats attenuated colonic mucin secretion and mast cell activation following immobilization stress, indicating a critical role for NT in stress-related colonic responses (19).Clostridium difficile is the primary pathogenic factor of antibiotic-associated diarrhea in humans and animals The neuropeptide neurotensin mediates several intestinal functions, including chloride secretion, motility, and cellular growth. However, whether this peptide participates in intestinal inflammation is not known. Toxin A, an enterotoxin from Clostridium difficile, mediates pseudomembranous col...

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Direct evidence of mast cell involvement in Clostridium difficile toxin a—induced enteritis in mice☆☆☆

Cited by 114 publications

References 44 publications

Corticotropin-releasing hormone (CRH) requirement inClostridium difficiletoxin A-mediated intestinal inflammation

Corticotropin-releasing hormone (CRH) requirement inClostridium difficiletoxin A-mediated intestinal inflammation

The Comparative Pathology ofClostridium difficile-associated Disease

Neurotensin is a proinflammatory neuropeptide in colonic inflammation

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