Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pseudomembranous colitis is most often caused by toxins secreted by Clostridium difficile following bowel flora overgrowth after antibiotic use. The secretory and inflammatory effects observed in C. difficile toxin A-induced enterocolitis in the rat ileum are inhibited by CP-96,345, a substance P (SP) receptor antagonist. To determine if SP plays a role in the pathogenesis of human pseudomembranous colitis, SP receptor distribution was examined in a toxin A-positive specimen of bowel. Quantitative receptor autoradiography was used to examine SP receptors in tissue from a patient who tested positive for C. Difficile toxin. SP receptors were massively increased in small blood vessels and lymphoid aggregates in the pseudomembranous colitis bowel in comparison to control specimens. The SP binding was saturable and exhibited similar affinities for SP and CP-96,345. SP may contribute to the inflammatory response in pseudomembranous colitis via a massive increase in SP receptor antagonists may offer a novel therapeutic intervention for pseudomembranous colitis.
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PMID:Increased substance P receptor expression by blood vessels and lymphoid aggregates in Clostridium difficile-induced pseudomembranous colitis. 861 45

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 colitis in humans. In animal models, toxin A causes an acute inflammatory response characterized by activation of sensory neurons and intestinal nerves and immune cells of the lamina propria. Here we show that neurotensin and its receptor are elevated in the rat colonic mucosa following toxin A administration. Pretreatment of rats with the neurotensin receptor antagonist SR-48, 692 inhibits toxin A-induced changes in colonic secretion, mucosal permeability, and histologic damage. Exposure of colonic explants to toxin A or neurotensin causes mast cell degranulation, which is inhibited by SR-48,692. Because substance P was previously shown to mediate mast cell activation, we examined whether substance P is involved in neurotensin-induced mast cell degranulation. Our results show that neurotensin-induced mast cell degranulation in colonic explants is inhibited by the substance P (neurokinin-1) receptor antagonist CP-96,345, indicating that colonic mast activation in response to neurotensin involves release of substance P. We conclude that neurotensin plays a key role in the pathogenesis of C. difficile-induced colonic inflammation and mast cell activation.
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PMID:Neurotensin is a proinflammatory neuropeptide in colonic inflammation. 1007 5

Clostridium difficile is a spore forming, gram-positive anaerobic bacillus first described in 1935 by Hall and O'Toole as a commensal organism in the fecal flora of healthy newborn infants (1). The organism was given its unusual name because it grew slowly and was difficult to isolate in pure culture. Its presence in the stool of healthy neonates suggested that C. difficile was a nonpathogen, even though it produced toxins in broth culture. Following its original description, C. difficile passed quickly into relative obscurity in the 1960's and 1970's when antibiotic-associated pseudomembranous colitis became prevalent following the introduction into clinical practice of broad spectrum antibiotics. The frequent association of clindamycin and lincomycin therapy with pseudomembranous colitis led to the term "clindamycin colitis" (2). A breakthrough occurred in 1978 when C. difficile was identified as the source of a cytotoxin in the stool of patients with pseudomembranous colitis (3). During the two decades since its rediscovery, a great deal has been learned about the pathophysiology, epidemiology and management of C. difficile infection, yet many challenges remain. Currently this organism infects over 30% of individuals admitted to United States hospitals, making C. difficile colitis one of the most common nosocomial infections (4). It is estimated that approximately 10-12 million adults are infected with this organism each year in the United States, about a third of whom become symptomatic. The disease burden in the elderly is particularly severe as they are hospitalized more frequently and for longer duration. The pathophysiology of C. difficile diarrhea requires alteration of the colonic microflora by antibiotics, colonization by C. difficile, and release of two potent enterotoxins designated A and B (5). The toxins of Clostridium difficile are required virulence factors in both animals and humans since non-toxigenic strains do not cause disease. Recent cloning and sequencing of the toxin genes reveals extensive amino acid homology between them that is reflected in common molecular and cellular mechanisms. Both toxins damage cells by modifying the rho family of proteins, key regulators of cellular actin. C. difficile infection causes a florid acute inflammatory response seen in patients with pseudomembranous colitis. It is now realized that neurons and immune cells of the lamina propria are major determinants of toxin-induced diarrhea and mucosal damage. Early critical events following toxin exposure are release of the neuropeptides substance P and calcitonin gene related peptide (CGRP) from sensory afferent neurons and activation of lamina propria macrophages and intestinal mast cells. These peptides in turn release a complex cascade of other inflammatory mediators from lamina propria cells (5). The importance of the host immune response, specifically serum IgG directed against toxin A, is now recognized as a critical determinant of disease expression in man.
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PMID:Theodore E. Woodward Award. How bacterial enterotoxins work: insights from in vivo studies. 1205 8