Neurokinin-1 (NK-1) receptor is required in Clostridium difficile- induced enteritis.
Toxin A, a 308,000-Mr enterotoxin from Clostridium difficile, mediates antibiotic-associated diarrhea and colitis in humans. Injection of toxin A into animal intestine triggers an acute inflammatory response characterized by activation of sensory neurons and immune cells of the intestinal lamina propria, including mast cells and macrophages, and migration of circulating neutrophils in the involved intestinal segment. In this study we show that mice genetically deficient in the neurokinin-1 receptor are protected from the secretory and inflammatory changes as well as from epithelial cell damage induced by toxin A. The protective effect of neurokinin-1R deletion correlates with diminished intestinal levels of the cytokine TNF-alpha and its mRNA and the leukocyte enzyme myeloperoxidase. These results demonstrate a major requirement for substance P receptors in the pathogenesis of acute inflammatory diarrhea.
Castagliuolo
I
I
Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Riegler
M
M
Pasha
A
A
Nikulasson
S
S
Lu
B
B
Gerard
C
C
Gerard
N P
NP
Pothoulakis
C
C
D000818:Animals; D001427:Bacterial Toxins / Q000633:toxicity; D016360:Clostridioides difficile / Q000472:pathogenicity*; D004761:Enterocolitis, Pseudomembranous / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D004768:Enterotoxins / Q000633:toxicity; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013373:Substance P / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D001427:Bacterial Toxins; D004768:Enterotoxins; D012333:RNA, Messenger; D018040:Receptors, Neurokinin-1; D014409:Tumor Necrosis Factor-alpha; C041348:tcdA protein, Clostridium difficile; D013373:Substance P