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MUSCLE CELL BIOLOGY AND CELL MOTILITY

Production of IL-1, hydrogen peroxide, and nitric oxide by colonic mucosa decreases sigmoid smooth muscle contractility in ulcerative colitis

¹Department of Medicine and ²Department of Surgery, Rhode Island Hospital and Brown Medical School, Providence, Rhode Island; ³Division of Gastroenterology, Case Western Reserve University School of Medicine, Cleveland, Ohio

Submitted 18 February 2005 ; accepted in final form 15 July 2005

We have previously shown that sigmoid circular muscle cells from patients with ulcerative colitis (UC) exhibit reduced contraction and Ca²⁺ signaling in response to the neurotransmitter neurokinin A (NKA) and that IL-1 and H₂O₂ may contribute to these reduced responses in UC. In addition, we have found that nitric oxide (NO) levels were significantly increased in UC circular muscle. To establish the site of origin for IL-1, H₂O₂, and NO, we assembled an in vitro system in which normal or UC mucosa were sealed between two chambers filled with oxygenated Krebs solution. Because the mucosa consists of full-thickness mucosa and submucosa, it is expected that whatever is released into the undernatant from the submucosal side may diffuse to the circular muscle layer in the intact colon. Treatment of normal sigmoid circular muscle cells for 2 h with undernatants collected from the UC submucosal side (UCS) significantly decreased contraction induced by NKA and thapsigargin and the NKA- and caffeine-induced Ca²⁺ signal in Ca²⁺-free medium. In addition, UC mucosa released into the undernatant on its submucosal side significantly more H₂O₂, IL-1, and NO than normal mucosa. The reduction in contraction and Ca²⁺ signal induced by UCS was partially reversed by pretreatment with an IL-1 antibody or with catalase. The NO scavenger hemoglobin partially prevented UCS-induced reduction in contraction and Ca²⁺ signaling in response to NKA but not the reduced response to thapsigargin or caffeine. Sodium nitroprusside inhibited NKA but not the caffeine-induced Ca²⁺ signal. We conclude that in UC the mucosa releases IL-1, H₂O₂, and NO, which may contribute to the impaired Ca²⁺ release and altered sigmoid muscle contractility.

neurokinin A; calcium; human; colon

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