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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

A Single Intraperitoneal Dose of Carbon Monoxide-Saturated Ringer's Lactate Solution Ameliorates Postoperative Ileus in Mice

Thomas E. Starzl Transplantation Institute (A.N., K.T., N.M.), Department of Medicine (J.S., B.S., A.J.B.), Department of Critical Care Medicine (T.H., R.J.C., M.P.F.), and Department of Surgery (A.T., J.K., X.P.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Treatment with inhaled carbon monoxide (CO) has been shown to ameliorate bowel dysmotility caused by surgical manipulation of the gut in experimental animals. We hypothesized that administration of CO dissolved in lactated Ringer's solution (CO-LR) might provide similar protection to that observed with the inhaled gas while obviating some of its inherent problems. Postoperative gut dysmotility (ileus) was induced in mice by surgical manipulation of the small intestine. Some mice were treated with a single intraperitoneal dose of CO-LR immediately after the surgical procedure, whereas other mice received only the LR vehicle. Twenty-four hours later, intestinal transit of a nonabsorbable marker (70-kDa fluorescein isothiocyanate-labeled dextran) was delayed in mice subjected to intestinal manipulation but not the sham procedure. Gut manipulation also was associated with increased expression within the muscularis propria of transcripts for interleukin-1, cyclooxygenase-2, inducible nitric-oxide synthase, intracellular adhesion molecule-1, and Toll-like receptor-4, as well as infiltration of the muscularis propria with polymorphonuclear leukocytes and activation of mitogen-activated protein kinases and nuclear factor-B. All of these effects were attenuated by treatment with CO-LR. The salutary effect of CO-LR on gut motility, as well as many of the anti-inflammatory effects of CO-LR, was diminished by treatment with a soluble guanylyl cyclase (sGC) inhibitor, suggesting that the effects of CO are mediated via activation of sGC. These data support the view that a single intraperitoneal dose of CO-LR ameliorates postoperative ileus in mice by inhibiting the inflammatory response in the gut wall induced by surgical manipulation, possibly in a sGC-dependent fashion.

Address correspondence to: Dr. Mitchell P. Fink, Department of Critical Care Medicine, 615 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261. E-mail: finkmp{at}ccm.upmc.edu

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