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Am J Physiol Gastrointest Liver Physiol 286: G225-G233, 2004; doi:10.1152/ajpgi.00447.2002
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INFLAMMATION/IMMUNITY/MEDIATORS

Induced nitric oxide promotes intestinal inflammation following hemorrhagic shock

Christian Hierholzer,1 Jörg C. Kalff,1 Timothy R. Billiar,1 Anthony J. Bauer,2 David J. Tweardy,3 and Brian G. Harbrecht1

1Departments of Surgery and Medicine and 2Division of Gastroenterology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213; and 3Department of Medicine, Baylor College of Medicine, Houston, Texas 77030

Submitted 18 October 2002 ; accepted in final form 15 August 2003

In hemorrhagic shock (HS), increased cytokine production contributes to tissue inflammation and injury through the recruitment of neutrophils [polymorphonuclear cells (PMN)]. HS stimulates the early expression of inducible nitric oxide synthase (iNOS) that modulates proinflammatory activation after hemorrhage. Experiments were performed to determine the contribution of iNOS to gut inflammation and dysmotility after HS. Rats subjected to HS (mean arterial pressure 40 mmHg for 2.5 h followed by resuscitation and death at 4 h) demonstrated histological signs of mucosal injury, impairment of intestinal smooth muscle contractility, extravasation of PMN, and increased gut mRNA levels of ICAM-1, IL-6, and granulocyte colony-stimulating factor (G-CSF). In addition, DNA binding activity of NF-{kappa}B and Stat3, an IL-6 signaling intermediate, was significantly increased. In shocked rats treated with the selective iNOS inhibitor L-N6-(1-iminoethyl)lysine at the time of resuscitation, histological signs of intestinal injury and PMN infiltration were reduced and muscle contractility was almost completely restored. Selective iNOS inhibition in shocked animals reduced the binding activity of NF-{kappa}B and Stat3 and reduced mRNA levels of ICAM-1, IL-6, and G-CSF. The results of studies using iNOS knockout mice subjected to HS were similar. We propose that early upregulation of iNOS contributes to the inflammatory response in the gut wall and participates in the activation of signaling cascades and cytokine expression that regulate intestinal injury, PMN recruitment, and impaired gut motility.

nuclear factor-{kappa}B; cytokines; intestinal function; ileus


Address for reprint requests and other correspondence: B. G. Harbrecht, Univ. of Pittsburgh Medical Center, F1264-200 Lothrop St., Pittsburgh, PA 15213 (E-mail: harbrechtbg{at}msx.upmc.edu).




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