Inhaled carbon monoxide suppresses the development of postoperative ileus in the murine small intestine.
OBJECTIVE
The induction of heme oxygenase (HO-1), the rate-limiting enzyme in heme metabolism, is protective against injury in acute and chronic inflammation. Inhalation of low levels of carbon monoxide (CO), a byproduct of heme metabolism, has anti-inflammatory effects equal to HO-1 induction. This study examined whether inhaled CO was protective against the development of postoperative ileus.


METHODS
Ileus was induced by surgical anesthesia and gentle manipulation of the mouse small intestine. Animals were exposed to CO (250 ppm) in air 1 hour before and continuously for 24 hours after surgery.


RESULTS
CO inhalation prevented the manipulation-induced suppression of circular muscle contractility in vitro, and significantly improved gastrointestinal transit in vivo. Proinflammatory messenger RNA (mRNA) expression (interleukin [IL]-6, IL-1beta, cyclooxygenase 2 [COX-2], inducible nitric oxide [iNOS]) and anti-inflammatory mediator expression (IL-10 and HO-1) were elevated 3 to 6 hours after surgery relative to controls. CO treatment reduced IL-1beta and iNOS peak expression by 75%, but not IL-6 or COX-2. In manipulated mice treated with CO, HO-1 expression peaked earlier (3 hours after surgery) and at levels 300% higher than in mice not exposed to CO. IL-10 expression at 3 hours also was 300% higher after CO treatment.


CONCLUSIONS
These findings suggest that CO attenuates postoperative ileus by inhibiting selective elements within the inflammatory cascade and by enhanced induction of the anti-inflammatory cytokine IL-10. In addition, the early and enhanced induction of HO-1 potentially amplifies the anti-inflammatory effects of the HO-1 pathway by protection from free radical stress and by increasing the tissue availability of CO directly at the sites of inflammation.
Moore
Beverley A
BA
Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh Medical Center, Pennsylvania 15261, USA.
Otterbein
Leo E
LE
Türler
Andreas
A
Choi
Augustine M K
AM
Bauer
Anthony J
AJ
D000005:Abdomen / Q000601:surgery*; D000280:Administration, Inhalation; D000818:Animals; D000893:Anti-Inflammatory Agents; D002248:Carbon Monoxide / Q000008:administration & dosage*; D051546:Cyclooxygenase 2; D016207:Cytokines / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1; D006651:Histocytochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics; D007415:Intestinal Obstruction / Q000209:etiology* / Q000517:prevention & control*; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009195:Peroxidase / Q000378:metabolism; D011183:Postoperative Complications; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D018836:Inflammation Mediators; D007527:Isoenzymes; D008565:Membrane Proteins; D016753:Interleukin-10; D002248:Carbon Monoxide; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases