title: Low-dose inhaled carbon monoxide attenuates the remote intestinal inflammatory response elicited by hindlimb ischemia-reperfusion.
abstract: Heme oxygenase (HO) represents the rate-limiting enzyme in the degradation of heme into carbon monoxide (CO), iron, and biliverdin. Recent evidence suggests that several of the beneficial properties of HO, may be linked to CO. The objectives of this study were to determine if low-dose inhaled CO reduces remote intestinal leukocyte recruitment, proinflammatory cytokine expression, and oxidative stress elicited by hindlimb ischemia-reperfusion (I/R). Male mice underwent 1 h of hindlimb ischemia, followed by 3 h of reperfusion. Throughout reperfusion, mice were exposed to AIR or AIR + CO (250 ppm). Following reperfusion, the distal ileum was exteriorized to assess the intestinal inflammatory response by quantifying leukocyte rolling and adhesion in submucosal postcapillary venules with the use of intravital microscopy. Ileum samples were also analyzed for proinflammatory cytokine expression [tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta] and malondialdehyde (MDA) with the use of enzyme-linked immunosorbent assay and thiobarbituric acid reactive substances assays, respectively. I/R + AIR led to a significant decrease in leukocyte rolling velocity and a sevenfold increase in leukocyte adhesion. This was also accompanied by a significant 1.3-fold increase in ileum MDA and 2.3-fold increase in TNF-alpha expression. Treatment with AIR + CO led to a significant reduction in leukocyte recruitment and TNF-alpha expression elicited by I/R; however, MDA levels remained unchanged. Our data suggest that low-dose inhaled CO selectively attenuates the remote intestinal inflammatory response elicited by hindlimb I/R, yet does not provide protection against intestinal lipid peroxidation. CO may represent a novel anti-inflammatory therapeutic treatment to target remote organs following acute trauma and/or I/R injury.
authors.affiliation: Dept. of Medical Biophysics and Surgery, Univ. of Western Ontario, Centre for Critical Illness Research, London Health Sciences Centre, Victoria Hospital, Rm A6-132, London, Ontario, Canada N6A 4G5.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Scott
authors.forename: Mark A
authors.initials: MA
authors.lastname: Cukiernik
authors.forename: Michael C
authors.initials: MC
authors.lastname: Ott
authors.forename: Aurelia
authors.initials: A
authors.lastname: Bihari
authors.forename: Amit
authors.initials: A
authors.lastname: Badhwar
authors.forename: Daryl K
authors.initials: DK
authors.lastname: Gray
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Harris
authors.forename: Neil G
authors.initials: NG
authors.lastname: Parry
authors.forename: Richard F
authors.initials: RF
authors.lastname: Potter
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D002248:Carbon Monoxide / Q000008:administration & dosage*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005765:Gastrointestinal Agents / Q000008:administration & dosage*; D006614:Hindlimb; D007079:Ileitis / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D053583:Interleukin-1beta / Q000378:metabolism; D036904:Leukocyte Rolling / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000187:drug effects; D018482:Muscle, Skeletal / Q000098:blood supply*; D018384:Oxidative Stress / Q000187:drug effects; D015427:Reperfusion Injury / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D018746:Systemic Inflammatory Response Syndrome / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D005765:Gastrointestinal Agents; D053583:Interleukin-1beta; D017392:Thiobarbituric Acid Reactive Substances; D014409:Tumor Necrosis Factor-alpha; D008315:Malondialdehyde; D002248:Carbon Monoxide