Inhalation of carbon monoxide prevents liver injury and inflammation following hind limb ischemia/reperfusion.
The induction of heme oxygenase (HO), the rate limiting enzyme in the conversion of heme into carbon monoxide (CO) and biliverdin, limits liver injury following remote trauma such as hind limb ischemia/reperfusion (I/R). Using intravital video microscopy, we tested the hypothesis that inhaled CO (250 ppm) would mimic HO-derived liver protection. Hind limb I/R significantly decreased sinusoidal diameter and volumetric flow, increased leukocyte accumulation within sinusoids, increased leukocyte rolling and adhesion within postsinusoidal venules, and significantly increased hepatocyte injury compared with naive animals. Inhalation of CO alone did not alter any microcirculatory or inflammatory parameters. Inhalation of CO following I/R restored volumetric flow, decreased stationary leukocytes within sinusoids, decreased leukocyte rolling and adhesion within postsinusoidal venules, and significantly reduced hepatocellular injury following hind limb I/R. HO inhibition did not alter microcirculatory parameters in naive mice, but did increase inflammation, as well as increase hepatocyte injury following hind limb I/R. Inhalation of CO during HO inhibition significantly reduced such microcirculatory deficits, hepatic inflammation, and injury in response to hind limb I/R. In conclusion, these results suggest that HO-derived hepatic protection is mediated by CO, and inhalation of low concentrations of CO may represent a novel therapeutic approach to prevent remote organ injury during systemic inflammatory response syndrome, or SIRS.
Ott
Michael C
MC
Victoria Research Lab, 6th Floor, Rm. A6-105, 800 Commissioners Rd., London, ON, Canada N6A 4G4. rpotter@uwo.ca.
Scott
Jeffrey R
JR
Bihari
Aurelia
A
Badhwar
Amit
A
Otterbein
Leo E
LE
Gray
Daryl K
DK
Harris
Kenneth A
KA
Potter
Richard F
RF
D000280:Administration, Inhalation; D000818:Animals; D002248:Carbon Monoxide / Q000008:administration & dosage / Q000494:pharmacology*; D004790:Enzyme Induction / Q000502:physiology; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis / Q000378:metabolism; D006504:Hepatic Veno-Occlusive Disease / Q000209:etiology / Q000517:prevention & control*; D006505:Hepatitis / Q000517:prevention & control*; D006614:Hindlimb / Q000098:blood supply* / Q000473:pathology*; D001239:Inhalation / Q000502:physiology*; D008099:Liver / Q000098:blood supply* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015427:Reperfusion Injury / Q000150:complications*
D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing)