Heme oxygenase modulates hepatic leukocyte sequestration via changes in sinusoidal tone in systemic inflammation in mice.
Heme oxygenase (HO) modulates the accumulation of leukocytes within the liver during the early stages of a systemic inflammatory response syndrome (SIRS), but the anti-inflammatory mechanism(s) remain to be tested. The influence of HO on the adhesion molecule expression within the liver and on circulating leukocytes was assessed. In addition, the effect of HO and nitric oxide synthase (NOS) on the liver microcirculation was tested. Mice were subjected to 1 h bilateral hindlimb ischemia followed by 3 h of reperfusion, at which time blood samples and the liver were harvested and adhesion molecule expression determined (ICAM-1, CD49d and CD11b). Direct measures of sinusoidal diameter and estimates of volumetric blood flow were obtained using intravital microscopy. HO was specifically induced and inhibited by hemin and chromium mesoporphyrin (CrMP), respectively, whereas NOS was inhibited by N-nitro-L-arginine methyl ester (L-NAME). ICAM-1 expression was increased following hindlimb ischemia-reperfusion. Hemin caused only a modest, but significant decrease in ICAM-1 expression, whereas inhibition of HO had no effect. However, HO inhibition significantly reduced sinusoidal diameters and volumetric flow and such vessels were correlated with significantly increased numbers of stationary leukocytes. Inhibition of NOS had no effect on sinusoidal diameter or volumetric flow. In conclusion, the anti-inflammatory benefits afforded by HO activity within the liver appear to involve the control of sinusoidal diameter and volumetric blood flow rather than altered adhesion molecule expression during the early stages of SIRS.
Wunder
Christian
C
Klinik und Poliklinik für Anästhesiologie, Julius-Maximilians-Universität, Würzburg, Germany. christian.wunder@mail.uni-wuerzburg.de
Scott
Jeffrey R
JR
Lush
Cameron W
CW
Brock
Robert W
RW
Bihari
Aurelia
A
Harris
Kenneth
K
Eichelbrönner
Otto
O
Potter
Richard F
RF
D000818:Animals; D039481:CD11b Antigen / Q000096:biosynthesis; D002448:Cell Adhesion; D006419:Heme Oxygenase (Decyclizing) / Q000502:physiology*; D006427:Hemin / Q000378:metabolism; D007249:Inflammation / Q000097:blood* / Q000378:metabolism; D039441:Integrin alpha4 / Q000096:biosynthesis; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007962:Leukocytes / Q000378:metabolism*; D008099:Liver / Q000098:blood supply / Q000378:metabolism*; D008297:Male; D008652:Mesoporphyrins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D015427:Reperfusion Injury; D013997:Time Factors
D039481:CD11b Antigen; D008652:Mesoporphyrins; C427471:chromium mesoporphyrin; D018799:Intercellular Adhesion Molecule-1; D039441:Integrin alpha4; D009569:Nitric Oxide; D006427:Hemin; D019001:Nitric Oxide Synthase; D006419:Heme Oxygenase (Decyclizing); D019331:NG-Nitroarginine Methyl Ester