Carbon monoxide modulates endotoxin-induced microvascular leukocyte adhesion through platelet-dependent mechanisms.
BACKGROUND
Although precise mechanisms remain to be determined, recent studies show that heme oxygenase-1 (HO-1), providing endogenous carbon monoxide (CO) and bilirubin, serves as an antiinflammatory enzyme. This study aimed to clarify roles of CO in regulation of microvascular adhesion of platelets and leukocytes in endotoxemia.


METHODS
Rats pretreated with or without hemin were anesthetized with pentobarbital and received continuous infusion of endotoxin. Platelets labeled with carboxyfluorescein diacetate succinimidyl ester and leukocyte behavior in mesenteric venules were visualized using intravital ultra-high-speed intensified fluorescence videomicroscopy. To examine the mechanisms for the effects of HO-1 on platelet and leukocyte behavior during endotoxemia, these studies were repeated with superfusion of either CO, bilirubin, or zinc protoporphyrine-IX.


RESULTS
Endotoxin caused a marked depression of platelet velocity traversing along periendothelial regions, accompanied by augmented rolling and adhesion of leukocytes in venules. The endotoxin-elicited changes were attenuated by the HO-1 induction with hemin and restored by blockade of the enzyme activity with zinc protoporphyrine-IX, a potent inhibitor of HO-1. Such an inhibitory action of HO-1 on microvascular cell adhesion was reproduced by local superfusion of the buffer containing CO at micromolar concentrations. Such antiadhesive actions of CO on leukocytes disappeared under immunoneutralization of glycoprotein Ibalpha, an adhesion molecule against platelets, but not against leukocytes. Platelets isolated from hemin-treated rats increased their ability to generate CO and displayed lesser sensitivity of agonist-induced aggregation than those from controls.


CONCLUSIONS
These results suggest that CO desensitizes endotoxin-induced adhesive responses of leukocytes, mainly through its ability to ameliorate platelet activation.
Morisaki
Hiroshi
H
Department of Anesthesiology, Keio University School of Medicine, Tokyo, Japan. anesmrsk@sc.itc.keio.ac.jp
Katayama
Tomihiro
T
Kotake
Yoshifumi
Y
Ito
Masaharu
M
Handa
Makoto
M
Ikeda
Yasuo
Y
Takeda
Junzo
J
Suematsu
Makoto
M
D000818:Animals; D001663:Bilirubin / Q000097:blood; D001783:Blood Flow Velocity; D001792:Blood Platelets / Q000378:metabolism / Q000502:physiology*; D002196:Capillaries / Q000502:physiology; D002248:Carbon Monoxide / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects*; D004731:Endotoxins / Q000494:pharmacology*; D006419:Heme Oxygenase (Decyclizing) / Q000502:physiology; D007834:Lasers; D007962:Leukocytes / Q000187:drug effects*; D008297:Male; D010973:Platelet Adhesiveness / Q000187:drug effects; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012212:Rheology; D012542:Scattering, Radiation
D004731:Endotoxins; D019038:Platelet Glycoprotein GPIb-IX Complex; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); D001663:Bilirubin