Functional inactivation of neutrophils with a Mac-1 (CD11b/CD18) monoclonal antibody protects against ischemia-reperfusion injury in rat liver.
The role of neutrophil CD11b/CD18 (Mac-1) adhesion proteins in the pathogenesis of hepatic reperfusion injury was investigated in an experimental model. Male Fischer rats were treated with a CD11b monoclonal antibody or an isotype-matched IgM control antibody and subjected to 45 min of hepatic ischemic followed by 24 hr of reperfusion. Large numbers of neutrophils were present in postischemic liver lobes (1,241 +/- 64 polymorphonuclear cells/50 high-power fields) compared with numbers in baseline measurements (14 +/- 3 polymorphonuclear cells/50 high-power fields), and severe liver injury was observed after 24 hr of reperfusion (hepatic necrosis: 88% +/- 2%). Pretreatment with the CD11b antibody (two doses of 2 mg/kg each significantly attenuated liver injury and reduced the number of polymorphonuclear cells in the post-ischemic liver by 59%. Selective treatment with the antibody only during reperfusion was similarly effective. The increased spontaneous superoxide formation of neutrophils isolated from postischemic liver (1.05 +/- 0.11 nmol O2-/hr/10(6) cells) was reduced by 56% in neutrophils from CD11b antibody-treated animals. Flow cytometric analysis of CD11b/CD18 expression on circulating neutrophils demonstrated significant upregulation at all time points during reperfusion. Clone 17 also effectively inhibited neutrophil extravasation in a glycogen peritonitis model. Our data are consistent with a dual protective effect of the CD11b antibody in hepatic reperfusion injury in vivo (i.e., reduced accumulation of neutrophils and their functional inactivation).
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030.
H
H
Jaeschke
A
A
Farhood
A P
AP
Bautista
Z
Z
Spolarics
J J
JJ
Spitzer
C W
CW
Smith
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D007511:Ischemia / Q000150:complications*; D008099:Liver / Q000098:blood supply*; D016177:Macrophage-1 Antigen / Q000502:physiology*; D008297:Male; D009504:Neutrophils / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D015427:Reperfusion Injury / Q000209:etiology / Q000517:prevention & control*; D013481:Superoxides / Q000378:metabolism
D000911:Antibodies, Monoclonal; D016177:Macrophage-1 Antigen; D013481:Superoxides