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).
Jaeschke
H
H
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030.
Farhood
A
A
Bautista
A P
AP
Spolarics
Z
Z
Spitzer
J J
JJ
Smith
C W
CW
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