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 pat hogenesis of hepatic reperfusion injury was investigated in an experim ental model. Male Fischer rats were treated with a CD11b monoclonal an tibody or an isotype-matched IgM control antibody and subjected to 45 min of hepatic ischemia followed by 24 hr of reperfusion. Large number s of neutrophils were present in postischemic liver lobes (1,241 +/- 6 4 polymorphonuclear cells/50 high-power fields) compared with numbers in baseline measurements (14 +/- 3 polymorphonuclear cells/50 high-pow er fields), and severe liver injury was observed after 24 hr of reperf usion (hepatic necrosis: 88% +/- 2%). Pretreatment with the CD11b anti body (two doses of 2 mg/kg each) significantly attenuated liver injury and reduced the number of polymorphonuclear cells in the postischemic liver by 59%. Selective treatment with the antibody only during reper fusion was similarly effective. The increased spontaneous superoxide f ormation of neutrophils isolated from postischemic liver (1.05 +/- 0.1 1 nmol O2-/hr/10(6) cells) was reduced by 56% in neutrophils from CD11 b antibody-treated animals. Flow cytometric analysis of CD11b/CD18 exp ression on circulating neutrophils demonstrated significant up-regulat ion at all time points during reperfusion. Clone 17 also effectively i nhibited neutrophil extravasation in a glycogen peritonitis model. Our data are consistent with a dual protective effect of the CD11b antibo dy in hepatic reperfusion injury in vivo (i.e., reduced accumulation o f neutrophils and their functional inactivation.