Functional inactivation of neutrophils with a Mac-1 (CD11b/CD18) monoclonal antibody protects against ischemia-reperfusion injury in rat liver

• Published in: Hepatology (Baltimore, Md.) Vol. 17; no. 5; p. 915
• Main Authors: Jaeschke, H, Farhood, A, Bautista, A P, Spolarics, Z, Spitzer, J J, Smith, C W
• Format: Journal Article
• Language: English
• Published: United States 01.05.1993
• Subjects: Animals; Antibodies, Monoclonal - immunology; Ischemia - complications; Liver - blood supply; Macrophage-1 Antigen - physiology; Male; Neutrophils - physiology; Rats; Rats, Inbred F344; Reperfusion Injury - etiology; Reperfusion Injury - prevention & control; Superoxides - metabolism
• ISSN: 0270-9139
• DOI: 10.1002/hep.1840170523

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).