Inhibition of CD11-CD18 complex prevents acute lung injury and reduces mortality after peritonitis in rabbits

Acute lung injury is frequent after severe peritonitis. The aim of this stu dy was to investigate whether inhibition of the adhesion molecule CD11-CD18 on polymorphonuclear leukocytes (PMNs) would have any beneficial effects o n pulmonary function and mortality in an animal model reproducing these cli nical conditions. Acute peritonitis was induced in 36 rabbits by intraperit oneal injection of zymosan (0.6 g/kg) suspended in mineral oil; 20 were pre treated with a murine-specific IgG2a anti-CD18 monoclonal antibody, 46 (con trols) with nonspecific purified murine Ige (1 mg/kg), The animals were fol lowed for 10 d, then killed for histologic examination of the lungs, blood samples were taken on Days 0, 1, 3, 7 and 10 for red blood cell (RBC), whit e blood cell (WBC), and platelet counts, pH, Po-2, Pco(2), carbon dioxide c ontent (HCO3-) measurements, and renal and liver tests. Treatment with the anti-CD18 monoclonal antibody reduced mortality by approximately 40% (p < 0 .05). Po-2 was higher in these treated animals than in the control animals throughout the study (p < 0.05 on Day 1, 3, and 10). On Day 1 control anima ls had significant leukopenia, whereas anti-CD18-treated animals had a mode rate increase of the number of circulating WBC compared with baseline value s (p < 0.05 between groups). The lungs of the anti-CD18-treated animals sho wed minor signs of inflammation and PMN infiltration whereas controls had i nterstitial and intra-alveolar edema and a large number of granulocytes. Qu antification of PMNs by morphometry showed that there were constantly less granulocytes in the lungs of the animals treated with the antl-CD18 antibod y (p< 0.001), PMN infiltration correlated with the levels of Po-2 (p < 0.00 1). Lung tissue of anti-CD18-treated rabbits contained less malonyldialdehy de, a by-product of membrane lipid peroxidation by PMN oxygen radicals (950 +/- 120 versus 1,710 +/- 450 pM/mg of protein) and, conversely, more of th e antioxidant cr-tocopherol (136 +/- 22 versus 40 +/- 9 ng/mg of protein), than the control rabbits (p < 0.01). In this particular model of ARDS the m onoclonal antibody against the CD11-CD18 complex had a beneficial effect, r educing PMN infiltration and oxygen radical release in the lungs, preventin g alveolocapillary membrane damage, improving gas exchange and, finally, si gnificantly reducing mortality.