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Am. J. Respir. Crit. Care Med., Volume 161, Number 3, March 2000, 1022-1029

Inhibition of CD11-CD18 Complex Prevents Acute Lung Injury and Reduces Mortality after Peritonitis in Rabbits

MARCO GARDINALI, EMMA BORRELLI, OSVALDO CHIARA, CLAES LUNDBERG, PIETRO PADALINO, LUISA CONCIATO, CRISTINA CAFARO, STEFANO LAZZI, PIETRO LUZI, PIER PAOLO GIOMARELLI, and ANGELO AGOSTONI

Dipartimento di Medicina Interna and Istituto di Chirurgia d'Urgenza, IRCCS Ospedale Policlinico, Università di Milano, Milano; Istituto di Chirurgia Toracica e Cardiovascolare and Istituto di Istologia ed Anatomia Patologica, Università di Siena, Siena, Italy; and Läkemedelsverket Medical Products Agency, Üppsala, Sweden

Acute lung injury is frequent after severe peritonitis. The aim of this study was to investigate whether inhibition of the adhesion molecule CD11-CD18 on polymorphonuclear leukocytes (PMNs) would have any beneficial effects on pulmonary function and mortality in an animal model reproducing these clinical conditions. Acute peritonitis was induced in 36 rabbits by intraperitoneal injection of zymosan (0.6 g/kg) suspended in mineral oil; 20 were pretreated with a murine-specific IgG2a anti-CD18 monoclonal antibody, 16 (controls) with nonspecific purified murine IgG (1 mg/kg). The animals were followed 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), white blood cell (WBC), and platelet counts, pH, PO2, PCO2, carbon dioxide content (HCO3-) measurements, and renal and liver tests. Treatment with the anti-CD18 monoclonal antibody reduced mortality by approximately 40% (p < 0.05). PO2 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 animals had significant leukopenia, whereas anti-CD18-treated animals had a moderate increase of the number of circulating WBC compared with baseline values (p < 0.05 between groups). The lungs of the anti-CD18-treated animals showed minor signs of inflammation and PMN infiltration whereas controls had interstitial and intra-alveolar edema and a large number of granulocytes. Quantification of PMNs by morphometry showed that there were constantly less granulocytes in the lungs of the animals treated with the anti-CD18 antibody (p < 0.001). PMN infiltration correlated with the levels of PO2 (p < 0.001). Lung tissue of anti-CD18-treated rabbits contained less malonyldialdehyde, 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 the antioxidant alpha -tocopherol (136 ± 22 versus 40 ± 9 ng/mg of protein), than the control rabbits (p < 0.01). In this particular model of ARDS the monoclonal antibody against the CD11-CD18 complex had a beneficial effect, reducing PMN infiltration and oxygen radical release in the lungs, preventing alveolocapillary membrane damage, improving gas exchange and, finally, significantly reducing mortality. Gardinali M, Borrelli E, Chiara O, Lundberg C, Padalino P, Conciato L, Cafaro C, Lazzi S, Luzi P, Giomarelli PP, Agostoni A. Inhibition of CD11-CD18 complex prevents acute lung injury and reduces mortality after peritonitis in rabbits.




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