Blocking pulmonary ICAM-1 expression ameliorates lung injury in established diet-induced pancreatitis

Objective To determine whether blocking the cell surface expression of intr acellular adhesion molecules (ICAM-1) in established severe acute pancreati tis (AP) would ameliorate pulmonary injury. Summary Background Data Lung injury in AP is in part mediated by infiltrati ng leukocytes, which are directed to lung tissue by ICAM-1. The authors' la boratory has previously demonstrated that AP results in overproduction of i nflammatory cytokines, upregulation of pulmonary ICAM-1 expression, and a c oncomitant infiltration of neutrophils, which results in lung injury. Methods Young female mice were fed a choline-deficient/ethionine-supplement ed diet to induce AP and were treated with a blocking dose of monoclonal an tibody specific to the ICAM-1 receptor. Antibody treatment was administered at 72, 96, and 120 hours after beginning the diet, and all animals were ki lled at 144 hours. The degree of pancreatitis was evaluated by serum bioche mical and tumor necrosis factor cu levels as well as histology. The dual ra diolabeled monoclonal antibody method was used to quantitate ICAM-1 cell su rface expression in pulmonary tissue. Lung injury was assessed histological ly and by determining lung microvascular permeability by measuring accumula ted I-125-radiolabeled albumin. Pulmonary neutrophil sequestration was dete rmined by the myeloperoxidase assay. Results All mice developed severe AP, and pancreatic injury was equally sev ere in both treated and untreated groups. Pulmonary ICAM-1 expression was s ignificantly upregulated in animals with AP compared with controls. Treatme nt with a blocking dose of anti-ICAM-1 antibody after the induction of AP r esulted in inhibited ICAM-1 cell surface expression to near control levels. Compared to untreated animals with AP, mice treated with anti-ICAM-1 mice had significantly reduced histologic lung injury and neutrophil sequestrati on, and a decreased microvascular permeability by more than twofold. Conclusions These results demonstrate for the first time that treatment tar geting the cell surface expression of ICAM-1 after the induction of AP amel iorates pulmonary injury, even in the face of severe pancreatic disease.