Blocking Pulmonary ICAM-1 Expression Ameliorates Lung Injury in Established Diet-Induced Pancreatitis

Abstract

ObjectiveTo determine whether blocking the cell surface expression of intracellular adhesion molecules (ICAM-1) in established severe acute pancreatitis (AP) would ameliorate pulmonary injury. Summary Background DataLung injury in AP is in part mediated by infiltrating leukocytes, which are directed to lung tissue by ICAM-l. The authors' laboratory has previously demonstrated that AP results in overproduction of inflammatory cytokines, upregulation of pulmonary ICAM-1 expression, and a concomitant infiltration of neutrophils, which results in lung injury. MethodsYoung female mice were fed a choline-deficient/ethioninesupplemented diet to induce AP and were treated with a blocking dose of monoclonal antibody specific to the ICAM-1 receptor. Antibody treatment was administered at 72, 96, and 120 hours after beginning the diet, and all animals were killed at 144 hours. The degree of pancreatitis was evaluated by serum biochemical and tumor necrosis factor ␣ levels as well as histology. The dual radiolabeled monoclonal antibody method was used to quantitate ICAM-1 cell surface expression in pulmonary tissue. Lung injury was assessed histologically and by determining lung microvascular permeability by measuring accumulated 125 I-radiolabeled albumin. Pulmonary neutrophil sequestration was determined by the myeloperoxidase assay. ResultsAll mice developed severe AP, and pancreatic injury was equally severe in both treated and untreated groups. Pulmonary ICAM-1 expression was significantly upregulated in animals with AP compared with controls. Treatment with a blocking dose of anti-ICAM-1 antibody after the induction of AP resulted 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 sequestration, and a decreased microvascular permeability by more than twofold. ConclusionsThese results demonstrate for the first time that treatment targeting the cell surface expression of ICAM-1 after the induction of AP ameliorates pulmonary injury, even in the face of severe pancreatic disease.

Treatment with bindarit, a blocker of MCP-1 synthesis, protects mice against acute pancreatitis

“…Depletion of circulating neutrophils with antineutrophil serum (9,22,23) or strategies that interfere with neutrophil migration, such as the use of a blocking antibody to ICAM-1 reduce neutrophil infiltration and pancreatic damage in acute pancreatitis (27,31).…”

Mechanical Stress Upregulates Intercellular Adhesion Molecule-1 in Pulmonary Epithelial Cells

“…Although ICAM-1 is expressed constitutively at low levels on multiple cell types, its expression can be significantly increased in the presence of inflammatory cytokines such as interleukin (IL)-1, tumor necrosis factor-α, and shear stress [12,13,14,15,16]. In the lung, this expression has been illustrated in several animal models of acute lung injury, in which inhibition of ICAM-1 expression with blocking antibodies decreases leukocyte recruitment and parameters of lung injury [17,18,19,20]. Research groups have found that ICAM-1 also exists on alveolar epithelium [21].…”

Involvement of Soluble Adhesion Molecules in Acute Pancreatitis

“…It was also found that the plasma levels of these soluble adhesion molecules reliably reflect the severity of disease, suggesting that they can serve as indicators. Anti-ICAM-1 antibody suppresses not only pancreatic damage, but also damage to the lungs which are located at a distance from the pancreas [13,14,21]. These results suggest that antibodies against adhesion molecules may be potentially useful in the treatment of acute pancreatitis.…”