Mechanisms of acute inflammatory lung injury induced by abdominal sepsis

Sequestration of neutrophils and release of histotoxic mediators are consid ered important for the development of pathologic alterations of the lung de fined as adult respiratory distress syndrome. Mechanisms of inflammatory lu ng injury caused by abdominal sepsis were investigated using the colon asce ndens stent peritonitis (CASP) model that closely mimics the human disease. In the GASP model, a continuous leakage of intraluminal bacteria into the peritoneal cavity is induced by implantation of a stent in the ascending co lon, generating a septic focus. In contrast to the cecal ligation and punct ure model of peritonitis, survival of mice following GASP surgery is depend ent on IFN-gamma, but independent of tumor necrosis factor (TNF). Here we s how that the systemic inflammation induced by GASP surgery results in a rap id and profound increase of lung vascular permeability that was associated with the activation and recruitment of neutrophils to the lung. Activation of circulating granulocytes was characterized by increased production of se rine proteinases and reactive oxygen metabolites, as well as elevated expre ssion of cell surface Mac-1. Expression of MIP-2, KC, MIP-1 alpha and E-sel ectin mRNA in lung was strongly increased within 3 h following GASP surgery , whereas up-regulation of IP-10, MCP-1 and P-selectin was delayed. In cont rast, induction of RANTES, LIX, ICAM-1 and VCAM-1 mRNA was weak or not dete ctable after GASP surgery. Importantly, recruitment of leukocytes to the lu ng was normal in lipopolysaccharide-resistant mice, and was not affected by antibody neutralization of TNF or the chemokines MIP-2 and KC.