Angiostatin (ANG) Inhibits Acute Lung Inflammation in Mice

Abstract

ALI is characterized by the migration of activated neutrophils into lungs and causes significant mortality. Although necessary, activated neutrophils cause significant tissue damage and delay repair of inflamed lungs. Because the mechanisms of neutrophil migration and pathogenesis of ALI are not fully understood, we investigated effect of ANG in a mouse model of E. coli lipopolysaccharide (LPS) induced ALI. ANG expression was increased in inflamed lung extracts as well as BAL supernatant (P<0.007). ANG treatment of the LPS-treated mice decreased total cell counts, and protein concentration (P<0.05) but increased (P<0.05) apoptotic neutrophils in BAL and decreased (P<0.05) myeloperoxidase in lung extracts. The protein and mRNA expression of IL-1β, KC, MCP-1 and MIP-1α was not altered in LPS+ANG mice. Immunohistochemistry of lungs from LPS+ANG mice revealed a lack of staining for phosphorylated p38 MAPK. Time dependent phase contrast as well as diffraction enhanced imaging of live mice using synchrotron radiation (performed at Canadian Light Source facility) shows reduction in lung fluid accumulation in LPS+ANG treated mice when compared to LPS treated mice. We conclude that ANG expression is increased in inflamed lungs and exogenous ANG treatment inhibits neutrophil migration into the inflamed lungs, induces apoptosis in neutrophils and inhibits lung inflammation. ANG treatment may hasten repair processes in inflamed lungs. Grant Funding Source: NSERC Discovery Grant, CIHR, NRC