Effect of IGF Blockade on Hyperoxia-Induced Lung Injury.
American journal of respiratory cell and molecular biology 2012 Apr 5; In press
Kim TH, Chow YH, Gill SE, Schnapp LM
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Hanyang University College of Medicine, Seoul, Washington, Korea, Republic of.
Insulin-like Growth Factor-1 (IGF-1) is increased in different models of acute lung injury and is an important determinant of survival and proliferation in many cells. We previously demonstrated that treatment of mice with IGF-1 Receptor blocking antibody (A12) improved early survival in bleomycin-induced lung injury. We now examined whether administration of A12 improved markers of lung injury in hyperoxia model of lung injury. C57BL/6 mice underwent i.p. administration of A12 or control antibody (KLH), then were exposed to 95% hyperoxia for 88-90h. Mice were sacrificed and bronchoalveolar lavage (BAL) and lung tissue were obtained for analysis. Hyperoxia caused a significant increase in IGF levels in BAL and lung lysates. Peripheral blood neutrophils expressed IGF-1R at baseline and after hyperoxia. BAL neutrophils from hyperoxia treated mice and patients with acute lung injury also expressed cell surface IGF-1R. A12-treated mice had significantly decreased PMN cell count in BAL compared to KLH control mice (p=0.02). BAL from A12 treated mice demonstrated decreased PMN chemotactic activity compared to BAL from KLH-treated mice. Pretreatment of PMN with A12 decreased their chemotactic response to BAL from hyperoxia-exposed mice. Furthermore, IGF-1 induced a dose-dependent chemotaxis of PMN. There were no difference in other chemotactic cytokines in BAL, including CXCL1, and CXCL2. In summary, IGF blockade decreased PMN recruitment to the alveolar space in mouse model of hyperoxia. Furthermore, decreased BAL PMN was at least partially due to a direct effect of A12 on PMN chemotaxis.