title: Effect of insulin-like growth factor blockade on hyperoxia-induced lung injury.
abstract: Insulin-like growth factor (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 have now examined whether administration of A12 improved markers of lung injury in hyperoxia model of lung injury. C57BL/6 mice underwent intraperitoneal administration of A12 or control antibody (keyhole limpet hemocyanin [KLH]), then were exposed to 95% hyperoxia for 88-90 hours. Mice were killed 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 polymorphonuclear cell (PMN) count in BAL compared with KLH control mice (P = 0.02). BAL from A12-treated mice demonstrated decreased PMN chemotactic activity compared with BAL from KLH-treated mice. Pretreatment of PMNs with A12 decreased their chemotactic response to BAL from hyperoxia-exposed mice. Furthermore, IGF-1 induced a dose-dependent chemotaxis of PMNs. There were no differences in other chemotactic cytokines in BAL, including CXCL1 and CXCL2. In summary, IGF blockade decreased PMN recruitment to the alveolar space in a mouse model of hyperoxia. Furthermore, the decrease in BAL PMNs was at least partially due to a direct effect of A12 on PMN chemotaxis.
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Hanyang University College of Medicine, Seoul, Korea.
authors.forename: Tae-Hyung
authors.initials: TH
authors.lastname: Kim
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Chow
authors.forename: Sean E
authors.initials: SE
authors.lastname: Gill
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Schnapp
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D002634:Chemotaxis, Leukocyte; D016207:Cytokines / Q000378:metabolism; D005260:Female; D018496:Hyperoxia / Q000150:complications*; D055370:Lung Injury / Q000209:etiology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D013002:Somatomedins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D016207:Cytokines; D013002:Somatomedins