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Insulin-like Growth Factor-I Receptor Blockade Improves Outcome in Mouse Model of Lung Injury

¹ Divison of Pulmonary and Critical Care Medicine, Department of Medicine, Harborview Medical Center, University of Washington, Seattle, Washington; ² Department of Medicine, Harborview Medical Center, University of Washington, and Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington; and ³ Divison of Pulmonary Medicine, Department of Medicine, University of Michigan Medical Center, Ann Arbor, Michigan

Correspondence and requests for reprints should be addressed to Lynn M. Schnapp, M.D., Box 358052, 815 Mercer Street, Seattle, WA 98109. E-mail: lschnapp{at}u.washington.edu

Rationale: The insulin-like growth factor-I (IGF-I) pathway is an important determinant of survival and proliferation in many cells. However, little is known about the role of the IGF-I pathway in lung injury. We previously showed elevated levels of IGF-I in bronchoalveolar lavage fluid from patients with acute respiratory distress syndrome. Furthermore, immunodepletion of IGF from acute respiratory distress syndrome bronchoalveolar lavage increased fibroblast apoptosis.

Objectives: We examined the effect of blockade of type 1 IGF tyrosine kinase receptor (IGF-IR) in a murine model of bleomycin-induced lung injury and fibrosis.

Methods: Mice were treated with a monoclonal antibody against the IGF-I receptor (A12) or vehicle after intratracheal bleomycin instillation.

Measurements and Main Results: Mice treated with A12 antibody had significantly improved survival after bleomycin injury compared with control mice. Both groups of mice had a similar degree of fibrosis on days 7 and 14, but by Day 28 the A12-treated group had significantly less fibrosis. Delayed treatment with A12 also resulted in decreased fibrosis. A12-treated mice had significantly decreased apoptotic cells on Day 28 compared with control mice. We confirmed that A12 treatment induced mouse lung fibroblast apoptosis in vitro. In addition, IGF-I increased lung fibroblast migration. The primary pathway activated by IGF-I in lung fibroblasts was the insulin receptor substrate-2/phosphatidylinositol 3-kinase/Akt axis.

Conclusions: IGF-I regulated survival and migration of fibrogenic cells in the lung. Blockade of the IGF pathway increased fibroblast apoptosis and subsequent resolution of pulmonary fibrosis. Thus, IGF-IR may be a potential target for treatment of lung injury and fibrosis.

Key Words: insulin-like growth factor • lung injury • lung fibrosis

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Insulin-like growth factor (IGF) levels have been shown to be elevated in early acute respiratory disease syndrome (ARDS) and decreased in late ARDS. However, it is unknown if decreased IGF contributed to the resolution of ARDS. What This Study Adds to the Field We found that an antibody against IGF-I receptor (IGF-IR) improved survival and resolution of fibrosis in bleomycin-treated mice. Thus, IGF-IR is a potential target for treatment of lung injury and fibrosis.