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- Title
Insulin-like growth factor-I receptor blockade improves outcome in mouse model of lung injury.
- Authors
Choi JE; Lee SS; Sunde DA; Huizar I; Haugk KL; Thannickal VJ; Vittal R; Plymate SR; Schnapp LM; Choi, Jung-Eun; Lee, Sung-Soon; Sunde, Donald A; Huizar, Isham; Haugk, Kathy L; Thannickal, Victor J; Vittal, Ragini; Plymate, Stephen R; Schnapp, Lynn M
- Abstract
<bold>Rationale: </bold>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.<bold>Objectives: </bold>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.<bold>Methods: </bold>Mice were treated with a monoclonal antibody against the IGF-I receptor (A12) or vehicle after intratracheal bleomycin instillation.<bold>Measurements and Main Results: </bold>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.<bold>Conclusions: </bold>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.
- Publication
American Journal of Respiratory & Critical Care Medicine, 2009, Vol 179, Issue 3, p212
- ISSN
1073-449X
- Publication type
journal article
- DOI
10.1164/rccm.200802-228OC