| Insulin-like growth factor-I receptor blockade improves outcome in mouse model of lung injury. | |
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MedLine Citation:
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PMID: 19011156 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Jung-Eun Choi; Sung-Soon Lee; Donald A Sunde; Isham Huizar; Kathy L Haugk; Victor J Thannickal; Ragini Vittal; Stephen R Plymate; Lynn M Schnapp |
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Publication Detail:
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Type: Comparative Study; Journal Article Date: 2008-11-14 |
Journal Detail:
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Title: American journal of respiratory and critical care medicine Volume: 179 ISSN: 1535-4970 ISO Abbreviation: Am. J. Respir. Crit. Care Med. Publication Date: 2009 Feb |
Date Detail:
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Created Date: 2009-01-22 Completed Date: 2009-03-04 Revised Date: 2010-09-23 |
Medline Journal Info:
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Nlm Unique ID: 9421642 Medline TA: Am J Respir Crit Care Med Country: United States |
Other Details:
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Languages: eng Pagination: 212-9 Citation Subset: AIM; IM |
Affiliation:
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Divison of Pulmonary and Critical Care Medicine, Department of Medicine, Harborview Medical Center, University of Washington, Seattle,Washington, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Acute Lung Injury
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drug therapy*,
metabolism,
pathology Animals Antibodies, Monoclonal / administration & dosage, therapeutic use* Apoptosis Bleomycin / toxicity Blotting, Western Bronchoalveolar Lavage Fluid / chemistry, cytology Cell Movement / drug effects Cell Proliferation / drug effects Disease Models, Animal Dose-Response Relationship, Drug Fibroblasts / drug effects, pathology Follow-Up Studies Gene Expression Immunohistochemistry Lung / metabolism, pathology Mice Mice, Inbred C57BL Polymerase Chain Reaction Pulmonary Fibrosis / drug therapy, metabolism, pathology RNA, Messenger / genetics Receptor, IGF Type 1 / antagonists & inhibitors*, genetics, metabolism Treatment Outcome |
| Chemical | |
Reg. No./Substance:
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0/Antibodies, Monoclonal; 0/RNA, Messenger; 11056-06-7/Bleomycin; EC 2.7.10.1/Receptor, IGF Type 1 |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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