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(American Journal of Pathology. 2006;169:86-95.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.050612

Mining the Acute Respiratory Distress Syndrome Proteome: Identification of the Insulin-Like Growth Factor (IGF)/IGF-Binding Protein-3 Pathway in Acute Lung Injury

Lynn M. Schnapp*, Samuel Donohoe{dagger}, Jinzhi Chen{ddagger}, Donald A. Sunde*, Patricia M. Kelly*, John Ruzinski*, Thomas Martin§ and David R. Goodlett{ddagger}

From the Division of Pulmonary and Critical Care Medicine,* Harborview Medical Center, University of Washington, Seattle; the Institute of Systems Biology,{dagger} Seattle; the Department of Medicinal Chemistry,{ddagger} University of Washington, Seattle; and the Medical Research Service,§ Veterans Affairs Puget Sound Health Care System, Seattle, Washington

To obtain a more complete protein profile of the airspace milieu in acute respiratory distress syndrome (ARDS) and to identify new mediators, we analyzed bronchoalveolar lavage fluid (BALF) by shotgun proteomics. Using BALF from three patients, we identified a total of 870 different proteins, a nearly 10-fold increase from previous reports. Among the proteins identified were known markers of lung injury, such as surfactant, proteases, and serum proteins. We also identified several biologically interesting proteins not previously identified in patients with ARDS, including insulin-like growth factor-binding protein-3 (IGFBP-3). Because of the known role of IGFBP-3 in regulating cell survival, we measured IGFBP-3 levels by enzyme-linked immunosorbent assay in ARDS BALF. Normal controls had low levels of IGFBP-3, whereas patients with early ARDS had a significant increase in IGFBP-3. The IGF pathway, acting through the type 1 IGF-receptor, repressed apoptosis of lung fibroblasts but not lung epithelial cells. Furthermore, depletion of IGF in ARDS BALF led to enhanced fibroblast apoptosis. Our data suggest that the IGFBP-3/IGF pathway is involved in the pathogenesis of lung injury, illustrating the power of shotgun proteomics to catalog proteins present in complex biological fluids, such as BALF, from which hypotheses can be developed and tested.






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Copyright © 2006 by the American Society for Investigative Pathology.