Mining the acute respiratory distress syndrome proteome: identification of the insulin-like growth factor (IGF)/IGF-binding protein-3 pathway in acute lung injury.
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.
Schnapp
Lynn M
LM
Division of Pulmonary and Critical Care Medicine, Harborview Medical Center, University of Washington, 325 9th Ave., Box 359640, Seattle, WA 98104, USA. lschnapp@u.washington.edu
Donohoe
Samuel
S
Chen
Jinzhi
J
Sunde
Donald A
DA
Kelly
Patricia M
PM
Ruzinski
John
J
Martin
Thomas
T
Goodlett
David R
DR
D000328:Adult; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000032:analysis / Q000378:metabolism*; D008168:Lung / Q000473:pathology; D055370:Lung Injury; D008297:Male; D008875:Middle Aged; D040081:Protein Array Analysis; D020543:Proteome; D012128:Respiratory Distress Syndrome / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology; D013002:Somatomedins / Q000378:metabolism*
D018972:Insulin-Like Growth Factor Binding Protein 3; D020543:Proteome; D013002:Somatomedins