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Microarray Analysis Indicates That Pulmonary Edema Fluid From Patients With Acute Lung Injury Mediates Inflammation, Mitogen Gene Expression, and Fibroblast Proliferation Through Bioactive Interleukin-1* FREE TO VIEW

Mitchell A. Olman, MA, MD; Kimberly E. White, BS; Lorraine B. Ware, MD; Michael T. Cross, MD; Sha Zhu, PhD; Michael A. Matthay, MD
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*From the Department of Medicine (Drs. Olman, Cross, and Zhu, and Ms. White), Division of Pulmonary and Critical Care Medicine, the University of Alabama, Birmingham, AL; and the Cardiovascular Research Institute (Drs. Ware and Matthay), University of California at San Francisco, CA This research was supported by the Veterans Affairs Merit Review Board and the National Heart, Lung, and Blood Institute (grant HL-58655 to M.A.O.).

Correspondence to: Mitchell A. Olman, MD, Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Alabama at Birmingham Medical Center, 1900 University Blvd, 215 THT, Birmingham, AL 35294; e-mail: Olman@uab.edu

Chest. 2002;121(3_suppl):69S-70S. doi:10.1378/chest.121.3_suppl.69S
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Although the fibroproliferative response to lung injury occurs with a high frequency in patients with acute lung injury (ALI), the mechanisms of this response are largely unknown. This study was undertaken to identify alveolar mitogenic factors and to determine the fibroblast gene response profile to pulmonary edema fluid collected early in the course of clinical ALI. Pulmonary edema fluid obtained from ALI patients (as defined by the American-European Consensus Committee) within 4 h of intubation has a direct mitogenic effect on human lung fibroblasts that was 50% greater than that from well-characterized control patients with hydrostatic pulmonary edema. Conditioned media studies revealed that fibroblasts also produce additional soluble mitogenic factors that act in an autocrine manner to stimulate their own proliferation in response to ALI edema fluid. In order to identify the mitogens and inflammation-modulating factors produced in fibroblasts in response to ALI edema fluid, we performed complementary DNA microarray analysis on RNA harvested from human lung fibroblasts that had been exposed either to ALI or hydrostatic pulmonary edema fluids. This analysis revealed that ALI edema fluid induces fibroblast expression of at least 15 inflammation, adhesion, and proliferation-modulating genes at greater than twofold levels in fibroblasts compared with that seen in hydrostatic edema-exposed cells. Interestingly, many of these genes are interleukin-1 (IL)-1-responsive. IL-1 antigen levels were therefore measured and found to be ninefold higher (587 ± 690 vs 71 ± 76 pg/mL; p = 0.009 [Mann-Whitney test]) in edema fluid from patients with ALI (n = 19) compared with that from hydrostatic control subjects (n = 17). Furthermore, IL-1 receptor antagonist abrogates both ALI edema fluid-induced fibroblast proliferation by 30% as well as ALI edema fluid-induced gene expression of individual genes by 50 to 90%, as confirmed by Northern blot analysis. For example, both ALI edema fluid induction of IL-6 messenger RNA (induced 17-fold) and protein (induced fourfold) were abrogated > 90% by IL-1 receptor antagonist in a dose-dependent and specific manner. These novel findings establish that soluble alveolar IL-1 bioactivity is a critical initiator of the early alveolar fibroproliferative response. The spectrum of inflammatory, mitogenic, and adhesion-related genes induced by ALI edema fluid further indicates that fibroblasts are important sources of paracrine and autocrine mediators that are capable of altering the course of ALI.

Abbreviations: ALI = acute lung injury; IL = interleukin.




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