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* Department of Medicine and
Department of Pathology, Division of Pulmonary and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL 35294;
Department of Medicine, University of Michigan, Ann Arbor, MI 48109;
Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, TN 37232; and
¶ Cardiovascular Research Institute, Departments of Medicine and Anesthesia, University of California, San Francisco, CA 94143
The fibroproliferative response to acute lung injury (ALI) results in severe, persistent respiratory dysfunction. We have reported that IL-1β is elevated in pulmonary edema fluid in those with ALI and mediates an autocrine-acting, fibroblast mitogenic pathway. In this study, we examine the role of IL-1β-mediated induction of cyclooxygenase-2 and PGE2, and evaluate the significance of individual E prostanoid (EP) receptors in mediating the fibroproliferative effects of IL-1β in ALI. Blocking studies on human lung fibroblasts indicate that IL-1β is the major cyclooxygenase-2 mRNA and PGE2-inducing factor in pulmonary edema fluid and accounts for the differential PGE2 induction noted in samples from ALI patients. Surprisingly, we found that PGE2 produced by IL-1β-stimulated fibroblasts enhances fibroblast proliferation. Further studies revealed that the effect of fibroblast proliferation is biphasic, with the promitogenic effect of PGE2 noted at concentrations close to that detected in pulmonary edema fluid from ALI patients. The suppressive effects of PGE2 were mimicked by the EP2-selective receptor agonist, butaprost, by cAMP activation, and were lost in murine lung fibroblasts that lack EP2. Conversely, the promitogenic effects of mid-range concentrations of PGE2 were mimicked by the EP3-selective agent, sulprostone, by cAMP reduction, and lost upon inhibition of Gi-mediated signaling with pertussis toxin. Taken together, these data demonstrate that PGE2 can stimulate or inhibit fibroblast proliferation at clinically relevant concentrations, via preferential signaling through EP3 or EP2 receptors, respectively. Such mechanisms may drive the fibroproliferative response to ALI.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the Veterans Administration MERIT Review and National Institutes of Health Grants HL-58655 (to M.A.O.), HL-51856 and HL-51854 (to M.A.M.), HL-70521 (to L.B.W.), HL-56402 and HL-071586 (to B.B.M.), and HL-56402 (to M.P.-G.), and the American Heart Association (to Q.D.).
2 Address correspondence and reprint requests to Dr. Mitchell A. Olman, Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham Medical Center, 1900 University Boulevard, 422 Tinsley Harrison Tower, Birmingham, AL 35294. E-mail address: Olman{at}uab.edu
3 Abbreviations used in this paper: ALI, acute lung injury; HYDRO, hydrostatic edema; COX, cyclooxygenase; IL-1ra, IL-1 receptor antagonist; SCM, serum-conditioned medium; SFM, serum-free medium; SAPS, simplified acute physiology score; EP, E prostanoid; EIA, enzyme immunoassay.
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