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1 Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama; 2 Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University, Nashville, Tennessee; 3 Department of Medicine, University of Michigan, Ann Arbor, Michigan; and 4 Departments of Medicine and Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, California
Correspondence and requests for reprints should be addressed to Mitchell A. Olman, M.D., M.A., Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Alabama at Birmingham Medical Center, 1900 University Blvd., 422 THT, Birmingham, AL 35294. E-mail: Olman{at}uab.edu
The fibroproliferative response to acute lung injury results in severe, persistent respiratory dysfunction. We have previously reported that IL-1β mediates an autocrine-acting, fibroblast mitogenic pathway in those with acute lung injury. In this study, we evaluate the significance of individual prostanoid receptors in mediating the fibroproliferative effects of IL-1β. IL-1β induces cyclooxygenase (COX)-2 and prostaglandin E2 (PGE2) synthesis in normal human lung fibroblasts in a dose-dependent manner, with an EC50 close to that seen in acute lung injury pulmonary edema fluid samples. Blocking studies indicate that IL-1β is the major COX-2 mRNA and PGE2-inducing factor in pulmonary edema fluid, and accounts for the differential PGE2 induction noted in samples from patients with acute lung injury, compared with patients with hydrostatic edema. Surprisingly, we found that PGE2 produced by fibroblasts, in response to IL-1β, enhances fibroblast proliferation. Further studies revealed that PGE2 exhibits a bi-phasic effect on fibroblast proliferation in a concentration-dependent manner. To evaluate this biphasic effect, we determined the effects of the four known PGE2 EP receptors on fibroblast proliferation. The suppressive effects of PGE2 were mimicked by the EP2-selective prostanoid receptor agonist, butaprost, by direct cAMP activation, and were lost in murine lung fibroblasts that lack EP2 receptors. These data demonstrate that high concentration PGE2 (>300 nM) mediates proliferative suppression. Conversely, the pro-mitogenic effects of mid-range concentrations (3–30 nM) 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 suppress fibroblast proliferation, via preferential signaling through EP3 or EP2 receptors, respectively. Further, the data demonstrate that clinically relevant concentrations of IL-1β can induce the expression of PGE2 to the threshold for either stimulation or suppression of fibroblast proliferation. Such mechanisms may drive the differential fibroproliferative response to acute lung injury.
FOOTNOTES
Supported by grants from the Veterans Administration MERIT Review and the 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-71586 (to B.M.), HL-56402 (to M.P.-G.), and The American Heart Association (to Q.D.).
Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
(Received in original form November 13, 2007; accepted in final form November 16, 2007)
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