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* Immunology Graduate Program and
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109
Pulmonary fibrosis is characterized by the accumulation of fibroblasts and myofibroblasts. These cells may accumulate from three potential sources: the expansion of resident lung fibroblasts, the process of epithelial-mesenchymal transition, or the recruitment and differentiation of circulating mesenchymal precursors known as fibrocytes. We have previously demonstrated that fibrocytes participate in lung fibrogenesis following administration of FITC to mice. We now demonstrate that leukotriene-deficient 5-LO–/– mice are protected from FITC-induced fibrosis. Both murine and human fibrocytes express both cysteinyl leukotriene receptor (CysLT) 1 and CysLT2. In addition, fibrocytes are capable of producing CysLTs and can be regulated via the autocrine or paracrine secretion of these lipid mediators. Exogenous administration of leukotriene (LT) D4, but not LTC4 induces proliferation of both murine and human fibrocytes in a dose-dependent manner. Consistent with this result, CysLT1 receptor antagonists are able to block the mitogenic effects of exogenous LTD4 on fibrocytes. Endogenous production of CysLTs contributes to basal fibrocyte proliferation, but does not alter fibrocyte responses to basic fibroblast growth factor. Although CysLTs can induce the migration of fibrocytes in vitro, they do not appear to be essential for fibrocyte recruitment to the lung in vivo, possibly due to compensatory chemokine-mediated recruitment signals. However, CysLTs do appear to regulate the proliferation of fibrocytes once they are recruited to the lung. These data provide mechanistic insight into the therapeutic benefit of leukotriene synthesis inhibitors and CysLT1 receptor antagonists in animal models of fibrosis.
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 National Institutes of Health Grants HL071586 (to B.B.M.) and P50HL56402 (to B.B.M., G.B.T., and M.P.G.), a Career Investigator Award (to B.B.M.) from the American Lung Association of Michigan, and a research grant from the Martin Edward Galvin Fund for Fibrosis Research.
2 Address correspondence and reprint requests to Dr. Bethany B. Moore, 4053 Biomedical Science Research Building, 109 Zina Pitcher Place, Ann Arbor, MI 48109. E-mail address: Bmoore{at}umich.edu
3 Abbreviations used in this paper: IPF, idiopathic pulmonary fibrosis; LT, leukotriene; AM, alveolar macrophage; CysLT, cysteinyl leukotriene; WT, wild type; SFM, serum-free medium; CT, cycle threshold; BAL, bronchoalveolar lavage; bFGF, basic fibroblast growth factor.
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