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The Lysophosphatidic Acid Receptor LPA₁ Links Pulmonary Fibrosis to Lung Injury by Mediating Fibroblast Recruitment and Vascular Leak

¹ Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, ² Pulmonary and Critical Care Unit, and ⁶ Division of Thoracic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; ³ Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico; ⁴ Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, Indiana; ⁵ Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; ⁷ Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico City, Mexico; and ⁸ Department of Molecular Biology, Helen L. Dorris Institute for Neurological and Psychiatric Disorders, The Scripps Research Institute, La Jolla, California

Correspondence and requests for reprints should be addressed to Andrew M. Tager, M.D., Center for Immunology and Inflammatory Diseases and Pulmonary and Critical Care Unit, Massachusetts General Hospital, CNY149-8301, 149 13th Street, Charlestown, MA 02129. E-mail: amtager{at}partners.org

Aberrant wound-healing responses to injury are implicated in the development of pulmonary fibrosis, but the mediators directing these pathologic responses remain to be fully identified. Lysophosphatidic acid (LPA), acting through specific G protein–coupled receptors, directs multiple biological processes that may participate in injury responses. We found that LPA was induced by lung injury in the bleomycin model of pulmonary fibrosis, and that mice lacking one of its receptors, LPA₁, were markedly protected from fibrosis and mortality in this model. Of LPA's receptors, fibroblasts predominantly express LPA₁, and fibroblast accumulation following lung injury was markedly attenuated in LPA₁-deficient mice. Reduced fibroblast accumulation resulted from diminished migration of LPA₁-deficient fibroblasts to the chemoattractant activity generated by lung injury, rather than from diminished generation of this activity or from reduced fibroblast proliferation. Reduced fibroblast accumulation, rather than impaired capacities of LPA₁-deficient fibroblasts to synthesize collagen or differentiate into myofibroblasts, in turn contributed to reduced collagen accumulation in bleomycin-injured LPA₁-deficient mice. Lung endothelial cells also express LPA₁, and the increase in vascular permeability caused by bleomycin injury was markedly reduced in LPA₁-deficient mice as well. In contrast, leukocytes express minimal LPA₁, and bleomycin-induced leukocyte recruitment was preserved in the absence of LPA₁ expression. These results demonstrate that LPA₁ links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak, two of the wound-healing responses that are thought to be inappropriately excessive when injury leads to fibrosis rather than repair. We found that LPA levels also were increased in bronchoalveolar lavage fluid samples of patients with idiopathic pulmonary fibrosis, and that inhibition of LPA₁ markedly reduced fibroblast responses to the chemotactic activity of this fluid. LPA₁ therefore represents a new target for lung diseases in which aberrant responses to injury contribute to the development of fibrosis, such as idiopathic pulmonary fibrosis.

FOOTNOTES

^* These authors contributed equally to this work.

Supported by a Pulmonary Fibrosis Foundation Grant, an ALA Dalsemer Grant, and a Nirenberg Center for Advanced Lung Disease Grant (to A.M.T.); by Universidad Nacional Autónoma de México Grant SDI.PTID.05.6 (to M.S. and A.P.); by NIH grants R01-CA89228 and R01-CA095042 (to Y.X.); by R01-MH51699, K02-MH01723, and R01-NS048478 (to J.C.); and by R01-CA69212 (to A.D.L.).

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 December 3, 2007; accepted in final form December 7, 2007)

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Tager, A. M. Articles by Luster, A. D. PubMed Articles by Tager, A. M. Articles by Luster, A. D.