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The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak

Nature Medicine volume 14, pages 45–54 (2008)Cite this article

Abstract

Aberrant wound-healing responses to injury have been implicated in the development of pulmonary fibrosis, but the mediators directing these pathologic responses have yet to be fully identified. We show that lysophosphatidic acid levels increase in bronchoalveolar lavage fluid following lung injury in the bleomycin model of pulmonary fibrosis, and that mice lacking one of its receptors, LPA1, are markedly protected from fibrosis and mortality in this model. The absence of LPA1 led to reduced fibroblast recruitment and vascular leak, two responses that may be excessive when injury leads to fibrosis rather than to repair, whereas leukocyte recruitment was preserved during the first week after injury. In persons with idiopathic pulmonary fibrosis, lysophosphatidic acid levels in bronchoalveolar lavage fluid were also increased, and inhibition of LPA1 markedly reduced fibroblast responses to the chemotactic activity of this fluid. LPA1 therefore represents a new therapeutic _target for diseases in which aberrant responses to injury contribute to fibrosis, such as idiopathic pulmonary fibrosis.

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Figure 1: Identification of LPA and LPA1 as possible mediators of fibroblast chemoattractant activity generated in the airspaces after bleomycin injury.
Figure 2: LPA1-deficient (LPA1 KO) mice are protected from bleomycin-induced fibrosis and mortality.
Figure 3: Fibroblast recruitment induced by bleomycin injury is diminished in LPA1-deficient mice.
Figure 4: Vascular leak induced by bleomycin injury is diminished in LPA1-deficient (LPA1 KO) mice.
Figure 5: Leukocyte recruitment and activation induced by bleomycin injury is preserved in LPA1-deficient (LPA1 KO) mice.
Figure 6: LPA and LPA1 contribute to the fibroblast chemoattractant activity of BAL from persons with IPF.

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Acknowledgements

The authors gratefully acknowledge that these studies were supported by a Pulmonary Fibrosis Foundation Grant, an American Lung Association 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.) and by US National Institutes of Health grants R01-CA89228 and R01-CA095042 (to Y.X.), R01-MH51699, K02-MH01723 and R01-NS048478 (to J.C.) and R01-CA69212 (to A.D.L.). The authors thank C.P. Leary for her assistance, S.D. Bercury, E.C. Poorvu and S.F. Brooks for their technical assistance, and K.R. Lynch for the gift of VPC12249.

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  1. Peter LaCamera and Barry S Shea: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Rheumatology, Center for Immunology and Inflammatory Diseases, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, CNY149-8301, 149 13th Street, Charlestown, 02129, Massachusetts, USA

    Andrew M Tager, Peter LaCamera, Barry S Shea, Gabriele S Campanella, John Wain, Banu A Karimi-Shah, Nancy D Kim, William K Hart & Andrew D Luster

  2. Pulmonary and Critical Care Unit, Massachusetts General Hospital, Harvard Medical School, CNY149-8301, 149 13th Street, Charlestown, 02129, Massachusetts, USA

    Andrew M Tager, Peter LaCamera, Barry S Shea & Banu A Karimi-Shah

  3. Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico

    Moisés Selman

  4. Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, 46202, Indiana, USA

    Zhenwen Zhao & Yan Xu

  5. Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, 37232, Tennessee, USA

    Vasiliy Polosukhin & Timothy S Blackwell

  6. Division of Thoracic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, 02114, Massachusetts, USA

    John Wain

  7. Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico City, Mexico

    Annie Pardo

  8. Department of Molecular Biology, Helen L. Dorris Institute for Neurological and Psychiatric Disorders, The Scripps Research Institute, La Jolla, 92037, California, USA

    Jerold Chun

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Contributions

A.M.T. conceived the idea for the study, designed, directed and interpreted all of the experiments, and prepared the manuscript. P.L. performed and analyzed the experiments comparing fibrosis and mortality in LPA1-deficient and wild-type mice. P.L. and B.S.S. performed and analyzed the experiments comparing fibroblast accumulation and vascular leak in LPA1-deficient and wild-type mice. P.L., B.S.S., B.A.K.-S. and W.K.H. performed and analyzed the experiments comparing leukocyte recruitment in LPA1-deficient and wild-type mice. G.S.C. performed and analyzed the chromatography and SDS-PAGE experiments. M.S., J.W., A.P., B.S.S. and A.M.T. collected and provided the human BAL samples. Z.Z. and Y.X. performed and analyzed the mass spectrometry experiments. V.P. and T.S.B. performed and analyzed the FSP1 staining. N.D.K. isolated and provided the primary mouse lung endothelial cells and mouse neutrophils. W.K.H. performed the chemotaxis and QPCR experiments. J.C. provided the LPA1-deficient mice. P.L., B.S.S., M.S. A.P., T.S.B., Y.X., and J.C. provided critical review and comments on the manuscript. A.D.L. supervised all aspects of the study, including experimental design, data interpretation, and manuscript preparation.

Corresponding author

Correspondence to Andrew D Luster.

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Tager, A., LaCamera, P., Shea, B. et al. The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak. Nat Med 14, 45–54 (2008). https://doi.org/10.1038/nm1685

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