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

Andrew M. Tager, Peter LaCamera, Barry S. Shea, Gabriele S. Campanella, Moisés Selman, Zhenwen Zhao, Vasiliy Polosukhin, John Wain, Banu A. Karimi-Shah, Nancy D. Kim, William K. Hart, Annie Pardo, Timothy S. Blackwell, Yan Xu, Jerold Chun, Andrew D. Luster

Research output: Contribution to journalArticle

465 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)45-54
Number of pages10
JournalNature Medicine
Volume14
Issue number1
DOIs
StatePublished - Jan 1 2008

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Tager, A. M., LaCamera, P., Shea, B. S., Campanella, G. S., Selman, M., Zhao, Z., Polosukhin, V., Wain, J., Karimi-Shah, B. A., Kim, N. D., Hart, W. K., Pardo, A., Blackwell, T. S., Xu, Y., Chun, J., & Luster, A. D. (2008). The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak. Nature Medicine, 14(1), 45-54. https://doi.org/10.1038/nm1685