The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak.
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.
Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, CNY149-8301, 149 13th Street, Charlestown, Massachusetts 02129 USA.
Andrew M
AM
Tager
Peter
P
LaCamera
Barry S
BS
Shea
Gabriele S
GS
Campanella
Moisés
M
Selman
Zhenwen
Z
Zhao
Vasiliy
V
Polosukhin
John
J
Wain
Banu A
BA
Karimi-Shah
Nancy D
ND
Kim
William K
WK
Hart
Annie
A
Pardo
Timothy S
TS
Blackwell
Yan
Y
Xu
Jerold
J
Chun
Andrew D
AD
Luster
D000818:Animals; D001761:Bleomycin / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D007962:Leukocytes / Q000378:metabolism; D008168:Lung / Q000473:pathology; D055370:Lung Injury; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D011658:Pulmonary Fibrosis / Q000473:pathology; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism / Q000502:physiology*
D008246:Lysophospholipids; D049368:Receptors, Lysophosphatidic Acid; D001761:Bleomycin; C032881:lysophosphatidic acid