Document Detail


The lysophosphatidic acid receptor LPA1 promotes epithelial cell apoptosis after lung injury.
MedLine Citation:
PMID:  22021336     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Increased epithelial cell apoptosis in response to lung injury has been implicated in the development of idiopathic pulmonary fibrosis (IPF), but the molecular pathways promoting epithelial cell apoptosis in this disease have yet to be fully identified. Lysophosphatidic acid (LPA), which we have previously demonstrated to mediate bleomycin lung injury-induced fibroblast recruitment and vascular leak in mice and fibroblast recruitment in patients with IPF, is an important regulator of survival and apoptosis in many cell types. We now show that LPA signaling through its receptor LPA(1) promotes epithelial cell apoptosis induced by bleomycin injury. The number of apoptotic cells present in the alveolar and bronchial epithelia of LPA(1)-deficient mice was significantly reduced compared with wild-type mice at Day 3 after bleomycin challenge, as was lung caspase-3 activity. Consistent with these in vivo results, we found that LPA signaling through LPA(1) induced apoptosis in normal human bronchial epithelial cells in culture. LPA-LPA(1) signaling appeared to specifically mediate anoikis, the apoptosis of anchorage-dependent cells induced by their detachment. Similarly, LPA negatively regulated attachment of R3/1 rat alveolar epithelial cell line cells. In contrast, LPA signaling through LPA(1) promoted the resistance of lung fibroblasts to apoptosis, which has also been implicated in IPF. The ability of LPA-LPA(1) signaling to promote epithelial cell apoptosis and fibroblast resistance to apoptosis may therefore contribute to the capacity of this signaling pathway to regulate the development of pulmonary fibrosis after lung injury.
Authors:
Manuela Funke; Zhenwen Zhao; Yan Xu; Jerold Chun; Andrew M Tager
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-10-20
Journal Detail:
Title:  American journal of respiratory cell and molecular biology     Volume:  46     ISSN:  1535-4989     ISO Abbreviation:  Am. J. Respir. Cell Mol. Biol.     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-03-02     Completed Date:  2012-04-23     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  8917225     Medline TA:  Am J Respir Cell Mol Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  355-64     Citation Subset:  IM    
Affiliation:
Pulmonary and Critical Care Unit, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, 149 13th Street, Room 8301, Charlestown, MA 02129, USA. amtager@partners.org
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MeSH Terms
Descriptor/Qualifier:
Animals
Anoikis
Apoptosis*
Bleomycin
Caspase 3 / metabolism
Cell Adhesion
Cells, Cultured
Disease Models, Animal
Epithelial Cells / metabolism*,  pathology
Fibroblasts / metabolism,  pathology
Humans
Lung / metabolism*,  pathology
Lung Injury / chemically induced,  genetics,  metabolism*,  pathology
Lysophospholipids / metabolism*
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Knockout
Pulmonary Fibrosis / chemically induced,  genetics,  metabolism*,  pathology
Rats
Receptors, Lysophosphatidic Acid / deficiency,  genetics,  metabolism*
Signal Transduction
Time Factors
Grant Support
ID/Acronym/Agency:
NIH-DA019674/DA/NIDA NIH HHS; NIH-HD050685/HD/NICHD NIH HHS; P30 AI060354/AI/NIAID NIH HHS; R01 HL108975/HL/NHLBI NIH HHS; R01-CA095042/CA/NCI NIH HHS; R01-HL095732/HL/NHLBI NIH HHS; R01-HL108975/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Lysophospholipids; 0/Receptors, Lysophosphatidic Acid; 11056-06-7/Bleomycin; 22002-87-5/lysophosphatidic acid; EC 3.4.22.-/Casp3 protein, mouse; EC 3.4.22.-/Caspase 3
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