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Blockade of lysophosphatidic acid receptors LPAR1/3 ameliorates lung fibrosis induced by irradiation.

Abstract
Lung fibrosis is a common and serious complication of radiation therapy for lung cancer, for which there are no efficient treatments. Emerging evidence indicates that lysophosphatidic acid (LPA) and its receptors (LPARs) are involved in the pathogenesis of fibrosis. Here, we reported that thoracic radiation with 16Gy in mice induced development of radiation lung fibrosis (RLF) accompanied by obvious increases in LPA release and LPAR1 and LPAR3 (LPAR1/3) transcripts. RLF was significantly alleviated in mice treated with the dual LPAR1/3 antagonist, VPC12249. VPC12249 administration effectively prolonged animal survival, restored lung structure, inhibited fibroblast accumulation and reduced collagen deposition. Moreover, profibrotic cytokines in radiation-challenged lungs obviously decreased following administration of VPC12249, including transforming growth factor β1 (TGFβ1) and connective tissue growth factor (CTGF). In vitro, LPA induced both fibroblast proliferation and CTGF expression in a dose-dependent manner, and both were suppressed by blockade of LPAR1/3. The pro-proliferative activity of LPA on fibroblasts was inhibited by siRNA directed against CTGF. Together, our data suggest that the LPA-LPAR1/3 signaling system is involved in the development of RLF through promoting fibroblast proliferation in a CTGF-dependent manner. The LPA-LPAR1/3-CTGF pathway may be a potential target for RLF therapy.
AuthorsLu Gan, Jian-Xin Xue, Xin Li, De-Song Liu, Yan Ge, Pei-Yan Ni, Lin Deng, You Lu, Wei Jiang
JournalBiochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 409 Issue 1 Pg. 7-13 (May 27 2011) ISSN: 1090-2104 [Electronic] United States
PMID21545790 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2011 Elsevier Inc. All rights reserved.
Chemical References
  • Oleic Acids
  • Organophosphates
  • Receptors, Lysophosphatidic Acid
  • Transforming Growth Factor beta
  • phosphoric acid mono-(3-(4-benzyloxyphenyl)-2-octadec-9-enoylaminopropyl) ester
  • Connective Tissue Growth Factor
Topics
  • Animals
  • Cell Proliferation
  • Connective Tissue Growth Factor (antagonists & inhibitors, metabolism)
  • Down-Regulation
  • Fibroblasts (drug effects, metabolism, radiation effects)
  • Mice
  • Mice, Inbred C57BL
  • Oleic Acids (therapeutic use)
  • Organophosphates (therapeutic use)
  • Pulmonary Fibrosis (drug therapy, etiology, pathology)
  • Radiation Injuries, Experimental (complications, drug therapy, pathology)
  • Receptors, Lysophosphatidic Acid (antagonists & inhibitors)
  • Transforming Growth Factor beta (antagonists & inhibitors, metabolism)

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