title: 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.
authors.affiliation: State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, PR China.
authors.forename: Lu
authors.initials: L
authors.lastname: Gan
authors.forename: Jian-Xin
authors.initials: JX
authors.lastname: Xue
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: De-Song
authors.initials: DS
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Ge
authors.forename: Pei-Yan
authors.initials: PY
authors.lastname: Ni
authors.forename: Lin
authors.initials: L
authors.lastname: Deng
authors.forename: You
authors.initials: Y
authors.lastname: Lu
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D055513:Connective Tissue Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015536:Down-Regulation; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009829:Oleic Acids / Q000627:therapeutic use; D010755:Organophosphates / Q000627:therapeutic use; D011658:Pulmonary Fibrosis / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology; D011833:Radiation Injuries, Experimental / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D009829:Oleic Acids; D010755:Organophosphates; D049368:Receptors, Lysophosphatidic Acid; D016212:Transforming Growth Factor beta; C556086:phosphoric acid mono-(3-(4-benzyloxyphenyl)-2-octadec-9-enoylaminopropyl) ester; D055513:Connective Tissue Growth Factor