Blockade of lysophosphatidic acid receptors LPAR1/3 ameliorates lung fibrosis induced by irradiation
| Autor: | Lu Gan, Xin Li, De-Song Liu, Yan Ge, Pei-Yan Ni, Jianxin Xue, You Lu, Wei Jiang, Lin Deng |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
medicine.medical_specialty
Pulmonary Fibrosis medicine.medical_treatment Biophysics Down-Regulation Oleic Acids Biology Biochemistry Mice chemistry.chemical_compound Transforming Growth Factor beta Fibrosis Internal medicine Lysophosphatidic acid medicine Animals Receptors Lysophosphatidic Acid Fibroblast Molecular Biology Cell Proliferation LPAR3 LPAR1 Growth factor Connective Tissue Growth Factor Cell Biology Fibroblasts medicine.disease Organophosphates Mice Inbred C57BL CTGF Radiation Injuries Experimental medicine.anatomical_structure Endocrinology chemistry Cancer research lipids (amino acids peptides and proteins) Transforming growth factor |
| Zdroj: | Biochemical and Biophysical Research Communications. 409:7-13 |
| ISSN: | 0006-291X |
| DOI: | 10.1016/j.bbrc.2011.04.084 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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