Effects of lysophosphatidic acid and its receptors LPA⅓ on radiation pneumonitis.
Radiation pneumonitis (RP) is a serious complication of radiation therapy for thoracic tumors. Lysophosphatidic acid (LPA) and its receptors LPA⅓ were reported to participate in the processes of inflammation. We tested the hypothesis that LPA and its receptors LPA⅓, take part in the pathogenesis of RP. In our study, irradiation increased LPA levels in the lung and expression of LPA⅓. To further determine the role of LPA⅓, we performed pharmacological knockout of LPA⅓ by a specific antagonist, VPC-12249. On day 60 post-irradiation, RP was significantly alleviated in a dose-dependent manner in mice treated with VPC-12249, as shown by H&E staining, malondialdehyde (MDA, an indicator of oxidative damage) assay in lung, and concentrations of proinflammatory and profibrotic cytokines in plasma, including IL-1β, TNF-α, and TGF-β1. Additionally, VPC-12249 administration decreased the phosphorylation of IκB-α (the initial event that activates the NF-κB signal way), and expression of TGF-β1, CTGF, and α-SMA mRNA. Our findings suggest that LPA and LPA⅓ may play a pivotal role in RP, and LPA-LPA⅓ may serve as novel therapeutic targets for the treatment of RP.
Department of Thoracic Oncology, Cancer Center, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, P.R. China.
Jianxin
J
Xue
Lu
L
Gan
Xin
X
Li
Jian
J
Li
Guohai
G
Qi
Yalan
Y
Wu
Xiaoyue
X
Fu
Qing
Q
Mao
Rui
R
Ao
Jingyi
J
Lang
You
Y
Lu
D000818:Animals; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008246:Lysophospholipids / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009829:Oleic Acids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D010755:Organophosphates / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects; D017564:Radiation Pneumonitis / Q000188:drug therapy* / Q000209:etiology* / Q000378:metabolism; D011837:Radiation-Protective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
C526318:CCN2 protein, mouse; D008246:Lysophospholipids; D009829:Oleic Acids; D010755:Organophosphates; D011837:Radiation-Protective Agents; D049368:Receptors, Lysophosphatidic Acid; D053773:Transforming Growth Factor beta1; C556086:phosphoric acid mono-(3-(4-benzyloxyphenyl)-2-octadec-9-enoylaminopropyl) ester; D055513:Connective Tissue Growth Factor; D051550:I-kappa B Kinase; C032881:lysophosphatidic acid