Effects of lysophosphatidic acid and its receptors LPA⅓ on radiation pneumonitis

Abstract

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.