Darapladib Ameliorates Radiation-Induced Skin Injury and Fibrosis by Lipoprotein-Associated Phospholipase A2 Inhibition.

Current studies have elucidated the mechanisms of radiation-induced skin injury (RISI) and identified several medical countermeasures to reduce its severity. However, no treatment has yet proven effective in preventing or reversing radiation-induced skin fibrosis. Here, we show that radiation upregulates lipoprotein-associated phospholipase A2 (Lp-PLA2) expression and induces endothelial cell dysfunction, characterized by an increased DNA damage response and reduced tube-forming capacity and mitochondrial function. To define the role of Lp-PLA2 in the progression of RISI, we treated human dermal microvascular endothelial cells and the skin of SKH1 hairless mice with darapladib, a selective Lp-PLA2 inhibitor. In endothelial cells, darapladib attenuated radiation-induced cellular damage and suppressed endothelial-to-mesenchymal transition (EndoMT). In irradiated mouse skin, darapladib reduced radiation-induced inflammation, adipose tissue disruption, dermal thickness, and skin fibrosis. Notably, darapladib modulated macrophage polarization and inhibited radiation-induced macrophage infiltration in irradiated skin. These findings suggest that Lp-PLA2 inhibition may reveal potential targets for the treatment of RISI and other fibrotic skin diseases.