ABSTRACT

Although lung inflammation and fibrosis are well-documented dose-limiting side effects oflung irradiation, the mechanisms underlying these pathologies are unknown. An improvedmechanistic understanding of radiation-induced pneumonitis is a prerequisite for thedevelopment of more effective radiotherapy; this was the rationale for the current study.Mouse lungs were focally irradiated with 75 Gy. The numbers of neutrophils, lympho-cytes, macrophages, and total cells in the bronchoalveolar lavage fluid were counted, andpro-inflammatory cytokine levels were measured. Histological analysis and immunohisto-chemical staining for Tgf-1 and Cd68 (a macrophage-specific protein) was also performed.After irradiation, mice developed pneumonitis, and exhibited higher numbers of neu-trophils, lymphocytes, eosinophils, macrophages, and total cells compared to controls. Inaddition, inflammasome (Nlrp3, and caspase 1, Il1a, and Il1), adhesion molecule (Vcam1),and cytokine (Il6) genes were significantly upregulated in the IR group. Cd68 and Tgfb1proteins were significantly increased after irradiation. Upregulation of Cd68 and Tgfb1correlates with the onset of radiation-induced pneumonitis and fibrosis. In addition,radiation-induced pneumonitis and fibrosis are accompanied by upregulation of pheno-typic markers of inflammasome activity. Our findings have implications for the onset andexacerbation of damage in normal lung tissue.