Although lung inflammation and fibrosis are well-documented dose-limiting side effects of lung irradiation, the mechanisms underlying these pathologies are unknown. An improved mechanistic understanding of radiation-induced pneumonitis is a prerequisite for the development of more effective radiotherapy; this was the rationale for the current study. Mouse lungs were focally irradiated with 75. Gy. The numbers of neutrophils, lymphocytes, macrophages, and total cells in the bronchoalveolar lavage fluid were counted, and pro-inflammatory cytokine levels were measured. Histological analysis and immunohistochemical staining for Tgf-β1 and Cd68 (a macrophage-specific protein) was also performed. After irradiation, mice developed pneumonitis, and exhibited higher numbers of neutrophils, lymphocytes, eosinophils, macrophages, and total cells compared to controls. In addition, inflammasome (Nlrp3, and caspase 1, Il1a, and Il1β), adhesion molecule (Vcam1), and cytokine (Il6) genes were significantly upregulated in the IR group. Cd68 and Tgfb1 proteins were significantly increased after irradiation. Upregulation of Cd68 and Tgfb1 correlates with the onset of radiation-induced pneumonitis and fibrosis. In addition, radiation-induced pneumonitis and fibrosis are accompanied by upregulation of phenotypic markers of inflammasome activity. Our findings have implications for the onset and exacerbation of damage in normal lung tissue.