Normal tissue injury poses a major limitation to the success of radiation therapy (RT) in the treatment of solid tumors. We propose that radiation-induced lung injury is a result of chronic oxidative stress propagated by hypoxia-induced macrophage activation and cytokine production. Therefore, the objective of our study was two-fold. First, in vivo studies were conducted to support our hypothesis suggesting radiation injury is characterized by chronic hypoxia associated with increased macrophage infiltration/activation and pro-fibrogenic/angiogenic cytokine production. Second, we investigated the proposed mechanism of radiation injury in vitro. We demonstrate that hypoxia (0.5% O2) elicits macrophages to produce higher levels of O2*-, TGF-beta, and VEGF than normoxia. Our hypothesis that O2*- is contributing to increased macrophage cytokine production was supported by a significant reduction in TGF-beta and VEGF when redox signaling was minimized using a small molecular weight metalloporphyrin antioxidant, MnTE-2-PyP5+ .