Radiation-Induced Lung Injury and Inflammation in Mice: Role of Inducible Nitric Oxide Synthase and Surfactant Protein D

Reactive nitrogen species (RNS) generated after exposure to radiation have been implicated in lung injury. Surfactant protein D (SP- D) is a pulmonary collectin that suppresses inducible nitric oxide synthase (iNOS)- mediated RNS production. Herein, we analyzed the role of iNOS and SP- D in radiation- induced lung injury. Exposure of wild- type (WT) mice to c- radiation (8 Gy) caused acute lung injury and inflammation, as measured by increases in bronchoalveolar lavage (BAL) protein and cell content at 24 h. Radiation also caused alterations in SP- D structure at 24h and 4 weeks post exposure. These responses were blunted in iNOS(-/-) mice. Conversely, loss of iNOS had no effect on radiation- induced expression of phospho- H2A. X or tumor necrosis factor (TNF)-alpha. Additionally, at 24h post radiation, cyclooxygenase expression and BAL lipocalin- 2 levels were increased in iNOS(-/-) mice, and heme oxygenase (HO)-1(+) and Ym1(+) macrophages were evident. Loss of SP- D resulted in increased numbers of enlarged HO-1(+) macrophages in the lung following radiation, along with upregulation of TNF-alpha, CCL2, and CXCL2, whereas expression of phospho- H2A. X was diminished. To determine if RNS play a role in the altered sensitivity of SP- D-/- mice to radiation, iNOS(-/-)/SP-D-/- mice were used. Radiation- induced injury, oxidative stress, and tissue repair were generally similar in iNOS(-/-)/SP-D-/- and SP-D-/- mice. In contrast, TNF-alpha, CCL2, and CXCL2 expression was attenuated. These data indicate that although iNOS is involved in radiation- induced injury and altered SP- D structure, in the absence of SP- D, it functions to promote proinflammatory signaling. Thus, multiple inflammatory pathways contribute to the pathogenic response to radiation.