title: Radiation-induced lung injury and inflammation in mice: role of inducible nitric oxide synthase and surfactant protein D.
abstract: 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 γ-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 24 h 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)-α. Additionally, at 24 h 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-α, 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-α, 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.
authors.affiliation: *Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, and Department of Environmental and Occupational Medicine, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey 08854.
authors.forename: Rama
authors.initials: R
authors.lastname: Malaviya
authors.affiliation: *Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, and Department of Environmental and Occupational Medicine, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey 08854.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Gow
authors.affiliation: *Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, and Department of Environmental and Occupational Medicine, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey 08854.
authors.forename: Mary
authors.initials: M
authors.lastname: Francis
authors.affiliation: *Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, and Department of Environmental and Occupational Medicine, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey 08854.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Abramova
authors.affiliation: *Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, and Department of Environmental and Occupational Medicine, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey 08854.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Laskin
authors.affiliation: *Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, and Department of Environmental and Occupational Medicine, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey 08854 laskin@eohsi.rutgers.edu.
authors.forename: Debra L
authors.initials: DL
authors.lastname: Laskin
mesh_terms: D055371:Acute Lung Injury / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D004195:Disease Models, Animal; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D037102:Lectins / Q000378:metabolism; D008168:Lung / Q000201:enzymology* / Q000473:pathology / Q000528:radiation effects; D008264:Macrophages / Q000378:metabolism / Q000528:radiation effects; D008565:Membrane Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000528:radiation effects; D010766:Phosphorylation; D011014:Pneumonia / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D037663:Pulmonary Surfactant-Associated Protein D / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011832:Radiation Injuries / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D026361:Reactive Nitrogen Species / Q000378:metabolism; D015398:Signal Transduction / Q000528:radiation effects; D013997:Time Factors; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
chemical_list: D015415:Biomarkers; D051547:Heme Oxygenase-1; D006657:Histones; D018836:Inflammation Mediators; D037102:Lectins; D008565:Membrane Proteins; D052247:Nitric Oxide Synthase Type II; D037663:Pulmonary Surfactant-Associated Protein D; D026361:Reactive Nitrogen Species; D001619:beta-N-Acetylhexosaminidases; C496317:Nos2 protein, mouse; C496542:Hmox1 protein, mouse; C429541:Chil3 protein, mouse; C475961:gamma-H2AX protein, mouse
keywords: iNOS; lung injury; radiation; reactive nitrogen species; surfactant protein D