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: Rama Malaviya, Andrew J Gow, Mary Francis, Elena V Abramova, Jeffrey D Laskin, Debra L Laskin
• Journal: Toxicological sciences : an official journal of the Society of Toxicology (Toxicol Sci) Vol. 144 Issue 1 Pg. 27-38 (Mar 2015) ISSN: 1096-0929 [Electronic] United States
• PMID: 25552309 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: [email protected].

Chemical References

• Biomarkers
• H2AX protein, mouse
• Histones
• Inflammation Mediators
• Lectins
• Membrane Proteins
• Pulmonary Surfactant-Associated Protein D
• Reactive Nitrogen Species
• Nitric Oxide Synthase Type II
• Nos2 protein, mouse
• Heme Oxygenase-1
• Hmox1 protein, mouse
• Chil3 protein, mouse
• beta-N-Acetylhexosaminidases

Topics

• Acute Lung Injury (enzymology, genetics, pathology)
• Animals
• Biomarkers (metabolism)
• Bronchoalveolar Lavage Fluid (chemistry, cytology)
• Disease Models, Animal
• Heme Oxygenase-1 (metabolism)
• Histones (metabolism)
• Inflammation Mediators (metabolism)
• Lectins (metabolism)
• Lung (enzymology, pathology, radiation effects)
• Macrophages (metabolism, radiation effects)
• Membrane Proteins (metabolism)
• Mice, Inbred C57BL
• Mice, Knockout
• Nitric Oxide Synthase Type II (deficiency, genetics, metabolism)
• Oxidative Stress (radiation effects)
• Phosphorylation
• Pneumonia (enzymology, genetics, pathology)
• Pulmonary Surfactant-Associated Protein D (deficiency, genetics, metabolism)
• Radiation Injuries (enzymology, genetics, pathology)
• Reactive Nitrogen Species (metabolism)
• Signal Transduction (radiation effects)
• Time Factors
• beta-N-Acetylhexosaminidases (metabolism)