title: Wound trauma increases radiation-induced mortality by activation of iNOS pathway and elevation of cytokine concentrations and bacterial infection.
abstract: Abstract Although it is documented that concurrent wounding increases mortality from radiation injury, the molecular mechanism of combined injury is unknown. In this study, mice were exposed to gamma radiation followed by skin wounding. Wound trauma exacerbated radiation-induced mortality, reducing the LD(50/30) from 9.65 Gy to 8.95 Gy. Analyses of histopathology, inducible nitric oxide synthase (iNOS), and serum cytokines were performed on mouse ileum and skin at various times after 9.75 Gy and/or wounding. In the ileum, the villi were significantly shortened 3 days postirradiation but not after wounding; combined injury resulted in decreased villus width and tunica muscularis thickness. The skin of mice subjected to combined injury was less cellular and had a smaller healing bud than the skin of mice subjected to wounding alone. Combined injury significantly delayed wound closure times; it also prolonged the increased levels of iNOS protein in the skin and ileum. iNOS up-regulation was correlated with increases in transcription factors, including NF-kappaB and NF-IL6. The increase in NF-IL6 may be due to increases in cytokines, including IL-1beta, -6, -8, -9, -10 and -13, G-CSF, eotaxin, INF-gamma, MCP-1, MIP-1alpha and MIP-1beta. Combined injury resulted in early detection of bacteria in the blood of the heart and liver, whereas radiation alone resulted in later detection of bacteria; only a transient bacteremia occurred after wounding alone. Results suggest that enhancement of iNOS, cytokines and bacterial infection triggered by combined injury may contribute to mortality. Agents that inhibit these responses may prove to be therapeutic for combined injury and may reduce related mortality.
authors.affiliation: Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20889-5603, USA. kiang@afrri.usuhs.mil
authors.forename: Juliann G
authors.initials: JG
authors.lastname: Kiang
authors.forename: Wan
authors.initials: W
authors.lastname: Jiao
authors.forename: Lynnette H
authors.initials: LH
authors.lastname: Cary
authors.forename: Steven R
authors.initials: SR
authors.lastname: Mog
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Elliott
authors.forename: Terry C
authors.initials: TC
authors.lastname: Pellmar
authors.forename: G David
authors.initials: GD
authors.lastname: Ledney
mesh_terms: D000818:Animals; D001424:Bacterial Infections; D001835:Body Weight / Q000528:radiation effects; D016207:Cytokines / Q000097:blood / Q000378:metabolism*; D004326:Drinking / Q000528:radiation effects; D004790:Enzyme Induction / Q000528:radiation effects; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000528:radiation effects; D006321:Heart / Q000382:microbiology / Q000528:radiation effects; D007082:Ileum / Q000378:metabolism / Q000528:radiation effects; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000382:microbiology / Q000528:radiation effects; D051379:Mice; D009026:Mortality; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011833:Radiation Injuries, Experimental / Q000378:metabolism* / Q000382:microbiology* / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction / Q000528:radiation effects*; D012867:Skin / Q000293:injuries / Q000378:metabolism / Q000503:physiopathology / Q000528:radiation effects; D013997:Time Factors; D014945:Wound Healing / Q000528:radiation effects
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D016328:NF-kappa B; D012333:RNA, Messenger; D052247:Nitric Oxide Synthase Type II