title: Hemorrhage Exacerbates Radiation Effects on Survival, Leukocytopenia, Thrombopenia, Erythropenia, Bone Marrow Cell Depletion and Hematopoiesis, and Inflammation-Associated microRNAs Expression in Kidney.
abstract: Exposure to high-dose radiation results in detrimental effects on survival. The effects of combined trauma, such as radiation in combination with hemorrhage, the typical injury of victims exposed to a radiation blast, on survival and hematopoietic effects have yet to be understood. The purpose of this study was to evaluate the effects of radiation injury (RI) combined with hemorrhage (i.e., combined injury, CI) on survival and hematopoietic effects, and to investigate whether hemorrhage (Hemo) enhanced RI-induced mortality and hematopoietic syndrome. Male CD2F1 mice (10 weeks old) were given one single exposure of γ- radiation (60Co) at various doses (0.6 Gy/min). Within 2 hr after RI, animals under anesthesia were bled 0% (Sham) or 20% (Hemo) of total blood volume via the submandibular vein. In these mice, Hemo reduced the LD50/30 for 30-day survival from 9.1 Gy (RI) to 8.75 Gy (CI) with a DMF of 1.046. RI resulted in leukocytopenia, thrombopenia, erythropenia, and bone marrow cell depletion, but decreased the caspase-3 activation response. RI increased IL-1β, IL-6, IL-17A, and TNF-α concentrations in serum, bone marrow, ileum, spleen, and kidney. Some of these adverse alterations were magnified by CI. Erythropoietin production was increased in kidney and blood more after CI than RI. Furthermore, CI altered the global miRNAs expression in kidney and the ingenuity pathway analysis showed that miRNAs viz., let-7e, miR-30e and miR-29b that were associated with hematopoiesis and inflammation. This study provides preliminary evidence that non-lethal Hemo exacerbates RI-induced mortality and cell losses associated with high-dose γ-radiation. We identified some of the initial changes occurring due to CI which may have facilitated in worsening the injury and hampering the recovery of animals ultimately resulting in higher mortality.
authors.affiliation: Radiation Combined Injury Program, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America; Department of Radiation Biology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America; Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America.
authors.forename: Juliann G
authors.initials: JG
authors.lastname: Kiang
authors.affiliation: Radiation Combined Injury Program, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America.
authors.forename: Joan T
authors.initials: JT
authors.lastname: Smith
authors.affiliation: Radiation Combined Injury Program, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America.
authors.forename: Marsha N
authors.initials: MN
authors.lastname: Anderson
authors.affiliation: Department of Radiation Biology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America; Department of Military and Emergency Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America; Undersea Medicine Department, Naval Medical Research Center, Silver Spring, Maryland, United States of America.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Swift
authors.affiliation: Comparative Pathology Division, Veterinary Sciences Department, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Christensen
authors.affiliation: Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America.
authors.forename: Paridhi
authors.initials: P
authors.lastname: Gupta
authors.affiliation: Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America.
authors.forename: Nagaraja
authors.initials: N
authors.lastname: Balakathiresan
authors.affiliation: Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America.
authors.forename: Radha K
authors.initials: RK
authors.lastname: Maheshwari
mesh_terms: D000740:Anemia / Q000209:etiology / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D001854:Bone Marrow Cells / Q000166:cytology* / Q000378:metabolism / Q000528:radiation effects; D053148:Caspase 3 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D018572:Disease-Free Survival; D004921:Erythropoietin / Q000378:metabolism; D006410:Hematopoiesis / Q000528:radiation effects*; D006470:Hemorrhage / Q000150:complications* / Q000401:mortality / Q000473:pathology; D007249:Inflammation / Q000378:metabolism; D007668:Kidney / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D007928:Lethal Dose 50; D007970:Leukopenia / Q000209:etiology; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011832:Radiation Injuries / Q000150:complications*; D013921:Thrombocytopenia / Q000209:etiology / Q000378:metabolism; D014867:Water / Q000378:metabolism
chemical_list: D016207:Cytokines; C547014:MIRN29 microRNA, mouse; D035683:MicroRNAs; D016328:NF-kappa B; C487931:mirnlet7 microRNA, human; D014867:Water; D004921:Erythropoietin; D053148:Caspase 3