title: Whole-thorax irradiation induces hypoxic respiratory failure, pleural effusions and cardiac remodeling.
abstract: To study the mechanisms of death following a single lethal dose of thoracic radiation, WAG/RijCmcr (Wistar) rats were treated with 15 Gy to the whole thorax and followed until they were morbid or sacrificed for invasive assays at 6 weeks. Lung function was assessed by breathing rate and arterial oxygen saturation. Lung structure was evaluated histologically. Cardiac structure and function were examined by echocardiography. The frequency and characteristics of pleural effusions were determined. Morbidity from 15 Gy radiation occurred in all rats 5 to 8 weeks after exposure, coincident with histological pneumonitis. Increases in breathing frequencies peaked at 6 weeks, when profound arterial hypoxia was also recorded. Echocardiography analysis at 6 weeks showed pulmonary hypertension and severe right ventricular enlargement with impaired left ventricular function and cardiac output. Histologic sections of the heart revealed only rare foci of lymphocytic infiltration. Total lung weight more than doubled. Pleural effusions were present in the majority of the irradiated rats and contained elevated protein, but low lactate dehydrogenase, when compared with serum from the same animal. Pleural effusions had a higher percentage of macrophages and large monocytes than neutrophils and contained mast cells that are rarely present in other pathological states. Lethal irradiation to rat lungs leads to hypoxia with infiltration of immune cells, edema and pleural effusion. These changes may contribute to pulmonary vascular and parenchymal injury that result in secondary changes in heart structure and function. We report that conditions resembling congestive heart failure contribute to death during radiation pneumonitis, which indicates new targets for therapy.
authors.affiliation: Department of Radiation Oncology, Medical College of Wisconsin, 8701, Watertown Plank Road, Milwaukee, WI 53226, USA Cardiovascular Center, Medical College of Wisconsin, 8701, Watertown Plank Road, Milwaukee, WI 53226, USA Division of Pulmonary Medicine, Medical College of Wisconsin, 8701, Watertown Plank Road, Milwaukee, WI 53226, USA Research Service, Department of Veteran's Affairs, Clement J. Zablocki VA Medical Center, Milwaukee, Wisconsin, USA medhoram@mcw.edu.
authors.forename: Meetha
authors.initials: M
authors.lastname: Medhora
authors.affiliation: Department of Radiation Oncology, Medical College of Wisconsin, 8701, Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.affiliation: Department of Radiation Oncology, Medical College of Wisconsin, 8701, Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Chad
authors.initials: C
authors.lastname: Glisch
authors.affiliation: Department of Radiation Oncology, Medical College of Wisconsin, 8701, Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Jayashree
authors.initials: J
authors.lastname: Narayanan
authors.affiliation: Department of Radiation Oncology, Medical College of Wisconsin, 8701, Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Ashish
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Cardiovascular Center, Medical College of Wisconsin, 8701, Watertown Plank Road, Milwaukee, WI 53226, USA Division of Cardiovascular Medicine, Medical College of Wisconsin, 8701, Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Leanne M
authors.initials: LM
authors.lastname: Harmann
authors.affiliation: Division of Pediatric Pathology, Medical College of Wisconsin, 8701, Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Lawlor
authors.affiliation: Marshfield Laboratories; Wisconsin Veterinary Referral Hospital, Waukesha, Wisconsin, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Snyder
authors.affiliation: Department of Radiation Oncology, Medical College of Wisconsin, 8701, Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Fish
authors.affiliation: Harvard-Massachusetts Institute of Technology Division of Health Sciences Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Julian D
authors.initials: JD
authors.lastname: Down
authors.affiliation: Department of Radiation Oncology, Medical College of Wisconsin, 8701, Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Moulder
authors.affiliation: Cardiovascular Center, Medical College of Wisconsin, 8701, Watertown Plank Road, Milwaukee, WI 53226, USA Division of Cardiovascular Medicine, Medical College of Wisconsin, 8701, Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Strande
authors.affiliation: Cardiovascular Center, Medical College of Wisconsin, 8701, Watertown Plank Road, Milwaukee, WI 53226, USA Division of Pulmonary Medicine, Medical College of Wisconsin, 8701, Watertown Plank Road, Milwaukee, WI 53226, USA Research Service, Department of Veteran's Affairs, Clement J. Zablocki VA Medical Center, Milwaukee, Wisconsin, USA.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Jacobs
mesh_terms: D000818:Animals; D005260:Female; D006333:Heart Failure; D010996:Pleural Effusion / Q000209:etiology / Q000503:physiopathology*; D011829:Radiation Dosage; D011832:Radiation Injuries / Q000209:etiology / Q000503:physiopathology*; D017564:Radiation Pneumonitis / Q000209:etiology / Q000503:physiopathology*; D051381:Rats; D012131:Respiratory Insufficiency / Q000209:etiology / Q000503:physiopathology*; D015996:Survival Rate; D013909:Thorax / Q000528:radiation effects*; D014916:Whole-Body Irradiation
keywords: mast cells; radiation pneumonitis; right ventricular mass; tachypnea