title: Enalapril mitigates focal alveolar lesions, a histological marker of late pulmonary injury by radiation to the lung.
abstract: The goal of our study was to identify a histological marker for testing countermeasures for mitigation of late radiation injury to the lung. Pulmonary fibrosis is currently the best described "late effect" in survivors of acute radiation pneumonitis. However, robust fibrosis does not develop in some rodent strains for years after a single dose of radiation to the whole thorax. We observed radiation-associated focal alveolar lesions that were rich in giant cells and macrophages containing cholesterol clefts in the lungs of irradiated WAG/RijCmcr rats. These lesions were first observed after pneumonitis, around 21 weeks after receiving a radiation dose of 13 Gy to the thorax but not until 71 weeks in unirradiated rats. The number of cholesterol clefts increased with time after irradiation through 64 weeks of observation, and at 30 weeks after 13 Gy, cholesterol clefts were associated with several indices of deterioration in lung function. The number of cholesterol clefts in irradiated lung sections were reduced by the angiotensin converting enzyme (ACE) inhibitor enalapril (25-42 mg/m²/day) from 18.7 ± 4.2/lung section to 6.8 ± 2.4 (P = 0.029), 5.2 ± 1.9 (P = 0.0051) and 6.7 ± 1.9 (P = 0.029) when the drug was started at 1 week, 5 or 15 weeks after irradiation, respectively, and continued. Similar lesions have been previously observed in the lungs of one strain of irradiated mice and in patients following radiotherapy. We propose that alveolar lesions with cholesterol clefts may be used as a histological marker of the severity of radiation lung injury and to study its mitigation in WAG/RijCmcr rats.
authors.affiliation: Departments of Radiation Oncology, Marquette University, Milwaukee, Wisconsin, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.forename: Jayashree
authors.initials: J
authors.lastname: Narayanan
authors.forename: Cortney
authors.initials: C
authors.lastname: Joneikis
authors.forename: Brian L
authors.initials: BL
authors.lastname: Fish
authors.forename: Aniko
authors.initials: A
authors.lastname: Szabo
authors.forename: John E
authors.initials: JE
authors.lastname: Moulder
authors.forename: Robert C
authors.initials: RC
authors.lastname: Molthen
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Jacobs
authors.forename: R Nagarjun
authors.initials: RN
authors.lastname: Rao
authors.forename: Meetha
authors.initials: M
authors.lastname: Medhora
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D002784:Cholesterol / Q000378:metabolism; D004656:Enalapril / Q000627:therapeutic use*; D005260:Female; D007150:Immunohistochemistry; D008168:Lung / Q000528:radiation effects*; D055370:Lung Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000473:pathology; D011832:Radiation Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D000097382:CD68 Molecule
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D002784:Cholesterol; D004656:Enalapril; D009195:Peroxidase; C539355:CD68 protein, rat; D000097382:CD68 Molecule