title: Repeated exposures to enzyme-generated oxidants cause alveolitis, epithelial hyperplasia, and fibrosis in hamsters.
abstract: Oxidant-mediated epithelial injury and repair processes may promote the development of pulmonary fibrosis. The authors examined this hypothesis by inducing oxidant injury in hamsters with intratracheally instilled mixtures of glucose, glucose oxidase (GO) and lactoperoxidase at weekly intervals. Solutions containing denatured GO (DE) served as a control treatment. One and six days after each treatment, anesthetized animals were sacrificed and lavaged, and their lungs and plasma were preserved for further study. Although DE-treatment consistently evoked a transient, neutrophil-rich inflammatory response, no significant biochemical or morphologic changes were detected at the ensuing 6-day time points. In contrast, repeated GO treatments prolonged inflammation and injured the alveolar epithelium, evidenced by significantly greater levels of neutrophils and macrophages in bronchoalveolar lavage fluid (BALF) and increased BALF levels of protein, beta-glucuronidase and lactic dehydrogenase activities. Active GO also altered BALF lymphocytes and monocytes, but no discernable pattern emerged. Fibrotic, consolidated parenchyma appeared after the second and third GO exposures, coinciding with increased levels of total collagen, prolyl hydroxylase activity, and anti-oxidant enzyme activities. Although alveolitis and type II cell hyperplasia were observed after the initial treatment, polyplike nodules covered by hyperplastic, undifferentiated epithelium were evident after the third treatment. After each exposure, GO-treated animals had larger volumes of parenchymal lesion than DE-treated hamsters. These data indicate that normal alveolar epithelial repair processes were greatly disrupted by repeated oxidant injury and suggest that repeated and/or continued epithelial injury may contribute to the development of pulmonary fibrosis.
authors.affiliation: Department of Veterinary Pharmacology and Toxicology, School of Veterinary Medicine, University of California, Davis 95616.
authors.forename: J M
authors.initials: JM
authors.lastname: Nakashima
authors.forename: J R
authors.initials: JR
authors.lastname: Levin
authors.forename: D M
authors.initials: DM
authors.lastname: Hyde
authors.forename: S N
authors.initials: SN
authors.lastname: Giri
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000378:metabolism / Q000473:pathology; D006224:Cricetinae; D004798:Enzymes / Q000378:metabolism*; D006965:Hyperplasia; D008168:Lung / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D008297:Male; D008647:Mesocricetus; D008854:Microscopy, Electron; D008855:Microscopy, Electron, Scanning; D016877:Oxidants; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000473:pathology
chemical_list: D004798:Enzymes; D016877:Oxidants