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Title: A new model of progressive pulmonary fibrosis in rats

Abstract

Sprague-Dawley rats were exposed for 6 h daily to 0.8 ppm of ozone and 14.4 ppm of nitrogen dioxide. Approximately 7 to 10 wk after the initiation of exposure, animals began to demonstrate respiratory insufficiency and severe weight loss. About half of the rats died between Days 55 and 78 of exposure; no overt ill effects were observed in animals exposed to filtered air, to ozone alone, or to nitrogen dioxide. Biochemical findings in animals exposed to ozone and nitrogen dioxide included increased lung content of DNA, protein, collagen, and elastin, which was about 300% higher than the control values. The collagen-specific crosslink hydroxy-pyridinium, a biomarker for mature collagen in the lung, was decreased by about 40%. These results are consistent with extensive breakdown and remodeling of the lung parenchyma and its associated vasculature. Histopathologic evaluation showed severe fibrosis, alveolar collapse, honeycombing, macrophage and mast cell accumulation, vascular smooth muscle hypertrophy, and other indications of severe progressive interstitial pulmonary fibrosis and end-stage lung disease. This unique animal model of progressive pulmonary fibrosis resembles the final stages of human idiopathic pulmonary fibrosis and should facilitate studying underlying mechanisms and potential therapy of progressive pulmonary fibrosis.

Authors:
; ; ; ;  [1]
  1. (Univ. of California, Davis (United States))
Publication Date:
OSTI Identifier:
6121848
Resource Type:
Journal Article
Resource Relation:
Journal Name: American Review of Respiratory Disease; (United States); Journal Volume: 148:2
Country of Publication:
United States
Language:
English
Subject:
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.; 59 BASIC BIOLOGICAL SCIENCES; LUNGS; FIBROSIS; HYPERTROPHY; NITROGEN DIOXIDE; ENVIRONMENTAL EXPOSURE; OZONE; RATS; MORTALITY; RESPIRATORY SYSTEM DISEASES; BIOLOGICAL MODELS; COLLAGEN; DNA; HYDROXYPROLINE; INHALATION; PROTEINS; PYRIDINES; AMINES; AMINO ACIDS; ANIMALS; AZINES; AZOLES; BODY; CARBOXYLIC ACIDS; CHALCOGENIDES; DISEASES; HETEROCYCLIC ACIDS; HETEROCYCLIC COMPOUNDS; HYDROXY ACIDS; INTAKE; MAMMALS; NITROGEN COMPOUNDS; NITROGEN OXIDES; NUCLEIC ACIDS; ORGANIC ACIDS; ORGANIC COMPOUNDS; ORGANIC NITROGEN COMPOUNDS; ORGANS; OXIDES; OXYGEN COMPOUNDS; PATHOLOGICAL CHANGES; PYRROLES; PYRROLIDINES; RESPIRATORY SYSTEM; RODENTS; SCLEROPROTEINS; VERTEBRATES; 560300* - Chemicals Metabolism & Toxicology; 550900 - Pathology

Citation Formats

Last, J.A., Gelzleichter, T.R., Pinkerton, K.E., Walker, R.M., and Witschi, H. A new model of progressive pulmonary fibrosis in rats. United States: N. p., 1993. Web. doi:10.1164/ajrccm/148.2.487.
Last, J.A., Gelzleichter, T.R., Pinkerton, K.E., Walker, R.M., & Witschi, H. A new model of progressive pulmonary fibrosis in rats. United States. doi:10.1164/ajrccm/148.2.487.
Last, J.A., Gelzleichter, T.R., Pinkerton, K.E., Walker, R.M., and Witschi, H. 1993. "A new model of progressive pulmonary fibrosis in rats". United States. doi:10.1164/ajrccm/148.2.487.
@article{osti_6121848,
title = {A new model of progressive pulmonary fibrosis in rats},
author = {Last, J.A. and Gelzleichter, T.R. and Pinkerton, K.E. and Walker, R.M. and Witschi, H.},
abstractNote = {Sprague-Dawley rats were exposed for 6 h daily to 0.8 ppm of ozone and 14.4 ppm of nitrogen dioxide. Approximately 7 to 10 wk after the initiation of exposure, animals began to demonstrate respiratory insufficiency and severe weight loss. About half of the rats died between Days 55 and 78 of exposure; no overt ill effects were observed in animals exposed to filtered air, to ozone alone, or to nitrogen dioxide. Biochemical findings in animals exposed to ozone and nitrogen dioxide included increased lung content of DNA, protein, collagen, and elastin, which was about 300% higher than the control values. The collagen-specific crosslink hydroxy-pyridinium, a biomarker for mature collagen in the lung, was decreased by about 40%. These results are consistent with extensive breakdown and remodeling of the lung parenchyma and its associated vasculature. Histopathologic evaluation showed severe fibrosis, alveolar collapse, honeycombing, macrophage and mast cell accumulation, vascular smooth muscle hypertrophy, and other indications of severe progressive interstitial pulmonary fibrosis and end-stage lung disease. This unique animal model of progressive pulmonary fibrosis resembles the final stages of human idiopathic pulmonary fibrosis and should facilitate studying underlying mechanisms and potential therapy of progressive pulmonary fibrosis.},
doi = {10.1164/ajrccm/148.2.487},
journal = {American Review of Respiratory Disease; (United States)},
number = ,
volume = 148:2,
place = {United States},
year = 1993,
month = 8
}
  • The net rate of collagen synthesis by lung minces prepared from rats exposed for 7 days to ozone was increased in a dose-dependent manner severalfold above the net rate obtained with lung minces prepared from rats that had breathed only filtered air. Concurrent administration of methylprednisolone during the exposure to ozone prevented the increase in rate of collagen synthesis in a dose-dependent manner for each level of ozone tested. These results could be correlted with lower levels of inflammatory edema measured in the same steroid-treated rats as decreased wet weights of their right apical lung lobes.
  • Changes in collagen metabolism were examined in 3 models of acute respiratory disease in rats. Fibrotic changes in the lungs of rats were provoked by exposing them to paraquat (intraperitoneal), ozone (inhaled), or bleomycin (intratracheally injected). After an interval sufficient to allow histologically discernible fibrosis to occur (6 to 7 days), lungs were removed from the rats, and apparent collagen synthesis rates were determined with cultured lung minces incubated in medium containing 3H-proline. Portions of the 3H-proline-labeled lung minces were then used for quantifying ratios of Type I to Type III collagen. There was no change in Type I/Type IIImore » collagen for total unlabeled collagen, nor was there any detectable increase of total collagen per lung after 1 week. We conclude that an early event in experimental acute respiratory disease is a marked increase in the relative synthesis of Type I collagen; this shift occurs before there is observable increased accumulation of collagen in the lung.« less
  • We investigated the modifying effects of preexisting, bleomycin-induced pulmonary fibrosis on the deposition, retention, and biological effects of inhaled 239PuO2 in the rat. Among rats exposed to similar airborne concentrations of 239PuO2, initial lung burdens of 239Pu per kilogram body mass were similar whether or not pulmonary fibrosis was present. However, clearance of 239Pu from the lungs was significantly decreased in the rats with preexisting pulmonary fibrosis. The incidence of lung lesions (epithelial hyperplasia, diffuse macrophage increases and aggregation, and loose and dense connective tissue) was significantly greater among rats with preexisting pulmonary fibrosis than among the exposed controls. Ratsmore » with preexisting fibrosis had shorter life spans than 239PuO2-exposed control rats. When groups of rats with similar alpha doses to the lungs were compared, the incidences of neoplastic lesions in the lung, the times to death of rats with lung neoplasms, and the risk of lung tumors per unit of alpha dose to the lungs in rats with or without pulmonary fibrosis were similar. The results of this study suggest that humans with uncomplicated pulmonary fibrosis may not be more sensitive to the carcinogenic effects of inhaled 239PuO2 than are individuals with normal lungs, assuming that the total alpha doses to the lungs are similar.« less
  • Rats were injected intraperitoneally with 1 mCi (each) of (3H)lysine at Day 11 of neonatal life to label their lung collagen. Five weeks later, half of the animals were given an intratracheal injection of 1.5 U of bleomycin sulfate via a tracheostomy; control animals received saline intratracheally by the same technique. Age-matched groups of control and bleomycin-treated rats were killed, and their lung collagen was analyzed at zero (control animals only), 1, 2, 4, 6, and 10 wk after bleomycin administration, a time course appropriate for development of pulmonary fibrosis in this animal model. We measured radioactivity in hydroxylysine andmore » in the difunctional collagen crosslinks hydroxylysinonorleucine and dihydroxylysinonorleucine at each time point. No evidence of breakdown of this pool of mature, preformed collagen was observed in lungs of either the control or the bleomycin-treated rats. We also measured the total lung content of hydroxypyridinium, a trifunctional collagen crosslink, by its intrinsic fluorescence. There was no evidence of collagen degradation in lungs of either group of rats by this criterion either. We conclude that there is no biochemically detectable turnover of mature lung collagen, defined as that pool of lung collagen that is obligatorily extracellular (i.e., crosslinked and containing labeled hydroxylysine from an injection of precursor 5 to 15 wk earlier), in either normal rat lungs or lungs of rats made fibrotic with bleomycin. Statistical analysis of the data suggests that our methodology was sensitive and precise enough to have detected turnover of less than 0.5% of lung collagen per day, some 20-fold less than estimates of lung collagen turnover that have been suggested to be occurring in vivo by others using different techniques and presumably studying different pools of lung collagen.« less