Inhibition of lung injury, inflammation, and interstitial pulmonary fibrosis by polyethylene glycol-conjugated catalase in a rapid inhalation model of asbestosis.
Several in vitro studies suggest the involvement of active oxygen metabolites in cell damage caused by asbestos. To determine if lung injury, inflammation, and asbestosis could be inhibited in vivo in a rapid-onset, inhalation model of disease, a novel method of chronic administration of antioxidant enzymes was developed. In brief, Fischer 344 rats were treated with polyethylene glycol-conjugated (PEG-) superoxide dismutase or catalase in osmotic pumps over a 10-day (5 days/wk for 2 wk) or 20-day (5 days/wk for 2 wk) period of exposure to crocidolite asbestos. Control rats included sham-exposed animals and those exposed to asbestos but receiving chemically inactivated enzymes. After 10 days of exposure to asbestos, lactic dehydrogenase (LDH), alkaline phosphatase, and total protein in bronchoalveolar lavage (BAL) were measured in one group of rats. Total and differnetial cell counts in BAL also were assessed. After 20 days of exposure, lungs of an additional group of rats were evaluated by histopathology and by measurement of hydroxyproline. Asbestos-associated elevations in LDH, protein, and total cell numbers in BAL were reduced in rats receiving PEG-catalase. Decreases in numbers of alveolar macrophages, polymorphonuclear leukocytes, and lymphocytes occurred in these animals. Exposure to asbestos for 20 days caused significant increases in both the amount of hydroxyproline in lung and the severity and extent of fibrotic lesions as determined by histopathology. These indicators of asbestosis were inhibited in a dosage-dependent fashion in rats receiving PEG-catalase. Use of inactivated PEG-catalase failed to boost serum levels of catalase and did not inhibit asbestos-induced elevation of hydroxyproline in lung.(ABSTRACT TRUNCATED AT 250 WORDS)
Mossman
B T
BT
Department of Pathology, University of Vermont, Burlington 05405.
Marsh
J P
JP
Sesko
A
A
Hill
S
S
Shatos
M A
MA
Doherty
J
J
Petruska
J
J
Adler
K B
KB
Hemenway
D
D
Mickey
R
R
D000818:Animals; D001194:Asbestos; D017638:Asbestos, Crocidolite; D001195:Asbestosis / Q000517:prevention & control*; D001992:Bronchoalveolar Lavage Fluid / Q000032:analysis; D002374:Catalase / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D006909:Hydroxyproline / Q000032:analysis; D008168:Lung / Q000032:analysis / Q000187:drug effects; D008297:Male; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000494:pharmacology*; D011658:Pulmonary Fibrosis / Q000517:prevention & control*; D051381:Rats; D011916:Rats, Inbred F344; D013482:Superoxide Dismutase / Q000008:administration & dosage / Q000494:pharmacology
D017638:Asbestos, Crocidolite; D001194:Asbestos; D011092:Polyethylene Glycols; D002374:Catalase; D013482:Superoxide Dismutase; D006909:Hydroxyproline