Inhibition of Lung Injury, Inflammation, and Interstitial Pulmonary Fibrosis by Polyethylene Glycol-conjugated Catalase in a Rapid Inhalation Model of Asbestosis

Abstract

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)

Asbestos-derived reactive oxygen species activate TGF-β1

“…In support of this concept, patients with IPF demonstrate increased oxidant/antioxidant balance 37 as well as increases of both active and latent TGF-b 1 in their BAL fluids correlating with disease. 38,39 Also, in vivo models of asbestos exposure have shown excessive oxidative stress in response to the initial fiber deposition, 4 and the extent of lesion formation and lung injury was ablated through the systemic administration of antioxidants. 4 We showed that asbestos-derived ROS activate TGF-b 1 in cell culture subsequent to growth factor transduction in A549 cells and MLE cells (Figures 4 and 7).…”

“…38,39 Also, in vivo models of asbestos exposure have shown excessive oxidative stress in response to the initial fiber deposition, 4 and the extent of lesion formation and lung injury was ablated through the systemic administration of antioxidants. 4 We showed that asbestos-derived ROS activate TGF-b 1 in cell culture subsequent to growth factor transduction in A549 cells and MLE cells (Figures 4 and 7). Activation was prevented through the use of the cellular antioxidants SOD and catalase and the iron chelator deferoxamine, supporting our postulate of an oxidative pathway for TGF-b 1 activation.…”

“…1 ROS have been demonstrated to contribute to asbestos-induced alveolar cell injury and carcinogenesis through generation of DNA strand breaks, 2 lipid peroxidation 3 and apoptosis. 1 These cytotoxic and fibrogenic effects can be decreased through the use of antioxidants 4 and through the treatment of asbestos with iron-chelating agents. 5 Some investigators assume that chrysotile asbestos does not contain bioavailable iron, but this is not the case.…”

Increased sensitivity to asbestos-induced lung injury in mice lacking extracellular superoxide dismutase

“…It has been previously shown that asbestos, particularly the highly fibrogenic amphibole fibers, can cause oxidative damage to the lung both directly, through hydroxyl radical formation via the Haber-Weiss reaction with fiber surface iron [10,11], and indirectly through recruitment and activation of ROS-producing inflammatory cells [12][13][14]. A variety of antioxidants including manganese superoxide dismutase, catalase, and iron chelators such as deferoxamine have shown protective effects in a variety of in vitro and in vivo models of asbestos-mediated lung disease [15][16][17][18].…”

Review: Ferruginous Bodies: Implications in the Mechanism of Fiber and Particle Toxicity

“…Treatment with iron chelators decreases this activity, suggesting metal catalysis (Ghio et al, 1992). In addition, fibers and particles can produce free radicals and tissue injury after exposure can be associated with such oxidant exposure (Mossman et al, 1990). An association between surface functional groups, metal complexation, oxidant generation, and biological effects in the lung could explain a differential in the toxicity of ultrafines, fine, and coarse particles.…”