Differences in lung glutathione metabolism may account for rodent susceptibility in elastase-induced emphysema development

Abstract

Borzone GR, Liberona LF, Bustamante AP, Saez CG, Olmos PR, Vecchiola A, Villagrán A, Serrano C, Reyes TP. Differences in lung glutathione metabolism may account for rodent susceptibility in elastase-induced emphysema development. Am J Physiol Regul Integr Comp Physiol 296: R1113-R1123, 2009. First published January 14, 2009 doi:10.1152/ajpregu.90361.2008.-Syrian Golden hamsters develop more severe emphysema than Sprague-Dawley rats after intratracheal instillation of the same dose of elastase/body weight. Although species variations in antielastase defenses may largely explain these results, other variables, such as differences in lung antioxidants, cannot be overlooked since oxidative stress modulates antiprotease activity. We propose that elastase instillation might affect lung glutathione (GSH) metabolism differently in these species. Our aim was to study in hamsters and rats, lung glutathione metabolism at different times, from the stage of diffuse alveolar damage to advanced emphysema. We measured total and oxidized glutathione content as well as activity and expression of enzymes related to GSH synthesis and redox cycling: ␥-glutamylcysteine synthetase, glutathione peroxidase, and glutathione reductase. Whereas rats showed no significant changes in these measurements, hamsters showed significant derangement in GSH metabolism early after elastase instillation: 25% fall in total GSH (P Ͻ 0.05) with no increase in oxidized glutathione associated with reduced enzyme activities 24 h after elastase [60% for ␥-glutamylcysteine synthetase (P Ͻ 0.01), 30% for glutathione peroxidase (P Ͻ 0.01), and 75% for glutathione reductase (P Ͻ 0.001)]. GSH homeostasis was restored at the end of the first week, involving transient increased expression of these enzymes. We conclude that elastase induces significant alterations in GSH metabolism of hamster lungs and no overall change in rat lungs. Although differences in disease severity may account for our findings, the hamster becomes vulnerable to functional inhibition of ␣ 1-antitrypsin by oxidants and thus, even more susceptible to injury than it would be, considering only its low ␣ 1-antitrypsin level.diffuse alveolar damage; ␥-glutamyl-cysteine synthetase; glutathione peroxidase; glutathione reductase; lung susceptibility to elastase; pulmonary emphysema MECHANISMS INVOLVED IN THE pathogenesis of pulmonary emphysema have been studied in animal models following elastase intratracheal (IT) instillation. A single dose of the protease in rodents induces within hours, diffuse alveolar damage with edema, hemorrhage, inflammatory cell infiltration, and rapid destruction of the extracellular matrix, resulting in airspace enlargement (25,28,29,34,39), which continues to develop over weeks and months (4, 5, 21). However, the severity of permanent lung damage after the initial injury differs among Syrian Golden hamsters and Sprague-Dawley rats. Indeed, the same dose/100 g body wt of elastase induces in hamsters a destructive lesion that resembles human panacinar emphysema, whereas ...

Elastase-induced pulmonary emphysema: insights from experimental models

“…Animal models also develop increased protein synthesis by lipid peroxidation products, such as 4-hydroxynonenal, and depletion of antioxidant substances, such as superoxide dismutase, catalase, ascorbic acid and glutathione (McCusker and Hoidal 1990, Churg and Cherukupalli 1993, Cavarra et al 2001, Aoshiba et al 2003a). Few studies have investigated the association of protease-induced emphysema with oxidative stress (Mattson et al 2002, Petrache et al 2008, Borzone et al 2009). It has been evidenced that oxidant attack diminishes α1-antitrypsin (α1-AT) affinity for elastase by the oxidation of a methionine residue at its active site.…”

“…1). Borzone and colleagues (2009) describe that the modulation of elastase over pulmonary glutathione metabolism depends on the animal species, suggesting a geneticspecific degree of oxidant-antioxidant imbalance (Borzone et al 2009). …”

“…Compared to mice and rats, hamsters are easily susceptible to lung inflammation, hemorrhage, and oxidative stress (Corteling et al 2002, Borzone et al 2009). Therefore, hamsters are often used in experimental COPD models.…”

“…It has been reported that hamsters present relatively low levels of α1-antitrypsin, which would favor emphysema caused by proteolytic attack on the lung (Lieberman 1976, Jannof 1985. Borzone and colleagues (2009) have used one single protocol (fixed dose/100 g body weight) to demonstrate different interspecies response (Borzone et al 2009). They evidenced that hamster lungs are highly susceptible to injury by elastase and present early total glutathione depletion and significant inhibition of the main enzymes involved in glutathione metabolism (γ -glutamylcysteine, glutathione peroxidase, glutathione reductase).…”

“…They evidenced that hamster lungs are highly susceptible to injury by elastase and present early total glutathione depletion and significant inhibition of the main enzymes involved in glutathione metabolism (γ -glutamylcysteine, glutathione peroxidase, glutathione reductase). In turn, rat lungs are less susceptible to elastase injury, and exhibit subtle or no reduction in glutathione content or in glutathione-related enzyme activities after elastase instillation (Borzone et al 2009). The induction of emphysema is thus easier in hamsters because of the low levels of α1-antitrypsin in this species.…”