Borzone G, Liberona L, Olmos P, Sáez C, Meneses M, Reyes T, Moreno R, Lisboa C. Rat and hamster species differences in susceptibility to elastase-induced pulmonary emphysema relate to differences in elastase inhibitory capacity. Am J Physiol Regul Integr Comp Physiol 293: R1342-R1349, 2007. First published July 18, 2007; doi:10.1152/ajpregu.00343.2007.-Syrian Golden hamsters develop severe emphysema after a single intratracheal dose of elastase, whereas Sprague-Dawley rats exhibit mild emphysema with the same dose per kilogram body weight. We hypothesized that the development of severe emphysema is prevented in rats by the high serum level of ␣1-antitrypsin reported in rats, compared with hamsters, which provides for a high lung elastase inhibitory capacity (EIC). To explore this possibility, we challenged the antiprotease system of the rats by treating them with three similar weekly doses of elastase. Four months after treatment, we evaluated changes in histology, volume, and elastic properties of rat lungs and compared them with those of hamsters receiving a single dose of elastase. We also measured serum ␣1-antitrypsin levels and serum and lung EIC in control rats and hamsters. Results showed that, in association with 40% less serum and lung EIC compared with rats (P Ͻ 0.001), hamster lungs had upperlobe bullae formation, severe microscopic emphysema, a fourfold increase in lung volume (P Ͻ 0.01) and a threefold increase in constant k, an index of compliance, of the lung deflation pressurevolume curve (P Ͻ 0.01). In contrast, rats developed mild emphysema, with only 50% increase in volume (P Ͻ 0.05) and 60% increase in constant k (P Ͻ 0.01). In conclusion, two species that differ in serum and lung EIC exhibit significant differences in emphysema development after elastase. Rats with high EIC, despite receiving three doses of elastase, showed significantly less derangement of morphological and physiological parameters than hamsters with low EIC receiving a single dose. alpha1-antitrypsin; disease models; lung mechanics; susceptibility THE DISCOVERY OF AN ASSOCIATION between emphysema and severe alpha1-antitrypsin (␣1-AT) deficiency (23, 24) and the finding that instilled papain into the lungs of experimental animals resulted in emphysema (15), support the hypothesis that an imbalance between proteases and antiproteases plays a major role in the pathogenesis of chronic obstructive pulmonary disease (COPD) (15,23,24,47). Animal models of intratracheal (IT) instillation of elastase have since been used to induce in a short period of time protease/antiprotease imbalance for the purpose of studying mechanisms involved in the pathogenesis of emphysema downstream protease release. Several investigators have shown that a single dose of elastase induces diffuse alveolar damage and rapid destruction of the alveolar septa, resulting in airspace enlargement (25, 40 -43).To date, studies specifically designed to compare the magnitude and/or the pattern of elastase-induced emphysema between rodent species are unavailable,...
The hypothesis that nitric oxide plays a key role in the regulation of adrenal blood flow and plasma concentrations of cortisol and catecholamines under basal and hypoxaemic conditions in the llama fetus was tested. At 0.6‐0.8 of gestation, 11 llama fetuses were surgically prepared for long‐term recording under anaesthesia with vascular and amniotic catheters. Following recovery all fetuses underwent an experimental protocol based on 1 h of normoxaemia, 1 h of hypoxaemia and 1 h of recovery. In nine fetuses, the protocol occurred during fetal i.v. infusion with saline and in five fetuses during fetal i.v. treatment with the nitric oxide synthase inhibitor l‐NAME. Adrenal blood flow was determined by the radiolabelled microsphere method during each of the experimental periods during saline infusion and treatment with l‐NAME. Treatment with l‐NAME during normoxaemia led to a marked fall in adrenal blood flow and a pronounced increase in plasma catecholamine concentrations, but it did not affect plasma ACTH or cortisol levels. In saline‐infused fetuses, acute hypoxaemia elicited an increase in adrenal blood flow and in plasma ACTH, cortisol, adrenaline and noradrenaline concentrations. Treatment with l‐NAME did not affect the increase in fetal plasma ACTH, but prevented the increments in adrenal blood flow and in plasma cortisol and adrenaline concentrations during hypoxaemia in the llama fetus. In contrast, l‐NAME further enhanced the increase in fetal plasma noradrenaline. These data support the hypothesis that nitric oxide has important roles in the regulation of adrenal blood flow and adrenal corticomedullary functions during normoxaemia and hypoxaemia functions in the late gestation llama fetus.
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 ...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.