Time course of airway remodelling after an acute chlorine gas exposure in mice

Abstract

Accidental chlorine (Cl 2 ) gas inhalation is a common cause of acute airway injury. However, little is known about the kinetics of airway injury and repair after Cl 2 exposure. We investigated the time course of airway epithelial damage and repair in mice after a single exposure to a high concentration of Cl 2 gas. Mice were exposed to 800 ppm Cl 2 gas for 5 minutes and studied from 12 hrs to 10 days post-exposure. The acute injury phase after Cl 2 exposure (≤ 24 hrs post-exposure) was characterized by airway epithelial cell apoptosis (increased TUNEL staining) and sloughing, elevated protein in bronchoalveolar lavage fluid, and a modest increase in airway responses to methacholine. The repair phase after Cl 2 exposure was characterized by increased airway epithelial cell proliferation, measured by immunoreactive proliferating cell nuclear antigen (PCNA), with maximal proliferation occurring 5 days after Cl 2 exposure. At 10 days after Cl 2 exposure the airway smooth muscle mass was increased relative to controls, suggestive of airway smooth muscle hyperplasia and there was evidence of airway fibrosis. No increase in goblet cells occurred at any time point. We conclude that a single exposure of mice to Cl 2 gas causes acute changes in lung function, including pulmonary responsiveness to methacholine challenge, associated with airway damage, followed by subsequent repair and airway remodelling.

Mitigation of chlorine gas lung injury in rats by postexposure administration of sodium nitrite

“…Similarly, the hypoxemia that is prevalent immediately after Cl 2 gas exposure recovers close to baseline levels by 6 h. Previous measurements of arterial PO 2 in rats exposed to 400 ppm Cl 2 for 30 min and returned to room air for 24 h were consistent with the presence of arterial hypoxemia, corresponding to an oxygen saturation of ϳ90%, similar to that found in this study (22), within the experimental error of the measurements. Importantly, however, and despite improvement in indexes of oxygenation, lung permeability, and inflammation within 24 h of exposure, emerging data show that long-term pulmonary dysfunction occurs (observed over several days after Cl 2 exposure), as evidenced by the development of reactive airway syndrome (23,35) and decreased pulmonary function (19,29). This further underscores the need for a better understanding of the mechanisms that mediate post-Cl 2 exposure lung injury and development of targeted postexposure therapies that can prevent secondary injury and/or facilitate repair.…”

Lung Function before and after a Large Chlorine Gas Release in Graniteville, South Carolina

“…Translational and animal studies demonstrate that acute chlorine-induced lung injury can produce precipitous functional decline, and the potential for irreversible epithelial damage (7)(8)(9)(10)(11). In humans, chlorine concentrations as low as 10 ppm can overcome upper airway defense mechanisms and penetrate into lower respiratory structures (12,13).…”

AEOL10150: A Novel Therapeutic For Rescue Treatment Following Toxic Gas Lung Injury

“…[3,[16][17][18] The mechanism of AHR following Cl 2 may be similar to that of ozone in that both forms of injury are associated with oxidant damage to the tissues. [19] In our study, mice received a single dose of Cl 2 and although baseline mechanical parameters were unchanged there was an increase in respiratory system resistance and elastance in response to MCh.…”

“…In addition, epithelial apoptosis and necrosis and airway hyperresponsivness can occur. [7,8] Epithelial cell damage has been observed in rodents exposed to Cl 2 gas including denudation of the epithelium, followed by repopulation of the epithelial cell layers. [8] The molecular properties of Cl 2 are such that it has an extremely high propensity to oxidize.…”

“…[7,8] Epithelial cell damage has been observed in rodents exposed to Cl 2 gas including denudation of the epithelium, followed by repopulation of the epithelial cell layers. [8] The molecular properties of Cl 2 are such that it has an extremely high propensity to oxidize. It has been shown to have greater toxicity than nitrogen dioxide (NO 2 ), oxygen (O 2 ) or ozone (O 3 ), a property that may be related, in part, to its high water solubility.…”