Acute lung injury and persistent small airway disease in a rabbit model of chlorine inhalation

Abstract

Chlorine is a pulmonary toxicant to which humans can be exposed through accidents or intentional releases. Acute effects of chlorine inhalation in humans and animal models have been well characterized, but less is known about persistent effects of acute, high-level chlorine exposures. In particular, animal models that reproduce the long-term effects suggested to occur in humans are lacking. Here, we report the development of a rabbit model in which both acute and persistent effects of chlorine inhalation can be assessed. Male New Zealand White rabbits were exposed to chlorine while the lungs were mechanically ventilated. After chlorine exposure, the rabbits were extubated and were allowed to survive for up to 24 h after exposure to 800 ppm chlorine for 4 min to study acute effects or up to 7 days after exposure to 400 ppm for 8 min to study longer term effects. Acute effects observed 6 or 24 h after inhalation of 800 ppm chlorine for 4 min included hypoxemia, pulmonary edema, airway epithelial injury, inflammation, altered baseline lung mechanics, and airway hyperreactivity to inhaled methacholine. Seven days after recovery from inhalation of 400 ppm chlorine for 8 min, rabbits exhibited mild hypoxemia, increased area of pressure-volume loops, and airway hyperreactivity. Lung histology 7 days after chlorine exposure revealed abnormalities in the small airways, including inflammation and sporadic bronchiolitis obliterans lesions. Immunostaining showed a paucity of club and ciliated cells in the epithelium at these sites. These results suggest that small airway disease may be an important component of persistent respiratory abnormalities that occur following acute chlorine exposure. This non-rodent chlorine exposure model should prove useful for studying persistent effects of acute chlorine exposure and for assessing efficacy of countermeasures for chlorine-induced lung injury.

Heme scavenging reduces pulmonary endoplasmic reticulum stress, fibrosis, and emphysema

“…Individuals and animals exposed to these toxic gases may develop noncardiogenic pulmonary edema and also significant myocardial injury within hours to days of exposure (23,55). Those that survive often suffer from residual chronic lung disease, with airflow obstruction, fibrosis, airway hyper-reactivity, and impaired gas exchange (57)(58)(59)(60). In our study, the histological examination of mouse lungs after halogen exposure showed evidence of airway fibrosis, alveolar Figure 6.…”

Disease‐modifying treatment of chemical threat agent–induced acute lung injury

“…102 Animals exposed to chlorine develop pulmonary edema and alveolar inflammation characterized by neutrophil recruitment and the appearance of foamy macrophages, alveolar damage with epithelial barrier dysfunction, capillary microthrombi, and fibrin deposition. [103][104][105][106] Similarly, inhalation of high doses of chlorine results in human ALI characterized by pneumonitis, pulmonary edema, and decrements in lung function. 102 Animal exposure models suggest that much of the damage induced by chlorine can be attributed to oxidative stress.…”

TRPA1 and issues relating to animal model selection for extrapolating toxicity data to humans

“…Indeed, until the Romanenko et al 184 article, there was no comparative analysis available between the karyotype of man and that of the guinea pig. In consequence, rodent models such as the mouse [185][186][187][188][189][190][191] and rat 106,[192][193][194][195] and other species such as the rabbit 196,197 have featured prominently in studies on the toxicology of chlorine exposure.…”