Histological Assessment of Lung Injury in Rats Exposed to Inhaled Sulfur Mustard across Dose and Time.

摘要

Sulfur mustard (HD) causes severe chemical bur ns to the skin, eyes, and airways. HD was used as a chemical warfare agent (CWA) in th e Iran/Iraq conflict, and more than half of surviving HD-exposed casualties continues to suffer from permanent lung injuries. The mechanisms and timing of the development of th ese pathologies are poorly defined, and there is no effective antidote. Rats were intubated a nd ventilated for 10 min with nebulized HD or vehicle to achieve total doses of 0, 0.5, 1.75, 2.25, or 3.0 mg/kg. Lung samples were removed at various time points from 3 h to 6 months post- exposure. Tissue samples were fixed using standard H&E processes. Throughout the disease time-course regardless of HD dose, the most striking histologic lesions were associated with the conducting airways, i.e., the trachea and "mainstem bronchioles" (specifically defined in this study as the intrapulmonary bronchi and the primary bronchioles). Epithelial necrosis, clefting, and loss; acute fibrinous inflammatory exudation; and pseudomembrane formation were common early. By the third week a combination of epithelial attenuation, goblet cell hyperplasia, and squamous metaplasia (often in the same airway) along with a mostly proteinaceous exudate were a noteworthy findings. Also by the third week and extending to 6 months post-challenge, focally extensive subepithelial fibrous proliferations that progressed to well-organized fibroepithelial polyps occluded airway lumina by as much as 50%. Such lesions were only seen in the mainstem bronchioles and never in the terminal bronchioles. Bronchoalveolar lymphoid tissue (BALT) lymphocytolysis was common in high-dosed animals but was not a significant feature 72 hours after challenge. Histologic lesions were also present in the centroacinar region (terminal bronchioles and alveoli), particularly adjacent to the mainstem bronchioles, but lessened in severity towards the periphery of the lobe.