Abstract
Mustard gas exposure causes adult respiratory distress syndrome associated with lung injury. The purpose of this study was to investigate whether an antioxidant, such as N‐acetylcysteine (NAC), has any protective effect. Guinea pigs were given single exposure (0.5–6 mg/kg body weight) of 2‐chloroethyl ethyl sulfide (CEES) as a mustard analogue intratracheally and maintained for various lengths of time (1 h to 21 days). Within 1 h of CEES infusion at 4 mg/kg, high levels of tumor necrosis factor α (TNF‐α), ceramides, and nuclear factor κB accumulated in lung and alveolar macrophages. Both acid and neutral sphingomyelinases were activated within 4 h. These signal transduction events were associated with alteration in the oxygen defense system. Within 1 h of exposure to CEES (6 mg/kg body weight), there was 10‐fold increase in the ^125^I‐BSA leakage into lung tissue, indicating severe lung injury. Although low level of CEES exposure (0.5 mg/kg body weight) produced symptoms of chemical burn in lung as early as 1 h after exposure, the severity of edema, congestion, hemorrhage, and inflammation increased progressively with time (1 h to 21 days). Feeding of single dose of NAC (0.5 g) by gavage just before the CEES infusion was ineffective to counteract these effects. However, consumption of the antioxidant in drinking water for 3 or 30 days prior to CEES exposure significantly inhibited the induction of TNF‐α, activation of neutral and acid sphingomyelinases, production of ceramides, activation of caspases, leakage of ^125^I‐bovine serum albumin (^125^I‐BSA) into lung tissue, and histological alterations in lung. Pretreatment with NAC for 3 and 30 days protected against 69–76% of the acute lung injury. Therefore, NAC may be an antidote for CEES‐induced lung injury. © 2003 Wiley Periodicals, Inc. J Biochem Mol Toxicol 17:177–184, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.10076