Prophylactic protection by N‐acetylcysteine against the pulmonary injury induced by 2‐chloroethyl ethyl sulfide, a mustard analogue

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 alpha (TNF-alpha), ceramides, and nuclear factor kappaB 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-alpha, 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.

Induction of neuronal damage in guinea pig brain by intratracheal infusion of 2‐chloroethyl ethyl sulfide, a mustard gas analog

“…Control animals were infused with 100 μL of vehicle only. The animals were sacrificed after 1 h of CEES exposure, and the leakage of 125 I-BSA into the brain and lung was monitored as described earlier [3]. Data are expressed as the permeability index.…”

“…Brain and lung injury were monitored by studying the leakage of 125 I-bovine serum albumin ( 125 I-BSA, MP Biochemicals Diagnostics, Irvine, CA) into the respective tissues after CEES exposure [3]. Ear veins of guinea pigs were injected with the 125 I-BSA solution (8 μCi/animal).…”

“…Our laboratory has developed a guinea pig model of mustard gas exposure used to study the induction of lung toxicity by 2-chloroethyl ethyl sulfide (CEES), a mustard gas analog. Inhalation of CEES is known to cause hemorrhagic inflammation of the tracheobronchial tree in addition to severe pulmonary complications such as adult respiratory distress syndrome [2,3].…”

A Role for Mitochondrial Oxidative Stress in Sulfur Mustard Analog 2-Chloroethyl Ethyl Sulfide-Induced Lung Cell Injury and Antioxidant Protection

“…CEES, like SM, is an alkylating agent that can bind DNA and other macromolecules within the cell. Recent research into counteragents has focused on bolstering the endogenous antioxidant defenses by supplementation with N-acetyl-cysteine (McClintock et al, 2002;McClintock et al, 2006;Hoesel et al, 2008), vitamin E (Hoesel et al, 2008), GSH (Han et al, 2004), or addition of exogenous SOD or catalase (McClintock et al, 2002(McClintock et al, , 2006Das et al, 2003). Although bolstering endogenous antioxidants can be effective, it is largely unknown how or why this protection occurs.…”

Topical Application of Liposomal Antioxidants for Protection Against CEES Induced Skin Damage

“…This potent antioxidant is capable of restoring intracellular GSH level, and has already been shown to be protective against CEES toxicity in vivo [25]. We have extensively studied the effect of NAC in CEES treated human keratinocytes.…”