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.

• Authors: Salil K Das, Shyamali Mukherjee, Milton G Smith, Diptendu Chatterjee
• Journal: Journal of biochemical and molecular toxicology (J Biochem Mol Toxicol) Vol. 17 Issue 3 Pg. 177-84 ( 2003) ISSN: 1095-6670 [Print] United States
• PMID: 12815614 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
• Copyright: Copyright 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

Chemical References

• Ceramides
• Free Radical Scavengers
• Free Radicals
• NF-kappa B
• Tumor Necrosis Factor-alpha
• Superoxide Dismutase
• Sphingomyelin Phosphodiesterase
• Caspases
• Mustard Gas
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Animals
• Caspases (metabolism)
• Ceramides (metabolism)
• Electrophoretic Mobility Shift Assay
• Free Radical Scavengers (pharmacology)
• Free Radicals (metabolism)
• Guinea Pigs
• Lung (pathology)
• Lung Diseases (chemically induced, pathology, prevention & control)
• Male
• Mustard Gas (toxicity)
• NF-kappa B (metabolism)
• Sphingomyelin Phosphodiesterase (metabolism)
• Superoxide Dismutase (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)