Inflammatory effects of inhaled sulfur mustard in rat lung.
Inhalation of sulfur mustard (SM), a bifunctional alkylating agent that causes severe lung damage, is a significant threat to both military and civilian populations. The mechanisms mediating its cytotoxic effects are unknown and were investigated in the present studies. Male rats Crl:CD(SD) were anesthetized, and then intratracheally intubated and exposed to 0.7-1.4mg/kg SM by vapor inhalation. Animals were euthanized 6, 24, 48h or 7days post-exposure and bronchoalveolar lavage fluid (BAL) and lung tissue collected. Exposure of rats to SM resulted in rapid pulmonary toxicity, including focal ulceration and detachment of the trachea and bronchial epithelia from underlying mucosa, thickening of alveolar septal walls and increased numbers of inflammatory cells in the tissue. There was also evidence of autophagy and apoptosis in the tissue. This was correlated with increased BAL protein content, a marker of injury to the alveolar epithelial lining. SM exposure also resulted in increased expression of markers of inflammation including cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNFα), inducible nitric oxide synthase (iNOS), and matrix metalloproteinase-9 (MMP-9), each of which has been implicated in pulmonary toxicity. Whereas COX-2, TNFα and iNOS were mainly localized in alveolar regions, MMP-9 was prominent in bronchial epithelium. In contrast, expression of the anti-oxidant hemeoxygenase, and the anti-inflammatory collectin, surfactant protein-D, decreased in the lung after SM exposure. These data demonstrate that SM-induced oxidative stress and injury are associated with the generation of cytotoxic inflammatory proteins which may contribute to the pathogenic response to this vesicant.
Malaviya
Rama
R
Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08854, USA.
Sunil
Vasanthi R
VR
Cervelli
Jessica
J
Anderson
Dana R
DR
Holmes
Wesley W
WW
Conti
Michele L
ML
Gordon
Ronald E
RE
Laskin
Jeffrey D
JD
Laskin
Debra L
DL
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis; D001343:Autophagy; D001992:Bronchoalveolar Lavage Fluid; D002619:Chemical Warfare Agents; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D009151:Mustard Gas / Q000633:toxicity*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011014:Pneumonia / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000975:Antioxidants; D002619:Chemical Warfare Agents; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II; D009151:Mustard Gas