Role of TNFR1 in lung injury and altered lung function induced by the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide.
Lung toxicity induced by sulfur mustard is associated with inflammation and oxidative stress. To elucidate mechanisms mediating pulmonary damage, we used 2-chloroethyl ethyl sulfide (CEES), a model sulfur mustard vesicant. Male mice (B6129) were treated intratracheally with CEES (3 or 6 mg/kg) or control. Animals were sacrificed 3, 7 or 14 days later and bronchoalveolar lavage (BAL) fluid and lung tissue collected. Treatment of mice with CEES resulted in an increase in BAL protein, an indication of alveolar epithelial damage, within 3 days. Expression of Ym1, an oxidative stress marker also increased in the lung, along with inducible nitric oxide synthase, and at 14 days, cyclooxygenase-2 and monocyte chemotactic protein-1, inflammatory proteins implicated in tissue injury. These responses were attenuated in mice lacking the p55 receptor for TNFα (TNFR1-/-), demonstrating that signaling via TNFR1 is key to CEES-induced injury, oxidative stress, and inflammation. CEES-induced upregulation of CuZn-superoxide dismutase (SOD) and MnSOD was delayed or absent in TNFR1-/- mice, relative to WT mice, suggesting that TNFα mediates early antioxidant responses to lung toxicants. Treatment of WT mice with CEES also resulted in functional alterations in the lung including decreases in compliance and increases in elastance. Additionally, methacholine-induced alterations in total lung resistance and central airway resistance were dampened by CEES. Loss of TNFR1 resulted in blunted functional responses to CEES. These effects were most notable in the airways. These data suggest that targeting TNFα signaling may be useful in mitigating lung injury, inflammation and functional alterations induced by vesicants.
Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08854, USA. sunilvr@eohsi.rutgers.edu
Vasanthi R
VR
Sunil
Kinal
K
Patel-Vayas
Jianliang
J
Shen
Andrew J
AJ
Gow
Jeffrey D
JD
Laskin
Debra L
DL
Laskin
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D007509:Irritants / Q000633:toxicity*; D008168:Lung / Q000187:drug effects* / Q000503:physiopathology; D055370:Lung Injury / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009151:Mustard Gas / Q000031:analogs & derivatives* / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D007509:Irritants; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; C031278:2-chloroethyl ethyl sulfide; D009151:Mustard Gas