Role of TNFR1 in lung injury and altered lung function induced by the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide

Journal Article · Mon Jan 31 23:00:00 EST 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2010.10.027· OSTI ID:21535221

Patel-Vayas, Kinal ^[1]; Shen, Jianliang ^[1]

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1. Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08854 (United States)

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 TNF{alpha} (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 TNF{alpha} 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 TNF{alpha} signaling may be useful in mitigating lung injury, inflammation and functional alterations induced by vesicants.

• OSTI ID: 21535221
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 3 Vol. 250; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANIMALS
BODY
BRASSICA
CHALCOGENIDES
CONTROL
ELEMENTS
ENZYMES
FOOD
INFLAMMATION
LAVAGE
LUNGS
MAGNOLIOPHYTA
MAGNOLIOPSIDA
MALES
MAMMALS
MICE
NITRIC OXIDE
NITROGEN COMPOUNDS
NITROGEN OXIDES
NONMETALS
ORGANIC COMPOUNDS
ORGANS
OXIDES
OXIDOREDUCTASES
OXYGEN COMPOUNDS
PATHOLOGICAL CHANGES
PLANTS
PROTEINS
RESPIRATORY SYSTEM
RODENTS
SULFIDES
SULFUR
SULFUR COMPOUNDS
SUPEROXIDE DISMUTASE
SYMPTOMS
TOXICITY
VEGETABLES
VERTEBRATES