Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08854, USA.
Toxicol Appl Pharmacol. 2011 Feb 1;250(3):245-55. doi: 10.1016/j.taap.2010.10.027. Epub 2010 Nov 9.
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.
芥子气诱导的肺毒性与炎症和氧化应激有关。为了阐明介导肺损伤的机制，我们使用了 2-氯乙基乙基硫醚（CEES），这是一种模型芥子气水疱剂。雄性小鼠（B6129）通过气管内给予 CEES（3 或 6mg/kg）或对照处理。动物在 3、7 或 14 天后处死，并收集支气管肺泡灌洗液（BAL）和肺组织。CEES 处理的小鼠在 3 天内导致 BAL 蛋白增加，这表明肺泡上皮损伤。氧化应激标志物 Ym1 的表达也在肺部增加，同时诱导型一氧化氮合酶增加，在 14 天时，环氧合酶-2 和单核细胞趋化蛋白-1，这些炎症蛋白与组织损伤有关。在缺乏 TNFα 受体 p55 的小鼠（TNFR1-/-）中，这些反应减弱，表明 TNFR1 信号传导是 CEES 诱导损伤、氧化应激和炎症的关键。CEES 诱导的 CuZn-超氧化物歧化酶（SOD）和 MnSOD 的上调在 TNFR1-/-小鼠中延迟或不存在，与 WT 小鼠相比，表明 TNFα介导对肺毒物的早期抗氧化反应。WT 小鼠给予 CEES 还导致肺功能改变，包括顺应性降低和弹性增加。此外，CEES 降低了乙酰甲胆碱诱导的总肺阻力和中央气道阻力的改变。TNFR1 的缺失导致 CEES 对功能反应的迟钝。这些影响在气道中最为明显。这些数据表明，靶向 TNFα 信号可能有助于减轻水疱剂引起的肺损伤、炎症和功能改变。
