Department of Pharmacology, Infectious Diseases Medical Research Center, College of Medicine, Hallym University, Chuncheon, Republic of Korea.
Toxicol Appl Pharmacol. 2012 Jan 1;258(1):82-8. doi: 10.1016/j.taap.2011.10.010. Epub 2011 Oct 18.
Sulfur mustard (2,2'-bis-chloroethyl-sulfide; SM) has been a military threat since the World War I. The emerging threat of bioterrorism makes SM a major threat not only to military but also to civilian world. SM injury elicits an inflammatory response characterized by infiltration of neutrophils. Although SM was reported to prime neutrophils, the mechanism has not been identified yet. In the present study, we investigated the mechanism of SM-induced priming in human neutrophils. SM increased Ca(2+) in human neutrophils in a concentration-dependent fashion. Transient receptor potential melastatin (TRPM) 2 inhibitors (clotrimazole, econazole and flufenamic acid) and silencing of TRPM2 by shRNA attenuated SM-induced Ca(2+) increase. SM primed degranulation of azurophil and specific granules in response to activation by fMLP as previously reported. SB203580, an inhibitor of p38 MAPK, inhibited SM-induced priming. Neither PD98057, an ERK inhibitor, nor SP600215, a JNK inhibitor, inhibited SM-induced priming. In addition, SM enhanced phosphorylation of NF-kB p65 and release of TNF-α, interleukin (IL)-6 and IL-8. SB203580 inhibited SM-induced NF-kB phosphorylation and cytokine release. These results suggest the involvement of TRPM2/p38 MAPK pathway in SM-induced priming and cytokines release in neutrophils.
芥子气（2,2'-双氯乙基硫醚；SM）自第一次世界大战以来一直是一种军事威胁。生物恐怖主义的新威胁不仅对军事，而且对平民世界都构成了重大威胁。SM 损伤会引发炎症反应，其特征是中性粒细胞浸润。尽管有报道称 SM 可引发中性粒细胞的致敏作用，但尚未确定其机制。在本研究中，我们研究了 SM 诱导人中性粒细胞致敏的机制。SM 以浓度依赖的方式增加人中性粒细胞中的 Ca(2+)。瞬时受体电位 melastatin (TRPM) 2 抑制剂（克霉唑、益康唑和氟芬那酸）和通过 shRNA 沉默 TRPM2 减弱了 SM 诱导的 Ca(2+)增加。SM 如先前报道的那样，可引发嗜苯胺和特异性颗粒的脱颗粒反应，以响应 fMLP 的激活。p38 MAPK 的抑制剂 SB203580 抑制了 SM 诱导的致敏作用。ERK 抑制剂 PD98057 和 JNK 抑制剂 SP600215 均未抑制 SM 诱导的致敏作用。此外，SM 增强了 NF-κB p65 的磷酸化和 TNF-α、白细胞介素 (IL)-6 和 IL-8 的释放。SB203580 抑制了 SM 诱导的 NF-κB 磷酸化和细胞因子释放。这些结果表明，TRPM2/p38 MAPK 途径参与了 SM 诱导的中性粒细胞致敏作用和细胞因子释放。
