Wormser Uri, Langenbach Robert, Peddada Shyamal, Sintov Amnon, Brodsky Berta, Nyska Abraham
Department of Pharmacology, School of Pharmacy, Faculty of Medicine, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
Toxicol Appl Pharmacol. 2004 Oct 1;200(1):40-7. doi: 10.1016/j.taap.2004.03.013.
Sulfur mustard (SM), a potent vesicant and chemical warfare agent, induces tissue damage involving an inflammatory response, including vasodilatation, polymorphonuclear infiltration, production of inflammatory mediators, and cyclooxygenase activity. To evaluate the role of cyclooxygenase-1 and -2 (COX-1, COX-2) in sulfur mustard-induced skin toxicity, we applied the agent to the ears of wildtype (WT) and COX-1- and COX-2-deficient mice. In the latter, ear swelling 24 and 48 h after exposure was significantly reduced (P < 0.05) by 55% and 30%, respectively, compared to WT. Quantitative histopathology revealed no epidermal ulceration in COX-2-deficient mice but some degree of severity in WT. COX-2-deficient mice showed significant reductions (P < 0.05) in severity of epidermal necrosis (29%), acute inflammation (42%), and hemorrhage (25%), compared to the WT mice. COX-1 deficiency resulted in significant exacerbation (P < 0.05) in severity of some parameters, including increases of 4.6- and 1.2-fold in epidermal ulceration and epidermal necrosis, respectively, compared to WT. Postexposure treatment of normal male ICR mice with the selective COX-2 inhibitor celecoxib resulted in significant reductions of 27% (P < 0.05) and 28% (P < 0.01) in ear swelling at intervals of 40 and 60 min between exposure and treatment, respectively. Histopathological evaluation revealed significant reductions (P < 0.05) in subepidermal microblister formation (73%) and dermal necrosis (32%), compared to the control group. These findings may indicate that COX-2 participates in the early stages of sulfur mustard-induced acute skin toxicity and that COX-1 might exert some protective function against this chemical insult.
硫芥（SM）是一种强效的糜烂性毒剂和化学战剂，可引起包括血管舒张、多形核白细胞浸润、炎症介质产生和环氧化酶活性在内的炎症反应，进而导致组织损伤。为了评估环氧化酶-1和-2（COX-1、COX-2）在硫芥诱导的皮肤毒性中的作用，我们将该毒剂涂抹于野生型（WT）小鼠以及COX-1和COX-2基因缺陷型小鼠的耳部。在基因缺陷型小鼠中，暴露后24小时和48小时的耳部肿胀与野生型小鼠相比分别显著降低了55%和30%（P<0.05）。定量组织病理学检查显示，COX-2基因缺陷型小鼠未出现表皮溃疡，而野生型小鼠有一定程度的严重程度。与野生型小鼠相比，COX-2基因缺陷型小鼠的表皮坏死严重程度（29%）、急性炎症（42%）和出血（25%）显著降低（P<0.05）。与野生型相比，COX-1基因缺陷导致某些参数的严重程度显著加重（P<0.05），包括表皮溃疡和表皮坏死分别增加4.6倍和1.2倍。用选择性COX-2抑制剂塞来昔布对正常雄性ICR小鼠进行暴露后处理，在暴露与处理间隔40分钟和60分钟时，耳部肿胀分别显著降低27%（P<0.05）和28%（P<0.01）。组织病理学评估显示，与对照组相比，表皮下微水疱形成（73%）和真皮坏死（32%）显著减少（P<0.05）。这些发现可能表明COX-2参与了硫芥诱导的急性皮肤毒性的早期阶段，而COX-1可能对这种化学损伤发挥一定的保护作用。
