Medeiros Rodrigo, Figueiredo Cláudia P, Passos Giselle F, Calixto João B
Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Santa Catarina, Brazil.
Biochem Pharmacol. 2009 Aug 15;78(4):390-5. doi: 10.1016/j.bcp.2009.04.021. Epub 2009 May 3.
The skin is the largest organ in the body and one of its main functions is to protect the body from environmental and endogenous noxious conditions, such as injury, infection and inflammation. The inducible nitric oxide synthase (iNOS) has been implicated as a key component in the inflammatory response. In the present study, we assessed the role of iNOS in the skin inflammation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). Mice deficient in iNOS had reduced edema and cellular infiltration in the skin following topical TPA application. Moreover, the genetic blockage of iNOS signaling inhibited the TPA-induced ERK and p38 activation resulting in reduced COX-2 upregulation. Finally, immunohistochemical studies revealed that iNOS knockout mice exhibited marked inhibition of AP-1, CREB and NF-kappaB transcriptional factors activation. Together, these results indicate that TPA induces the activation of several iNOS-dependent intracellular signaling pathways that have a key role in the control of inflammatory response in the skin. Therefore, selective iNOS inhibitors may be potentially relevant tools for cutaneous skin disease drug development.
皮肤是人体最大的器官，其主要功能之一是保护身体免受环境和内源性有害因素的侵害，如损伤、感染和炎症。诱导型一氧化氮合酶（iNOS）被认为是炎症反应的关键组成部分。在本研究中，我们评估了iNOS在12-O-十四酰佛波醇-13-乙酸酯（TPA）诱导的皮肤炎症中的作用。局部应用TPA后，iNOS缺陷小鼠皮肤中的水肿和细胞浸润减少。此外，iNOS信号通路的基因阻断抑制了TPA诱导的ERK和p38激活，导致COX-2上调减少。最后，免疫组织化学研究表明，iNOS基因敲除小鼠的AP-1、CREB和NF-κB转录因子激活受到明显抑制。这些结果共同表明，TPA诱导了几种依赖iNOS的细胞内信号通路的激活，这些通路在控制皮肤炎症反应中起关键作用。因此，选择性iNOS抑制剂可能是皮肤疾病药物开发的潜在相关工具。
