The roles of the COXs in normal physiology and in pathological conditions

在先前的研究（Gitlin等人，Cardiovascular Res.，73：227，2007），我们报道了考克斯-2参与腹主动脉瘤（AAA）的形成。此外，我们实验室的初步研究表明，B-抑制蛋白2介导的信号传导导致考克斯-2的诱导。在本研究中，我们继续这些研究，并调查了B-arrestin 2和考克斯-2在AAAs形成中的作用。AAA的形成涉及主动脉的异常扩张，随后是巨噬细胞浸润和血管壁的广泛重塑，随着时间的推移可能导致危及生命的AAA破裂。我们使用血管紧张素II（AngII）诱导的小鼠AAA模型来研究AAA的形成，并研究B-arrestin 2和考克斯-2在AAA诱导中的作用。我们以前证明了考克斯-2的缺乏减弱了小鼠中AAA的发生率（Gitlin等），此外，AngII诱导小鼠腹主动脉中显著的考克斯-2表达。与我们先前观察到的考克斯-2缺陷减少AAA形成相似，我们目前的研究表明，B-抑制蛋白2缺陷显著减少小鼠中AngII诱导的AAA形成。为了确定B-抑制蛋白2促进AAA形成的可能机制，我们比较了B-抑制蛋白2 +/+和-/-小鼠中考克斯-2、ERK 1/2激活、MCP-1和MIP 1的诱导。我们的结论是，B-arrestin 2的缺乏通过减少B-arrestin 2介导的ERK 1/2激活和考克斯-2的诱导来减少AngII诱导的AAA的发生率。 碳纳米管（CNT）是工程石墨烯圆柱体，在工程，电子和医学方面具有许多潜在的应用。然而，越来越多的证据表明，碳纳米管会导致啮齿动物肺部炎症和纤维化，并表明这些纳米材料可能会对健康构成潜在风险。为了阐明由CNT引起的炎症和纤维化的机制，我们确定多壁CNT（MWCNT）是否在野生型和考克斯-2缺陷小鼠的肺中诱导炎症介质IL-5、IL-13和IL-17 A的差异表达。这些数据表明，多壁碳纳米管诱导的气道炎症加剧了考克斯-2的缺陷与Th 1和Th 2免疫应答的差异激活。 在第三个研究考克斯-1/考克斯-2在生理学/病理生理学中的作用的项目中，我们与安大略省伦敦西部大学的Graham瓦格纳博士合作，证明了考克斯-2而不是考克斯-1在响应脱水的肾斯钙素-1诱导中发挥作用。

In a previous study (Gitlin et al. Cardiovascular Res., 73:227, 2007), we reported the involvement of COX-2 in the formation of abdominal aortic aneurysms (AAAs). Furthermore, preliminary studies in our laboratory have indicated that B-arrestin2-mediated signaling leads to the induction of COX-2. In the present research, we have continued these studies and investigated the roles of B-arrestin2 and COX-2 in the formation of AAAs. AAA formation involves an abnormal dilation of the aorta, followed by macrophage infiltration and extensive remodeling of the vessel wall, which with time may lead to life-threatening AAA rupture. We have used a model of angiotensin II (AngII) induced AAAs in mice to study AAA formation and investigate the roles of B-arrestin2 and COX-2 in the induction of AAAs. We previously demonstrated that the deficiency of COX-2 attenuates the incidence AAAs in mice (Gitlin et al.), and furthermore that AngII induces significant COX-2 expression in the abdominal aortas of mice. Similar to our previous observation that COX-2-deficiency reduced AAA formation, our current studies show that the deficiency of B-arrestin2 significantly reduced AngII-induced AAA formation in mice. To identify possible mechanisms by which B-arrestin2 contributes to AAA formation, we have compared the induction of COX-2, ERK1/2 activation, MCP-1 and MIP1 in B-arrestin2+/+ and -/- mice. Our conclusion is that the deficiency of B-arrestin2 attenuates the incidence of AngII-induced AAAs by decreasing B-arrestin2-mediated ERK1/2 activation and the induction of COX-2. Carbon nanotubes (CNTs) are engineered graphene cylinders that have numerous potential applications in engineering, electronics and medicine. However, a growing body of evidence indicates that CNTs cause inflammation and fibrosis in the rodent lung and suggests that these nanomaterials could pose a potential health risk. In order to elucidate mechanisms of inflammation and fibrosis caused by CNTs, we determined whether multi-walled CNTs (MWCNT) induced the differential expression of the inflammatory mediators, IL-5, IL-13 and IL-17A in the lungs of wild type and COX-2 deficient mice. The data indicated that MWCNTs induced airway inflammation was exacerbated by deficiency of COX-2 with differential activation of Th1 and Th2 immune responses. In a third project studying the role of COX-1/COX-2 in physiology/pathophysiology, in collaboration with Dr. Graham Wagner, Western University, London Ontario, we demonstrated that COX-2, but not COX-1, played a role in renal stanniocalcin-1 induction in response to dehydration.