Cellular Responses to Hypoxia

描述（由申请人提供）：组织缺氧是心肌缺血和慢性肺病等病理状态的核心。在肺血管系统中，缺氧引起血管收缩和血管壁重塑，导致右心室肥大。这些病理生理反应是肺动脉高压（PHTN）的标志。我们和其他人已经表明，缺氧诱导关键的平滑肌细胞有丝分裂原和血管收缩剂的表达，在体内血管壁重塑中发挥重要作用。我们以前曾报道，缺氧也增加血红素加氧酶-1（HO-1），一种细胞保护酶的表达。HO-1降解血红素产生一氧化碳（CO，一种具有抗炎特性的血管舒张气体），胆绿素（快速转化为抗氧化剂胆红素）和铁（被铁蛋白螯合）。由于HO-1及其产物的特性，目前的共识是HO-1可能在保护细胞和组织免受缺氧诱导的损伤中发挥重要作用。我们的研究小组使用HO-1空（-/-）小鼠和肺特异性HO-1过表达的转基因小鼠支持这一假设，表明缺氧导致所有HO-1缺乏的小鼠右心室扩张和梗死，而肺HO-1水平高的小鼠则免受PHTN的影响。此外，我们注意到，暴露于缺氧的野生型小鼠在PHTN表现之前出现了显著的肺部炎症，伴随着趋化因子和细胞因子的表达升高以及中性粒细胞浸润。与野生型对照组相比，HO-1缺陷小鼠对缺氧的炎症反应更明显和持续，而肺HO-1水平高的转基因小鼠表现出完全没有炎症。本提案的具体目标是：A.探讨低氧诱导趋化因子基因表达导致肺部炎症的分子机制和信号通路。B。探讨HO-1抑制缺氧诱导的炎症基因表达和血管通透性的机制。C.确定炎症是否在缺氧性PHTN的发展中起作用。

DESCRIPTION (provided by applicant): Tissue hypoxia is central to pathologic conditions such as myocardial ischemia and chronic lung disease. In the pulmonary vasculature, hypoxia causes vasoconstriction and vessel wall remodeling with resultant right ventricular hypertrophy. These pathophysiologic responses are the hallmark of pulmonary hypertension (PHTN). We and others have shown that hypoxia induces the expression of key smooth muscle cell mitogens and vasoconstrictors that play an important role in vessel wall remodeling in vivo. We have previously reported that hypoxia also increases the expression of heme oxygenase-1 (HO-1), a cytoprotective enzyme. HO-1 degrades heme to generate carbon monoxide (CO, a vasodilating gas that has anti-inflammatory properties), biliverdin (which is rapidly converted to the antioxidant bilirubin), and iron (sequestered by ferritin). Due to properties of HO-1 and its products, the consensus is that HO-1 may play an important role in protecting cells and tissues from hypoxia-induced injury. Studies by our group using HO-1 null (-/-) mice and transgenic mice with lung-specific HO-1 over expression support this hypothesis by showing that hypoxia produced right ventricular dilatation and infarction in all mice lacking HO-1 whereas mice with high lung HO-1 levels were protected from PHTN. Moreover, we noted that wild-type mice exposed to hypoxia developed marked lung inflammation with elevated expression of chemokines and cytokines as well as neutrophil infiltration prior to the manifestation of PHTN. Mice deficient in HO-1 had a more pronounced and sustained inflammatory response to hypoxia than wild-type controls whereas transgenic mice with high lung HO-1 levels manifested a complete absence of inflammation. The specific aims of this proposal are: A. To study the molecular mechanisms and signaling pathways by which hypoxia induces chemokine gene expression leading to lung inflammation. B. To investigate the mechanisms by which HO-1 inhibits inflammatory gene expression and vascular permeability induced by hypoxia. C. To determine whether inflammation plays a role in the development of hypoxic PHTN.