Heme Oxygenase-1/Carbon Monoxide in Lung Vascular Injury

描述（由申请人提供）：自噬表现为细胞质细胞器通过溶酶体途径降解，涉及细胞膜的重排，将受损的蛋白质或细胞器隔离在形成的膜泡或自噬体中。自噬体随后与溶酶体融合，在溶酶体中，其内容物被降解并再循环，成为内源性能量和营养物质的来源。自噬已经在酵母系统中被描述了几十年；然而，近年来，我们目睹了这一领域在哺乳动物系统中的爆炸式增长。自噬在肺部疾病中的作用知之甚少，自噬在肺动脉高压（PH）中的作用也没有得到严格的探讨。我们已经获得了有趣的初步数据，人体PH和PH实验模型表现出明显的自噬诱导。我们的实验室和其他实验室已经开始揭示一氧化碳（CO）在各种细胞和组织损伤模型中发挥保护作用的机制和信号通路。重要的是，我们最近的研究表明，在小鼠和大鼠中，CO可以分别保护缺氧或mct诱导的PH，甚至在PH发展之后，这表明CO可能影响血管重塑过程，包括血管细胞增殖和凋亡。有趣的是，我们已经获得了CO调节培养血管细胞和肺的自噬过程的初步数据。我们假设自噬代表了一种适应性应激反应来保护PH，而CO通过调节自噬来防止PH。此外，我们假设自噬调节炎性小体可以潜在地作为预测PH严重程度的诊断性生物标志物。我们将通过解决以下目标来验证这一假设：特定目标#1：确定CO诱导的自噬在实验PH中提供细胞保护的机制特异性目标2：确定CO抑制实验PH中炎性小体途径的机制特异性目标#3：确定CO是否能抑制炎症体及其调节的细胞因子

DESCRIPTION (provided by applicant): Autophagy is manifested by degradation of cytoplasmic organelles via a lysosomal pathway, involving rearrangement of intracellular membranes to sequester damaged proteins or organelles within formed membrane vesicles, or autophagosomes. Autophagosomes then fuse with lysosomes where the content is degraded and recycled to become an endogenous source of energy and nutrients. Autophagy has been described in the yeast system for decades; however, we have witnessed the explosion of this field in the mammalian system in recent years. Little is known on the role of autophagy in lung disease, and the role of autophagy in pulmonary hypertension (PH) has not been rigorously explored. We have obtained intriguing preliminary data that human PH and experimental models of PH exhibit marked induction of autophagy. Our laboratory and others have started to unravel the mechanisms and signaling pathways by which carbon monoxide (CO) imparts protective effects in various models of cellular and tissue injury. Importantly, our recent study illustrates that CO can protect against hypoxia or MCT-induced PH in mice and rats, respectively, even after the development of PH suggesting that CO may affect vascular remodeling processes including vascular cell proliferation and apoptosis. Interestingly, we have obtained preliminary data that CO regulates the autophagic process both in cultured vascular cells and in the lung. We hypothesize that autophagy represents an adaptive stress response to protect against PH, and that CO prevents PH via regulating autophagy. Furthermore, we hypothesize that autophagy regulated inflammasomes can potentially serve as diagnostic biomarker in predicting severity of PH. We will test the hypothesis by addressing the following aims: Specific Aim #1: To determine the mechanism by which CO-induced autophagy functions to provide cytoprotection in experimental PH Specific Aim 2: To determine the mechanism by which CO dampens the inflammasome pathway in experimental PH Specific Aim #3: To determine whether CO inhibits inflammasome and its regulated cytokines in human PH