Heme Oxygenase-1/Carbon Monoxide in Lung Vascular Injury

描述（由申请人提供）：自噬表现为通过溶酶体途径降解细胞质细胞器，涉及细胞内膜重排以将受损蛋白质或细胞器隔离在形成的膜囊泡或自噬体内。然后自噬体与溶酶体融合，在溶酶体中内容物被降解并回收，成为能量和营养的内源性来源。自噬在酵母系统中已经描述了几十年;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。自噬在肺部疾病中的作用知之甚少，自噬在肺动脉高压（PH）中的作用尚未得到严格的探索。我们已经获得了有趣的初步数据，人类PH和PH的实验模型表现出显着的诱导自噬。我们的实验室和其他实验室已经开始解开一氧化碳（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，CO可以分别保护小鼠和大鼠免受缺氧或MCT诱导的PH，即使在PH发生后也是如此，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，我们已经获得了初步的数据，CO调节培养的血管细胞和肺中的自噬过程。我们假设自噬代表了一种适应性应激反应，以防止PH，CO通过调节自噬来防止PH。此外，我们假设自噬调节的炎性小体可以潜在地作为预测PH严重程度的诊断生物标志物。我们将通过解决以下目标来测试假设：具体目标#1：确定CO诱导的自噬功能在实验PH中提供细胞保护的机制具体目标2：确定CO抑制实验性PH中炎性体途径的机制具体目标#3：确定CO是否抑制人PH中炎性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