Heme Oxygenase-1/Carbon Monoxide in Lung Vascular Injury

描述(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，涉及细胞内膜的重新排列，将受损的蛋白质或细胞器隔离在形成的膜小泡或自噬体内。然后，自噬小体与溶酶体融合，在溶酶体中，内容物被降解和循环，成为内源能量和营养来源。自噬在酵母系统中已经被描述了几十年，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性增长。对自噬在肺部疾病中的作用知之甚少，对自噬在肺动脉高压(PH)中的作用也没有进行严格的探讨。我们已经获得了有趣的初步数据，人类PH和PH的实验模型显示出显著的自噬诱导。我们的实验室和其他人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的影响，即使在PH发生之后也是如此。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CO调节培养的血管细胞和肺中的自噬过程的初步数据。我们假设自噬是一种适应性应激反应，以保护机体免受PH的侵袭，CO通过调节自噬来阻止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验证这一假说：特定目标1：确定一氧化碳诱导的自噬在实验性肺高压中提供细胞保护的机制特定目标2：确定一氧化碳在实验性肺高压中抑制炎症体途径的机制特定目标3：确定一氧化碳是否抑制人肺高压中的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