Heme Oxygenase-1/Carbon Monoxide in sepsis

摘要 科学界一直认为一氧化碳是一种环境污染物，令人窒息，有毒 职业或工业接触对健康的危害。与这种既定的毒性和流行的观点相反 CO作为一种致命物质，该实验室和其他实验室已经建立了一种细胞和组织保护功能 细胞培养和细胞和组织损伤的动物模型中的低浓度CO。虽然初步研究 已经证实了一氧化碳对啮齿动物的抗炎作用，但对一氧化碳的治疗潜力知之甚少 对抗多菌败血症。此外，很少有研究探讨这种治疗高危人群的潜力。 生物体，如非人灵长类或人类。尽管有迹象表明，一氧化碳的治疗作用 预防组织损伤包括抗炎、抗凋亡和抗增殖作用，分子 一氧化碳影响细胞内稳态的机制尚不完全清楚。 (宏观)-自噬作为一种基本的细胞内平衡机制最近得到了关注，它 通过循环内源性细胞大分子促进细胞在不利条件下的存活 溶酶体依赖的降解。自噬最初是以酵母为特征的，但最近 对哺乳动物这一过程的描述引起了人们对其生物学意义和 作为治疗靶点的潜力。自噬作为主角或适应性的内源性调节 其发病机制尚不十分清楚。此外，我们对此一无所知。 气态介质，如CO，可以调节这一过程。因此，对机制的表征 CO等气体分子可以调节自噬，其与组织保护的关系是高度 新的概念，对一氧化碳如何适应临床治疗具有深远的影响。检视 在这些关系中，我们提出了以下假设： 在内毒素血症/败血症中，一氧化碳通过维持细胞内稳态和 通过分子调控和激活自噬途径促进细菌清除。 为了解决这一假设，我们将检查以下具体目标： 具体目的1：确定一氧化碳诱导的自噬在介导细胞凋亡中的调节和功能。 一氧化碳在脓毒症中的细胞保护作用 特定目标2：确定一氧化碳诱导的自噬途径的中介机制 实验性脓毒症的细胞保护作用 具体目标3：对生物标记物检测和治疗效果进行概念验证研究，以帮助 关于一氧化碳治疗人类败血症疗效的1期/IIa期试验的规划

ABSTRACT CO has been regarded by the scientific community as an environmental pollutant, asphyxiant and noxious health hazard from occupational or industrial exposure. Counter to this established toxicity and popular view of CO as a lethal substance, this laboratory and others have established a cyto- and tissue protective function of low concentrations of CO in cell culture and animal models of cell and tissue injury. While preliminary studies have established an anti-inflammatory effect of CO in rodents, less is known of the therapeutic potential of CO against polymicrobial sepsis. Furthermore, few studies have addressed this therapeutic potential in higher organisms such as non-human primates or humans. Despite indications that the therapeutic effects of CO in preventing tissue injury involve anti-inflammatory, anti-apoptotic, and anti-proliferative effects, the molecular mechanisms by which CO impacts cellular homeostasis remain incompletely understood. (Macro)-autophagy has gained recent attention as a fundamental cellular homeostatic mechanism which facilitates cellular survival under adverse conditions by recycling endogenous cellular macromolecules through lysosomal-dependent degradation. Autophagy was originally characterized in yeast, but the recent characterization of this process in mammals has raised intensive interest in its biological significance and potential as a therapeutic target. The endogenous regulation of autophagy as a either a protagonist or adaptive mechanism during disease pathogenesis is not well understood. Furthermore, nothing is known of how gaseous mediators such as CO may regulate this process. Thus, the characterization of mechanisms by which gaseous molecules such as CO could regulate autophagy and its relationship to tissue protection is a highly novel concept, with far-reaching implications on how CO could be adapted to clinical therapies. To examine these relationships, we propose the following hypothesis: CO confers cyto- and tissue protection in endotoxemia/sepsis by preserving cellular homeostasis and promoting bacterial clearance through molecular regulation and activation of the autophagic pathway. To address this hypothesis will we examine the following Specific Aims: Specific Aim 1: To determine the regulation and function of CO-induced autophagy in mediating the cytoprotective effects of CO in sepsis Specific Aim 2: To determine the mechanism by which CO-induced autophagic pathway mediates cytoprotection in experimental sepsis Specific Aim 3: To perform proof-of-concept studies for biomarker detection and therapeutic efficacy to assist in the planning of Phase 1/Phase IIa trial for therapeutic efficacy of CO in human sepsis