Heme Oxygenase-1/Carbon Monoxide in sepsis

摘要 CO是一种环境污染物，具有窒息性和毒性 职业或工业接触对健康危害。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， 在细胞培养物和细胞及组织损伤的动物模型中的低浓度CO。虽然初步研究 虽然已经在啮齿类动物中建立了CO的抗炎作用，但对CO的治疗潜力知之甚少 对抗多种微生物败血症此外，很少有研究在更高水平上探讨这种治疗潜力。 生物体，如非人类灵长类动物或人类。尽管有迹象表明，CO的治疗效果， 预防组织损伤涉及抗炎、抗凋亡和抗增殖作用， CO影响细胞内稳态的机制仍然不完全清楚。 （宏观）自噬作为一种基本的细胞内稳态机制， 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， 溶酶体依赖性降解。自噬最初是在酵母中发现的，但最近 对哺乳动物中这一过程的表征引起了对其生物学意义的强烈兴趣， 作为治疗靶点的潜力。自噬的内源性调节作为一个主角或适应 疾病发病机制尚不清楚。此外，没有人知道如何 气体介质如CO可以调节该过程。因此，表征的机制， 气体分子如CO可以调节自噬，其与组织保护的关系是高度相关的。 这是一个新的概念，对CO如何适应临床治疗具有深远的影响。审查 这些关系，我们提出以下假设： 一氧化碳通过维持细胞内稳态，在内毒素血症/脓毒症中提供细胞和组织保护， 通过自噬途径的分子调节和激活促进细菌清除。 为了解决这一假设，我们将研究以下具体目标： 具体目标1：确定CO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 具体目标2：确定CO诱导的自噬途径介导的机制 实验性脓毒症的细胞保护 具体目标3：进行生物标志物检测和治疗有效性的概念验证研究， 在规划CO治疗人类脓毒症疗效的I期/IIa期试验时

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