Cytoprotection by Carbon Monoxide In Sepsis and Lung Injury

一氧化碳（CO）被认为是一种环境污染物和有害的健康危害， 工业暴露。针对这种已确定的CO毒性，本实验室和其他实验室已经建立了一个 低剂量CO的细胞和组织保护功能，内源性来源于血红素加氧酶 系统在组织损伤的临床前模型中。尽管有迹象表明一氧化碳在治疗中的作用 预防组织损伤可能涉及抗炎、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。此外，委员会认为， 虽然临床前研究已经确立了CO的细胞保护作用，但很少有研究涉及治疗性 CO在人类疾病，特别是急性肺损伤（ALI）中的潜在作用。自噬最近获得了 注意力作为一个基本的细胞稳态过程，通过循环促进细胞存活 内源性细胞大分子通过溶酶体依赖性降解。自噬最初是 在酵母中进行了表征，但最近在哺乳动物中的表征引起了人们对其生物学的浓厚兴趣 意义自噬在ALI中的功能尚未被探索，也不知道CO如何可能 规范这个过程。因此，CO调节自噬的机制及其作用机制的描述， 与组织保护的关系是一个非常新颖的概念，对如何吸入CO具有深远的影响。 可以用于ALI患者。为了检验这些关系，我们提出以下建议 假设：一氧化碳通过激活自噬依赖的细胞因子，对ALI和IVIODS的细胞和组织起到保护作用 抑制炎性小体途径。此外，概念证明“首先在ALI” I期安全性CO试验将为II/III期人类CO干预试验提供基础。 阿里为了解决这个假设，我们将检查以下内容 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。 一氧化碳对实验性脓毒症和急性肺损伤的细胞保护作用 具体目标2：确定CO抑制炎症体途径的机制， 实验性脓毒症和ALI 具体目标3：在人体中进行“首次用于ALI”的概念验证I期安全性CO试验

Carbon monoxide (CO) has been regarded as an environmental pollutant and noxious health hazard from industrial exposure. Counter to this established toxicity of CO, this laboratory and others have established a cyto- and tissue protective function of low dose of CO, endogenously derived from the heme oxygenase system. In preclinical models of tissue injury. Despite indications that the therapeutic effects of CO in preventing tissue injury may involve anti-inflammatory, anti-apoptotic, and anti-proliferative effects, the mechanism(s) by which CO impacts cellular homeostasis remains incompletely understood. Furthermore, while preclinical studies have established CO cytoprotection, few studies have addressed the therapeutic potential of CO in human disease, in particular acute lung injury (ALI). Autophagy has gained recent attention as a fundamental cellular homeostatic process which facilitates cellular survival by recycling endogenous cellular macromolecules through lysosomal-dependent degradation. Autophagy was originally characterized in yeast, but recent characterization in mammals has raised intense interest in its biological significance. The function of autophagy in ALI has not been explored and nothing is known of how CO may regulate this process. Thus, the delineation of mechanisms by which CO could regulate autophagy and its relationship to tissue protection is a highly novel concept, with far-reaching implications on how inhaled CO could be translated to use in patients with ALI. To examine these relationships, we propose the following hypothesis: CO confers cyto- and tissue protection in ALI and IVIODS through activation of autophagydependent suppression of infiammasome pathway. Furthermore, the proof of concept "first in ALI" Phase I safety CO trial will provide the groundwork for a Phase ll/lll CO intervention trial in human ALI. To address this hypothesis we will 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 experimental sepsis and ALI Specific Aim 2: To determine the mechanism by which CO dampens the inflammasome pathway in experimental sepsis and ALI Specific Aim 3: To perform proof of concept "flrst in ALI" Phase I safety CO trial in humans