Carbon Monoxide Delivery in Sepsis and Acute Lung Injury

脓毒症和急性肺损伤(ALI)的死亡率仍然高得令人无法接受，尽管最近在重症监护方面取得了进展，包括早期目标导向治疗和肺保护性呼吸机策略。这个肺部疾病翻译计划项目的总体目标是发现新的机制，并确定一氧化碳(CO)气体在脓毒症和ALI期间发挥细胞保护作用的创新分子靶点。为了实现本项目的目标。核心D，即Sepsis和Ali Core的CO交付，将为项目1-4中以标准化方式交付CO提供专业知识、资源、设施和质量控制(QC)服务。作为一氧化碳输送的核心，我们将为项目研究人员提供协调的资源和专业知识，以便在细胞培养系统、临床前动物模型以及在一期生物安全临床试验中集中输送一氧化碳在脓毒症诱发的ALI受试者中。 具体地说，Core D将制定和实施标准化的方案，以管理和监测细胞培养系统、脓毒症和ALI的动物模型以及作为项目研究人员中心服务的脓毒症诱发ALI的机械通风受试者中的CO浓度。这项建议的一个极具创新性的特点是为需要机械通气的危重患者开发和验证了一氧化碳输送方案。Core D还将负责标准化研究人员在所有四个项目中使用的脓毒症和ALI动物模型。通过使用同样训练有素和经验丰富的人员以及标准化的良好实验室操作规范(GLP)，我们将确保所有一氧化碳暴露在统一的条件下进行，一氧化碳暴露受到严格监管，并在整个实验过程中适当监测一氧化碳水平和动物。在我们的第一阶段生物安全临床试验中，Core D将提供标准化一氧化碳给药方案所需的专业知识，确保持续实时监测吸气和呼气气体中的一氧化碳浓度，并评估受试者的碳氧血红蛋白(COHb)水平，以确保高质量的安全性和监测标准。 通过整合和利用核心D的高技能和经验丰富的员工、设施和设备，并使其可用于所有项目，我们将极大地降低生产高质量数据的成本。这一方法将便利和促进不同项目中的调查人员之间的协同互动。 因此，核心D，即在Sepsis和Ali Core的CO交付，将在成功完成本计划项目中提出的工作中发挥不可或缺的作用。

Mortality from sepsis and acute lung injury (ALI) remains unacceptably high despite recent advances in critical care including early goal-directed therapy and lung protective ventilator strategies. The overall goal of this Translational Program Project in Lung Diseases is to discover novel mechanisms and identify innovative molecular targets by which carbon monoxide (CO) gas exerts cytoprotection during sepsis and ALI. In order to achieve this Program Project's goals. Core D, the CO Delivery in Sepsis and ALI Core, will provide the expertise, resources, facilities, and quality control (QC) services for the delivery of CO in a standardized fashion in Projects 1-4. As the CO Delivery Core, we will provide coordinated resources and expertise to the Project investigators for the centralized delivery of CO in cell culture systems, preclinical animal models, and in subjects with sepsis-induced ALI in a Phase I Biosafety Clinical Trial. Specifically, Core D will develop and implement standardized protocols to administer CO and monitor CO concentrations in cell culture systems, animal models of sepsis and ALI, and in mechanically ventilated subjects with sepsis-induced ALI as a central service for Project investigators. A highly innovative feature of this proposal is the development and validation of a CO delivery protocol for critically ill patients requiring mechanical ventilation. Core D will also be responsible for standardizing the animal models of sepsis and ALI employed by investigators in all four Projects. By using the same highly trained and experienced personnel as well as standardized Good Laboratory Practice (GLP)-like protocols, we will ensure that all CO exposures are performed under uniform conditions, that CO exposures are strictly regulated, and that CO levels and animals are properly monitored throughout experiments. In our Phase I Biosafety Clinical Trial, Core D will provide the expertise required to standardize the CO administration protocol, ensure continuous real-time monitoring of CO concentrations in the inspiratory and expiratory gases, and assess carboxyhemoglobin (COHb) levels in subjects to assure high quality safety and monitoring standards. By consolidating and leveraging highly skilled and experienced staff, facilifies, and equipment in Core D and making them available to all Projects, we will greatly reduce the cost of producing high-quality data. This approach will facilitate and promote synergisfic interactions between investigators in the different Projects. Therefore, Core D, the CO Delivery in Sepsis and ALI Core, will play an integral role in the successful completion of the work proposed in this Program Project.