Carbon Monoxide Delivery in Sepsis and Acute Lung Injury

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，但败血症和急性肺损伤（ALI）的死亡率仍然高得令人无法接受。这个肺疾病转化项目的总体目标是发现新的机制，并确定一氧化碳（CO）气体在败血症和ALI中发挥细胞保护作用的创新分子靶点。为了实现这个项目的目标。核心D，败血症CO交付和ALI核心，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CO递送核心，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、临床前动物模型和I期生物安全临床试验中败血症诱发的ALI受试者中集中递送CO。

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.