Carbon Monoxide Delivery in Sepsis and Acute Lung Injury

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Mortality from sepsis and acute lung injury (ALI) remains unacceptably high despite recent advances in crifical 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 idenfify 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 concentrafions 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 invesfigators. A highly innovative feature of this proposal is the development and validation of a CO delivery protocol for critically ill pafients requiring mechanical venfilation. 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 Pracfice (GLP)-like protocols, we will ensure that all CO exposures are performed under uniform conditions, that CO exposures are strictiy 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 confinuous 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.