Severe acute disease and their associated critical illness states are the commonest causes for Intensive Care Unit (ICU) admission. Surprisingly, despite the multiple initiating acute disease causes (infection, pancreatitis, trauma), they can all follow a common pathway of increasingly severe systemic inflammation, multiple organ failure and in a significant number of cases, death. Treatment in ICU remains largely supportive and non-specific. This Project will evaluate the effects of a new class of drug targeting a specific type of cell communication channel. These channels have recently emerged as significant in sustaining inflammation and other processes that can lead to tissue damage and organ failure in acute disease states. These studies will support the translation of this new drug class into clinical trials.