Neutrophil activation and trauma - Neutrophils (PMN) cause the systemic inflammatory response (SIRS) and multi-organ failure syndromes (MOFS) that damage host tissues. Approaches to block PMN can reduce SIRS and MOFS, but detailed knowledge of the mechanisms involved in PMN activation is still missing. The purpose of this proposal is to continue our work elucidating these mechanisms. Over the last several years, our research has revealed that hypertonic saline (HS) resuscitation can markedly suppress PMN activation. We identified that ATP release and autocrine signaling via purinergic receptors is the underlying molecular mecha- nism by which HS can suppress but also enhance PMN responses. An unexpected finding of our work has been that ATP release and autocrine purinergic signaling is a much more fundamental mechanism that is re- quired for PMN activation in general. We discovered that PMN require two separate signals for appropriate cell activation: (1) qualitative signals through receptors that recognize specific extracellular danger mediators, and (2) quantitative signals, generated by autocrine purinergic signaling, that regulate subsequent cellular re- sponses. Based on these important findings and our exciting preliminary data, we hypothesize that trauma influences the autocrine signaling system of PMN in several ways, which leads to excessive PMN activation, SIRS, and MOFS. The release of large amounts of ATP from damaged tissues disrupts the autocrine puriner- gic signaling system of PMN. Trauma changes purinergic receptor expression and distort PMN responses, re- sulting in inflammation, SIRS, MOFS, and sepsis. Modulating purinergic signaling can prevent this progression.
Specific Aim 1) Autocrine purinergic regulation of PMN: We will deepen our understanding of the autocrine purinergic signaling mechanisms that regulate PMN by studying upstream pathways leading to ATP release, mechanisms of ATP release and conversion of ATP to adenosine, and the roles of all puriner- gic receptors expressed by PMN.
Specific Aim 2) Effect of sepsis on purinergic signaling of PMN: We will study how septic shock influences the autocrine purinergic signaling system of PMN for example by changing the expression of purinergic re- ceptors and overloading the autocrine purinergic system of PMN by ATP that is released from injured and in- flamed tissues.
Specific Aim 3) Purinergic signaling as a therapeutic target: Finally, we will evaluate the feasibility of tar- geting purinergic signalin to improve outcome after sepsis. We anticipate that the proposed work will lead to entirely novel therapeutic strategies to block PMN activation and reduce SIRS and MOFS in critically ill patients.
Neutrophil activation and trauma - We have discovered that ATP release and autocrine signaling via purinergic receptors are fundamental processes required for neutrophil (PMN) activation. However, large quantities of ATP are also released from damaged tissues in response to major injury, inflammation, and sepsis. Our data show that this additional ATP overloads the autocrine purinergic signaling system of PMN, resulting in excessive PMN activation and aggravated host organ damage. We propose to fully define the autocrine purinergic signaling mechanisms that regulate PMN, how these mechanisms are affected in critically ill patients, and how novel therapeutic strategies targeting purinergic signaling can be used to prevent PMN activation, inflammation, organ damage, and sepsis.
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