The ineffectiveness of current interventions to better ameliorate the impact of sepsis upon patients in the intensive care unit demonstrates that more knowledge of the pathophysiology of sepsis is needed if we are to develop more effective therapies. During sepsis, exquisite control of inflammation is necessary to execute beneficial actions (bacterial clearance) while minimizing pathogenesis. Initially, activated leukocytes participate in the anti-microbial response. During sepsis, leukocytes can undergo apoptosis or become unresponsive. In other inflammatory models, both activated and apoptotic leukocytes have been shown to be precursors to microparticles (MPs). MPs are small vesicles of heterogeneous density and composition. The role of MPs in sepsis is currently poorly characterized. Our novel preliminary data demonstrate that neutrophil-derived MPs (NDMPs) are increased during sepsis, decrease survival and can increase immune suppression. This is important as there is an ongoing paradigm shift concerning our understanding of sepsis. Whereas early, uncontrolled inflammation was a prevailing therapeutic target in the past, recent reports have increased awareness of immune paralysis later during sepsis leading to difficulty clearing bacteria or fungus. Altogether, our overarching hypothesis is that the formation of sepsis- generated MPs will significantly contribute to immune paralysis such that mortality is increased. Mechanistic underpinnings of this hypothesis will be tested in the following aims:
Aim 1 : Determine TLR4- associated molecular mechanisms driving NDMP formation.
Aim 2 : Characterize how NDMPs influence T cell activation and homeostasis.
Aim 3 : Elucidate mechanisms of NDMP-associated macrophage de- activation. Successful completion of these aims may lead to therapies aimed towards reversing sepsis- induced immune paralysis.
The ineffectiveness of current interventions to better ameliorate the impact of sepsis upon patients in the intensive care unit demonstrates that more knowledge of the pathophysiology of sepsis is needed if we are to develop more effective therapies. Accordingly, we have found that microparticles are generated during sepsis and contribute to increased mortality and immune suppression, and through a series of studies described in this proposal, we will elucidate molecular mechanisms underlying how neutrophil-derived microparticles are generated and how they impact the immune response during sepsis. Data from these studies should not only provide new insights to the host response to sepsis, but also allow for better therapeutic targets for the management of this condition.
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