The interactions between the processes of inflammation and thrombosis are increasingly recognized as relevant to the pathogenesis of various diseases. A striking example of these interactions is evident in sepsis, a systemic inflammatory response to an infection. Sepsis is the leading cause of death in non-cardiac intensive care units in the United States, and microvascular thrombosis is a significant complication in sepsis. One aspect of the inflammatory response in sepsis involves the complement system, an integral part of the innate immune response. Recent data demonstrate that the complement system may provide a link between inflammation and thrombosis; this application will help understand the mechanisms involved in these interactions, with a particular emphasis on sepsis. The central hypothesis is that platelet-associated components of the complement system provide a link between inflammation and thrombosis in sepsis. The proposal will utilize genetically targeted complement deficient mice and their relevant controls to assess platelet function ex vivo and in vivo. Ex vivo experiments involve measures of platelet aggregation, and protocols to distinguish intrinsic platelet defects from effects due to complement factor deposition on platelets. In vivo experiments will utilize an intravital microscopy model of microvascular thrombosis, which allows assessment of the kinetics of platelet-microvessel interactions in real-time. Some experiments will use passive transfer of platelets to determine whether a platelet-bound complement receptor is sufficient to mediate the role of this receptor in microvascular thrombosis.
Two aims are proposed:
Aim 1 will determine which complement pathways and platelet-associated components of the complement system mediate abnormal platelet function in complement deficient mice.
Aim 2 will determine the role of components of the complement system in microvascular thrombosis in experimental sepsis. Completion of these aims will broaden understanding of the role of the complement system as a link between inflammation and thrombosis, with an emphasis on sepsis.
This research program will focus on sepsis, which is caused by the body's response to a severe infection. That response, or inflammation, can cause serious complications, including blood clots in very small blood vessels that may result in organ dysfunction. Sepsis is the most common cause of death in medical intensive care units in the United States, including the VA system. There is no specific treatment for these complications of sepsis, probably because it is unclear how they occur. The proposed work will help clarify how these clots form, by studying the role of an important aspect of inflammation, known as the complement system. This work may result in new treatments for the small blood clots and organ dysfunction in sepsis, with the long-term goal of improving the outcome of patients with this devastating condition.
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