Inflammatory responses in the microcirculation contribute to a number of important clinical entities, including shock, reperfusion injury, wound healing, burns and sickle cell disease, among many others. Much of the existing knowledge of these responses relates to how leukocytes interact with microvascular endothelium, including their adhesion and transendothelial migration. Platelets can also adhere to and extravasate across inflamed microvessels; our recent findings in a well-characterized model of corneal wound injury support a significant functional role for extravascular platelets in inflammation. Further, platelets can release microparticles, which are increasingly recognized to contribute to a number of important clinical conditions. The mechanisms by which platelets extravasate, and the role of platelet- derived microparticles in inflammation remain to be clarified. The central hypothesis of our application is that platelets are necessary for efficient inflammatory responses, via their extravasation across inflamed post-capillary venules and release of microparticles. This collaborative application will address two specific aims: 1) Determine the molecular mechanisms and kinetics of platelet extravasation in microvascular inflammation, and 2) Define the role of microparticles derived from platelets in the inflammatory responses to wound healing. Completion of the proposed work will fill significant gaps in current knowledge of the role of platelets and their microparticles in the inflamed microcirculation. These cellular interactions ar relevant for a number of serious clinical conditions such as shock, burns, and reperfusion injury. Defining the mechanisms involved is expected to help identify new treatment strategies for patients with these and other inflammatory conditions.

R01HL116524

2013-02-01

2019-01-31