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.

Public Health Relevance

Platelets are blood cells involved not only in clotting, but also in inflammation, the body's response to harmful stimuli. Interactions of platelets with tiny blood vessels (microcirculation) in inflammation are important for a number of significant human conditions, including wound healing, infections and shock. The proposed work will help expand our understanding of these interactions, with the goal of developing new treatments for patients with these conditions.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Hypertension and Microcirculation Study Section (HM)
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Kindzelski, Andrei L
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Baylor College of Medicine
Internal Medicine/Medicine
Schools of Medicine
United States
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Khatlani, T; Pradhan, S; Da, Q et al. (2014) The ? isoform of the catalytic subunit of protein phosphatase 2B restrains platelet function by suppressing outside-in ?II b ?3 integrin signaling. J Thromb Haemost 12:2089-101
Hanlon, Samuel D; Smith, C Wayne; Sauter, Marika N et al. (2014) Integrin-dependent neutrophil migration in the injured mouse cornea. Exp Eye Res 120:61-70