Vascular inflammation: pathophysiological mechanisms of induction and pathways of cellular activation

Abstract

The activation of the leukocytes and other inflammatory cells, and their consequent adhesion to the endothelium, play a key role in the initiation and propagation of vascular inflammation and may result in endothelial activation, vascular damage and even obstruction of microcirculatory blood flow with subsequent tissue damage. These mechanisms play a central role in the pathophysiology of several diseases that are characterized by acute or chronic vascular inflammation, such as atherosclerosis, sickle cell anemia, stroke and transfusion-related acute lung injury (TRALI). Therefore, understanding the mechanisms that result in the activation and adhesion of blood cells to the vascular wall should assist in developing new strategies for the prevention and treatment of chronic inflammatory diseases. The current project aims to further unravel the signaling pathway by which TNF-± causes the adhesion of neutrophils, as well as determine how the statin, simvastatin, inhibits this pathway. Furthermore, we plan to investigate the effects of hemolysis and the presence of plasma free hemoglobin / heme on the activity of inflammatory cells, observing the formation and activation of inflamassomes, and the adhesive properties of leukocytes and platelets in vivo and in vitro. These objectives will be studied using techniques developed in our laboratory during the last 3-4 years; the Venaflux platform will be used for the study of cell adhesion in vitro and intravital microscopy will be employed to observe cell recruitment in the microcirculation of mice. Understanding the mechanisms involved in the induction of activation and adhesion of inflammatory cells and the signaling pathways by which these cells become adhesive and activated, remains one of the challenges in the search for therapeutic targets for the development of approaches for the prevention and reversal of vascular inflammation. (AU)