Adhesion of hematopoietic cells: molecular and inflammatory mechanisms

Abstract

The recruitment of leukocytes to inflammatory sites is a fundamental step in the inflammatory response, involving the rolling of these cells along the vessel wall, their firm adhesion to the endothelium followed by their transendothelial migration and migration to the target tissue in response to a chemotactic gradient. Recent evidence suggests that, during this initial stage of rolling along the vascular endothelium, neutrophils relay signals that can induce the initiation of subsequent events, such as the firm adhesion of the leuckocyte to the endothelium and activation of the endothelium itself. Furthermore, when the neutrophil adheres to the endothelium, intracellular signaling inside the leukocyte allows the cell to, in turn, interact with other circulating blood cells, resulting in pathophysiological events in the vascular lumen that may significantly alter the blood flow. The molecular mechanisms involved in these interactions have yet to be elucidated and investigations regarding the dynamics of neutrophil-platelet and neutrophil-red blood cell (RBC) interactions are areas that are potentially important for study. As such, an understanding of the pathways involved in the adhesion of neutrophils to endothelial layers and their interactions with other cell types, using an flow adhesion assay that simulates the conditions of a human blood vessel (using the VenaFlux" microfluid platform), may aid in the identification of potential inflammatory therapeutic targets and increase our knowledge regarding some conditions characterized by vascular inflammation, such as sickle cell disease, atherosclerosis, stroke and TRALI, amongst other conditions. The aim of this project is to evaluate; 1) the adhesive interactions of blood cells obtained from healthy individuals (neutrophils, platelets and RBCs) with endothelial cells and extracellular matrix proteins; 2) the heterotypic interactions between neutrophils and RBC and neutrophils and platelets (in healthy subjects and, later on, in patients with sickle cell disease) under inflammatory conditions, investigating the adhesion molecules and signaling pathways involved, using in vitro flow adhesion assays. As such, this project aims to further our understanding of the molecular mechanisms involved in these processes in inflammatory diseases. (AU)