Characterization of the inflammatory effects of intravascular hemolytic processes, in vitro and in vivo

Abstract

Intravascular hemolysis, or the destruction of red blood cells, occurs in numerous pathological conditions, including the acquired hemolytic anemias and sickle cell disease, as well as during some transfusion reactions, preeclampsia, and infections, such as those caused by malaria or Clostridium perfringens. Hemolysis results in the release of large amounts of damage-associated molecular patterns (DAMPs), such as heme, heat shock proteins (Hsp), and adenosine triphosphate (ATP). Thus, hemolysis represents an important inflammatory mechanism that potentially contributes to the clinical manifestations associated with hemolytic diseases, such as pulmonary hypertension and leg ulcers, and associated pathophysiological mechanisms such as endothelial activation, leukocyte activation, angiogenic and vaso-occlusive processes and tissue damage, all of which are the result of constant inflammatory processes in the blood vessel. The aim of this project is to characterize some of the inflammatory consequences of the hemolytic process (acute and chronic) in vivo and to evaluate the effects of hemolysis products (hemoglobin and heme) on the adhesive properties of leukocytes and platelets in vitro. In addition, some of the intracellular activation and signaling mechanisms involved will be delineated, and therapeutic approaches to prevent or reduce the inflammatory effects of hemolysis will be investigated. We will use animal models of acute and chronic hemolysis, developed in our laboratory, in addition to state-of-the-art techniques, such as the use of a microfluidic platform to evaluate cellular adhesive properties, imaging flow cytometry, and intravital microscopy. Understanding the pathophysiological mechanisms of intravascular hemolysis and its consequences, as well as the study of approaches that can be used to neutralize its effects, may be important for the development of new strategies for the treatment of diseases and conditions in which hemolysis occurs. (AU)