Research Topic

Inflammatory Mechanisms of Hemolytic Diseases

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Hemolytic diseases have several underlying causes and result in reduced red blood cell (RBC) counts due to the destruction of these cells in the circulation. Hemolytic anemia can be induced by either intrinsic conditions, in which RBCs present abnormalities, or by extrinsic circumstances, in which RBC ...

Hemolytic diseases have several underlying causes and result in reduced red blood cell (RBC) counts due to the destruction of these cells in the circulation. Hemolytic anemia can be induced by either intrinsic conditions, in which RBCs present abnormalities, or by extrinsic circumstances, in which RBC destruction overtakes the bone marrow's capacity for production. Among the intrinsic causes of hemolytic diseases are alterations in hemoglobin (as occur in sickle cell disease and thalassemia); metabolic abnormalities (seen in glucose-6-phosphate dehydrogenase (G6PD) deficiency); and RBC membrane instability (e.g. hereditary spherocytosis) among others. Extrinsic causes of hemolysis, on the other hand, include the development of autoimmune reactions against RBCs (e.g. autoimmune hemolytic anemia (AIHA) and paroxysmal nocturnal hemoglobinuria (PNH)); mismatched transfusion; physical or chemical trauma; infections, such as Plasmodium sp.; and sepsis.

Under homeostatic conditions or mild hemolysis, free hemoglobin (Hb), heme or iron (Fe), released by RBCs in the intravascular environment, are neutralized by haptoglobin (Hp), hemopexin (Hx) and transferrin (Tf), respectively. Hepatocytes and macrophages express CD163, which binds to the Hp-Hb complex; CD91, which binds to Hx-heme; and CD71 that binds to Tf-Fe. Thus, these plasmatic complexes are interiorized, degraded and the Fe is recycled for use in new erythroblasts. During acute or chronic hemolytic diseases, however, the intravascular scavenger molecules become saturated, hence the accumulation of free RBC components in the circulation.

Free RBC constituents are potent danger-associated molecular patterns (DAMPs) that are sensed by pattern recognition receptors (PRRs) expressed by endothelial and innate immune cells, activating the endothelium, inducing the migration of leukocytes to the blood vessels and driving the systemic release of inflammatory mediators, such as TNF-, IL-6, and IL-1. Neutrophils and monocytes are recognized as major producers of inflammatory cytokines and extracellular traps into the vascular microenvironment during hemolysis. However, new evidence indicates the importance of other cells in the inflammatory and oxidative processes generated. Repeated events of hypoxia and reperfusion, caused by hemolysis, are also important initiators of vascular inflammation in hemolytic disorders. Moreover, free heme and Fe are extremely oxidative, generating reactive oxygen species (ROS) in the vascular milieu by different mechanisms. This oxidative stress has a direct cytotoxic effect, causing the oxidation of proteins, lipids, and DNA, which culminates in tissue damage, as well as the generation and release of new DAMPs, amplifying the inflammatory process. The DAMPs released during hemolysis are, therefore, key players in the pathophysiology of both sterile and infectious hemolytic diseases, and the mechanisms by which they can cause inflammation, oxidative stress and tissue damage has been the subject of extensive study.

In this Research Topic, we welcome the submission of Original Research, Review and Mini Review articles focusing on the mechanisms inducing inflammation and how it contributes to the pathology of acute and chronic hemolytic diseases in human patients and animal models. Potential subtopics include, but are not limited to:

- Hemoglobinopathies
- Red blood cell disorders
- Autoimmune hemolytic diseases
- Plasmodium infection
- Sepsis


Keywords: hemolysis, inflammation, anemia, DAMP, immune response


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