Cytokines in Sickle Cell Disease

Abstract

Sickle red cells express adhesion molecules including integrin alpha4beta1, CD36, band 3 protein, sulfated glycolipid, Lutheran protein, phosphatidylserine and integrin-associated protein. The proadhesive sickle cells may bind to endothelial cell P-selectin, E-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), CD36 and integrins leading to its activation. Monocytes also activate endothelium by releasing proinflammatory cytokines like tumor necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta). Sickle monocytes also express increased surface CD11b and cytoplasmic cytokines TNFalpha and IL-1beta indicating activated state. Polymorphonuclear leukocytes (PMNs) are also activated with reduced L-selectin expression, enhanced CD64 expression and elevated levels of sL-selectin, sCD16 and elastase resulting in increased adhesiveness to the endothelium. Platelets are also activated and secrete thrombospondin (TSP) and cytokine IL-1. They also form platelet- monocytes aggregates causing endothelial cell P-selectin expression. Endothelial cell activation by these multiple mechanisms leads to a loss of vascular integrity, expression of leukocyte adhesion molecules, change in the surface phenotype from antithrombotic to prothrombotic, excessive cytokine production and upregulation of HLA molecules. Furthermore, contraction of these activated endothelial cells leads to exposure of extracellular matrix proteins, such as TSP, laminin, and fibronectin and their participation in adhesive interactions with bridging molecules from the plasma such as von Willebrand factor (vWf) released from endothelial cells, ultimately culminating in vasoocclusion and local tissue ischemia, the pathognomonic basis of vasoocclusive crisis.

A multicenter randomized controlled trial of intravenous magnesium for sickle cell pain crisis in children

“…[8][9][10] Vasoconstriction and inflammation contribute to the initiation and prolongation of pain crises in sickle cell disease. [11][12][13][14][15] Magnesium, a known vasodilator with anti-inflammatory effects, has the potential to alter the pathophysiology of pain crises. [16][17][18][19][20] In addition to work exploring the use of magnesium administered orally to prevent pain crises, 21,22 2 previous single-institution studies examining the effects of IV magnesium on acute pain crisis yielded conflicting results: one showed a shortened length of stay (LOS) from a median of 5 days to a median of 3 days compared with previous hospitalizations by the same individuals.…”

Naloxone acts as a potent analgesic in transgenic mouse models of sickle cell anemia

“…Chemokines and their receptors have been implicated in the development of vascular inflammatory disorders, and, in this regard, higher levels of proinflammatory cytokines and chemokines have been reported to be present in patients with sickle cell disease (4)(5)(6).…”

Pulmonary Hypertension in Sickle Cell Disease Patients: Correlation of TRV Jet with Serum NT-Pro BNP Concentration

“…A literature review shows that the prevalence of PH is variable and this variability can also be related to the method of defining how PH is diagnosed [2,6,[18][19][20]. Minniti et al [19] reported 11% prevalence of PH using TRV jet in pediatric SCD population, whereas, Aliyu et al [6] and Oguanobi et al [20] reported 25% and 42% respectively in Nigerian adult SCD patients.…”

“…Upon deoxygenation in capillaries of peripheral tissues and organs, red blood cells (RBC's) containing the abnormal HbS become rigid and sickled in shape leading to obstruction of blood flow through small vessels, thereby causing painful vasoocculsive (VOC) events that lead to bone, tissue and organ damage [2]. Thus, because of the structural change to the RBC's caused by HbS, the RBC lifespan is greatly reduced resulting in a chronic hemolytic anemia.…”

“…However despite the apparent simplicity of the genotype, there is a considerable variability in the phenotypic presentation of this disease [2][3][4] with some of this variability being attributed to genetic or epigenetic factors as well as to social and environmental factors.…”