Sickle cell disease and nitric oxide: a paradigm shift?

Abstract

Traditionally the pathophysiology of sickle cell disease is thought to result from the polymerization of hemoglobin S in red cells, under hypoxic conditions, resulting in the occlusion of blood vessels. Adhesion of cells to the venular endothelium also appears to play a role. Recent studies have also suggested that in addition to the polymerization of hemoglobin S in the red blood cell, a deficiency of the endogenous vasodilator, nitric oxide may be involved. Hemoglobin released as a result of hemolysis rapidly consumes nitric oxide resulting in a whole program of events that inhibit blood flow. Therapies directed at decreasing the destruction of nitric oxide, increasing the production of nitric oxide, or amplifying the nitric oxide response may prove beneficial.

Fig. 1

New investigational therapeutic targets for patients with sickle cell disease at the level of the pre-capillary arteriole, capillary and post-capillary venule. These therapeutic targets include (a) potential NO donors, (b) drugs that decrease oxidative stress and (c) drugs that increase the response to NO. Hemolysis from sickle cell disease results in release of hemoglobin and arginase from the red cell. Cell free hemoglobin rapidly consumes nitric oxide, an important mediator of blood flow. Arginase breaks down arginine, the substrate for nitric oxide production. Under hypoxic conditions, polymerization of hemoglobin S results in a rigid, sickled shape cell that can occlude blood flow. As a result of hemolysis, young red blood cells enter the circulation and can stick to the endothelium via α4β1 integrins binding to VCAM-1. Due to occlusion of flow, ischemia-reperfusion pathophysiology may play a role in sickle cell disease with oxidative damage resulting in cell destruction. Xanthine oxidase and NADPH oxidase may increase oxidative damage in patients with sickle cell disease. (a) Hydroxyurea, inhaled nitric oxide, inhaled/intravascular nitrite may act as NO donors and decrease the expression of cell adhesion molecules which may prevent red cell adhesion to the endothelium and result in improved blood flow. L-Arginine supplementation may replenish arginine under conditions of hemolysis. (b) Allopurinol inhibits xanthine oxidase mediated superoxide production which may lead to decreased cellular damage. (c) Statin therapy may decrease the expression of a variety of adhesion molecules. Sildenafil is a phosphodiesterase 5 inhibitor which inhibits the breakdown of cGMP and results in improved NO responsiveness.