In this hypothetical model, impaired NO bioavailability that results from chronic hemolysis and oxidative stress triggers chronic pulmonary vasoconstriction, mildly elevating pulmonary vascular resistance and pulmonary artery pressures. Excess arginase liberated from the erythrocyte during hemolysis consumes arginine, the obligate substrate for NO production, and creates a shift towards ornithine production that contributes to collagen deposition and vascular smooth muscle proliferation. Overabundant thrombin generation contributes to a chronic hypercoagulable state, increases arginase activity, and stimulates polyamine synthesis in vascular smooth muscle cells. As this becomes more long-standing, vascular smooth muscle hyperplasia begins to create a relatively fixed lesion, compounded in later stages by irregular, activated endothelium with expression of adhesion molecules. In situ thrombosis further occludes the vessel lumen, and results in plexogenic changes, further accelerating the progression of the pulmonary artery hypertension. (Modified Figure reproduced with permission [31]).

Arginine is synthesized endogenously from citrulline primarily via the intestinal-renal axis. Arginase and nitric oxide synthase (NOS) compete for arginine, their common substrate. In sickle cell disease (SCD), bioavailability of arginine and nitric oxide (NO) are decreased by several mechanisms linked to hemolysis, and similar mechanisms are postulated for thalassemia and other hemolytic disorders. The release of erythrocyte arginase during hemolysis increases plasma arginase levels and shifts arginine metabolism towards ornithine production, decreasing the amount available for NO production. The bioavailability of arginine is further decreased by increased ornithine levels because ornithine and arginine compete for the same transporter system for cellular uptake. Endogenous synthesis of arginine from citrulline may be compromised by renal dysfunction, commonly associated with sickle cell disease. Despite an increase in NOS in SCD, NO bioavailability is low due to low substrate availability, NOS dysfunction, NO scavenging by cell-free hemoglobin released during hemolysis, and through reactions with free radicals such as superoxide. Superoxide is elevated in SCD due to low superoxide dismutase activity, high xanthine oxidase activity and potentially as a result of uncoupled NOS in an environment of low arginine and/or tetrahydrobiopterin concentration or potentially as a result of altered redox potential of NADPH, a critical NOS cofactor. Endothelial dysfunction resulting from NO depletion and increased levels of the downstream products of ornithine metabolism (polyamines and proline) likely contribute to the pathogenesis of lung injury, fibrosis and pulmonary hypertension. (Reproduced from Morris et al. [22], with permission from the American Medical Association).

Correlation of plasma arginase activity (µmol/ml/hr) to A.cell-free hemoglobin (Cell-Free Hb, n=138, p< 0 .001) (Reproduced from Morris et al. [22], with permission from the American Medical Association) and B. serum lactate dehydrogenase levels (LDH, n=121, p<0.001) in patients with sickle cell disease.