736319.fig.001
Figure 1: Altered arginine metabolism in hemolysis: a path to pulmonary dysfunction. Dietary glutamine serves as a precursor for the de novo production of arginine through the citrulline-arginine pathway. 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) and thalassemia, bioavailability of arginine and NO are decreased by several mechanisms linked to hemolysis. The release of erythrocyte arginase during hemolysis increases plasma arginase levels and shifts arginine metabolism towards ornithine production, limiting the amount of substrate available for NO production. The bioavailability of arginine is further diminished by increased ornithine levels because ornithine and arginine compete for the same transporter system for cellular uptake. Despite an increase in NOS, NO bioavailability is low due to low substrate availability, NO scavenging by cell-free hemoglobin released during hemolysis, and through reactions with free radicals such as superoxide and other reactive NO species. 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 insufficient NADPH. 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, pulmonary hypertension, and asthma in SCD. This model has implications for all hemolytic processes as well as pulmonary diseases associated with excess arginase production. This novel disease paradigm is now recognized as an important mechanism in the pathophysiology of SCD and thalassemia. Abnormal arginase activity emerges as a recurrent theme in the pathogenesis of a growing number of diverse pulmonary disorders. Regardless of the initiating trigger, excess arginase activity represents a common pathway in the pathogenesis of asthma and pulmonary hypertension, reproduced with permission from the American Society of Hematology [103].