Amino acids and the erythrocyte under stress?

Pulmonary hypertension is a major threat to the well-being of adults with sickle cell disease (SCD) that is linked epidemiologically and mechanistically to hemolysis.¹  As a result of hemolysis, hemoglobin is released into plasma, where it reacts with and destroys nitric oxide (NO).²  Hemolysis also releases erythrocyte arginase into plasma, depleting L-arginine, the substrate for NO synthesis.³  Together, these factors contribute to a state of decreased NO bioavailability and resistance to NO-dependent vasodilation.²  In addition, the accumulation of redox active heme and iron from lysed red blood cells can contribute to the generation of reactive oxygen species that could further impair NO-dependent vascular function.⁴  Increased reactive oxygen species generated by sickle erythrocytes can also compromise the integrity of the red blood cell.

As Morris and colleagues extensively review, the glutathione buffering system is critical for maintaining cellular redox balance. In the lung, glutathione is a major antioxidant, and excessive pulmonary production of oxidants leads to alterations in glutathione levels. Interestingly, in patients with idiopathic pulmonary arterial hypertension, glutathione content in the bronchoalveolar lavage fluid is increased, likely as an adaptive response to increased oxidants resulting from lung inflammation.⁵  In this context, Morris et al's study adds another pathway to the list of potential contributors to the pathogenesis of SCD related vasculopathy. The authors hypothesized that abnormal glutathione and glutamine metabolism may play a role in hemolysis and pulmonary hypertension in SCD. They show that total plasma and erythrocyte glutathione levels are significantly decreased in patients with SCD. Patients with pulmonary hypertension had significantly lower erythrocyte glutamine levels; these levels inversely correlated with the severity of pulmonary hypertension and were independently associated with an elevated tricuspid regurgitant jet velocity, an indicator of pulmonary hypertension. Finally, the erythrocyte glutamine-glutamate ratio was also decreased in patients with SCD and inversely correlated with the severity of pulmonary hypertension and markers of hemolysis. The authors conclude that decreased glutathione and glutamine contribute to alterations in the erythrocyte redox environment, compromised erythrocyte integrity, and NO bioavailability, which may be implicated in the pathogenesis of pulmonary hypertension associated with SCD.

The findings of this study are novel and potentially clinically significant. However, several questions still remain. The authors' conclusions are mostly supported by statistical associations that suggest, but do not conclusively establish, a direct link between the proposed pathways and the pathogenesis of pulmonary hypertension in SCD. As such, the mechanisms by which decreased glutathione and glutamine contribute to SCD-related vasculopathy need to be explored. For example, are these alterations a direct cause of oxidant stress to the erythrocyte or a marker of accumulation of redox active heme and iron from lysed red blood cells? Furthermore, the direct implications of these pathways to morbidity and mortality in these patients will have to be addressed in larger prospective studies. We hope that the study by Morris and colleagues will stimulate further research that will ultimately lead to new therapeutic options for patients with SCD and pulmonary hypertension.