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The Future of Pulmonary Hypertension Treatment
Novel Connection Identified Between Pulmonary
Hypertension in Sickle Cell Disease and Glutamine Depletion

CHORI scientists Claudia Morris, MD, Jung H. Suh, PhD, Frans A. Kuypers, PhD, and their colleagues have elucidated for the first time that alterations in glutathione and glutamine metabolism have a significant role in pulmonary hypertension (PH) in patients with sickle cell disease (SCD).

Dr. Morris' interest in glutathione, one of the most potent anti-oxidants found in red blood cells comes from her clinical work with sickle cell patients and her desire to uncover why PH occurs in this population.

"Pulmonary hypertension is the leading cause of death in sickle cell disease and one of the highest risk factors for early mortality, with a ten-fold increase risk for death," says Dr. Morris.

Previous studies have linked the rupturing of red blood cells that leads to anemia, called hemolysis, to low glutathione levels in the red blood cells in a number of disorders, including SCD. As a result, Dr. Morris believed that glutathione availability could be connected to the occurrence of PH.

"Since hemolysis is a trigger for the development of PH, we were expecting to find lower glutathione levels overall in SCD patients with PH, as compared with patients without PH. However when we actually did the analysis, there was no difference at all, so we had to go back to the drawing board."

This meant exploring in more detail the amino acid precursors to glutathione, and some intense collaboration with Dr. Suh, the lab scientist behind the breakthrough in order to accurately interpret the research findings, which were published in Blood online in September, with the hardcopy forthcoming.

With Dr. Suh's expertise, Dr. Morris and her colleagues found their way to the glutathione precursor glutamate, and the glutamate precursor, glutamine. The end result was the discovery that decreased glutamine levels within the red blood cell itself were tightly correlated with increased PH severity. Probing further, Dr. Morris and her team determined there was also a correlation with the ratio of glutamine to glutamate.

"Patients with SCD had much lower glutamine to glutamate ratios than controls, and patients with pulmonary hypertension had even lower ratios," Dr. Morris explains. "It's an incredibly tight correlation, providing a novel biomarker for pulmonary hypertension as robust as any other biomarkers that have been described to date."

Although this ratio has been used as a predictor of bad outcome in the cerebral spinal fluid (fluid around the brain and spinal cord) of patients with head trauma, this is the first time that levels in the red blood cell have been linked to PH.

In addition to suggesting that glutamine bioavailability thus has a very important role in SCD, the glutamine/glutamate
ratio also provides a clue as to a possible connection between oxidative stress - which is caused by the depletion of anti-oxidants like glutathione, and hemolysis - the abnormal breaking down of the red blood cell that occurs in diseases like SCD.

"What we found was that the glutamine/glutamate ratio inversely correlated with plasma arginase concentration and plasma-free hemoglobin, both of which are biomarkers for hemolysis," Dr. Morris says. "These findings provide further support for a link between oxidative stress and hemolysis and start to answer the question of why hemolysis is actually going on."

The full impact of the study is two-pronged. By identifying the importance of these amino acids in the red blood cell, Dr. Morris's work opens a whole new area of research. In addition, the correlation between oxidative stress causing hemolysis and PH provides novel clinical approaches to treating PH. It suggests there might be nutritional anti-oxidant supplements that could combat the problem.

"If oxidative stress is contributing to hemolysis and PH, then anti-oxidant supplementation might be a solution. It won't fix the problem, but it could alleviate it," says Dr. Morris. "The next step is to actually look at glutamine supplementation, and I'm hoping to put together a grant proposal looking at an anti-oxidant sickle cell cocktail that targets these mechanisms."


Tuesday, May 17, 2011 8:42 AM

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