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Discovery Promises Simpler Therapy For Sickle Cell Disease

 
  February, 8 2005 8:13
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Durham, N.C. – A new understanding of the causes for symptoms of sickle cell disease, a condition affecting one in every 600 African-Americans, has resulted from a study by researchers at Duke University Medical Center and Howard Hughes Medical Institute (HHMI). Their findings may lead to a new, more direct method for treating the disease, they said.

Their research suggests that an inability of red blood cells to relax blood vessels through the release of nitric oxide is a major factor behind the disease's primary symptoms -- including oxygen deprivation and blocked vessels that can lead to pain, clots and stroke. Thus, therapies that restore nitric oxide to blood cells might serve as a useful method for treating the disease, said HHMI researcher Jonathan Stamler, M.D., professor of pulmonary medicine and cardiology at Duke University Medical Center.

The researchers reported their findings on Jan. 31, 2005, in an early edition of Proceedings of the National Academy of Sciences.

The symptoms of sickle cell disease have generally been attributed to the physical obstruction of blood vessels by distorted, or "sickled," and rigid red cells, Stamler said. The new findings, for the first time, implicate abnormal vessel dilation by the red cells themselves in oxygen deficiency. That oxygen deficiency, in turn, may result in sickling and, ultimately, the irreversible obstruction of blood vessels.

Relieving the vascular constriction and resulting oxygen deficiency through the restoration of nitric oxide to red cell membranes might therefore prevent the disease symptoms, opening up a new realm of therapeutic possibilities, Stamler said. Current therapies fail to treat the disease itself and are instead geared toward minimizing pain and preventing infection, he added. In patients who become anemic, blood transfusions replenish the red blood cell supply in the body.

The team further found that differences among patients in their ability to process nitric oxide in the blood correspond to the severity of their disease symptoms. That result might explain a long-standing puzzle: patients with sickle cell exhibit extreme variability in the severity of their symptoms, despite the fact that the disease stems from a single genetic defect, Stamler said.

"This finding, if verified in clinical trials, could change physicians' approach to sickle cell disease," Stamler said. "Current efforts for managing the disease completely miss the role that red blood cell-derived nitric oxide plays. The disease might therefore be treated by more simple and effective methods than those now available to patients through the delivery of nitric oxide to blood cells."

The finding marks the first time that a defect in the ability of patients' red blood cells to process nitric oxide has been linked to a disease, the researchers said. The findings also raise the possibility that defective nitric oxide processing by red blood cells may represent a new class of blood diseases.

Patients with sickle cell disease have an abnormal form of hemoglobin. In the late 1990s, Stamler's team discovered that, in addition to its role in oxygen delivery, hemoglobin acts a biosensor, adjusting blood flow according to the oxygen demand of tissues and organs, by distributing nitric oxide.

Reports by the team in 2001 and 2002 further detailed nitric oxide's role in the red blood cell membrane, confirming it as the third major blood gas, along with oxygen and carbon dioxide. Those findings suggested that nitric oxide defects might play a role in the cardiovascular side effects of many disorders, including diabetes, heart attacks, septic shock and sickle cell disease.

In the current study, the researchers found that hemoglobin in the red cells of patients with sickle cell disease fails to process nitric oxide properly. As a result, they reported, the membranes of sickle red blood cells are deficient for the form of nitric oxide normally released by the cells. The blood cells therefore fail to open blood vessels normally.

Red cells taken from patients with mild sickle cell disease dilate blood vessels under low oxygen conditions, but to a lesser extent than normal red cells. In contrast, red cells from those with severe disease symptoms cause blood vessels to constrict when oxygen levels drop, they found, a response which would further exacerbate the oxygen deficiency. Treatment of red blood cells with nitric oxide reversed that effect, they reported.

"Our results suggest that abnormal blood vessel control by red blood cells contributes to the vessel obstruction characteristic of sickle cell disease, and that variation in symptom severity among patients may be explained, in part, by variable deficiency in the processing of nitric oxide," Stamler said.

In light of the discovery, the researchers call for a re-evaluation of the role that nitric oxide may play in other blood diseases and conditions characterized by a deficiency in oxygen delivery to tissues, such as heart failure, diabetes and pulmonary hypertension.

Collaborators on the study include lead author John Pawloski and Douglas Hess. The work was supported by the National Institutes of Health and a Doris Duke Clinical Scientist Development Award.

© 2005 Duke University Medical Center

John R. Pawloski, Douglas T. Hess, and Jonathan S. Stamler. Impaired vasodilation by red blood cells in sickle cell disease
PNAS published February 7, 2005


Message posted by: Frank S. Zollmann

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