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.