"The effect of inhaled nitric oxide on sickle hemoglobin is totally separate from its effects in the lungs, which have proven life-saving for people with several critical illnesses," says C. Alvin Head, MD, the MGH anesthesiologist who led the study. "This is a totally new application of this molecule, which has generated a lot of interest over the past several years."
Study co-author Kenneth Bridges, MD, director of the Joint Center for Sickle Cell and Thalassemic Disorders at Brigham and Women's Hospital and the MGH, adds, "This discovery gives us two things: a possible means of interrupting sickle cell crisis once it's started -- something we don't have right now -- and a real possibility for long-term, outpatient treatment."
In sickle cell disease, a genetic disorder, affected individuals have an abnormal form of hemoglobin, the protein in red blood cells that carries oxygen from the lungs to tissues and organs throughout the body. After this abnormal hemoglobin releases its oxygen, it clumps together into an abnormal shape, deforming the red blood cells -- normally flexible discs -- into rigid, elongated "sickle cells." These sickle cells can become stuck in tiny blood vessels, blocking blood flow to various parts of the body. The result is sickle cell crisis, excruciating pain in the affected area that can require hospitalization in the most serious cases.
The current report describes how nitric oxide causes sickle hemoglobin molecules to bind oxygen with greater affinity, which should reduce formation of the sickle cells. The result was seen both in laboratory studies and in several volunteer patients with sickle cell disease who breathed low concentrations of nitric oxide.
The common gas nitric oxide -- not to be confused with the anesthetic nitrous oxide -- plays many roles in the body, including relaxation of blood vessels. Researchers at the Massachusetts General Hospital (MGH) Department of Anesthesia and Critical Care pioneered the study of nitric oxide by inhalation and have shown that it can effectively treat several life-threatening lung conditions. The gas has been successful in expanding constricted blood vessels in the lung without effecting the rest of the body's circulatory system. The effect is limited to the lungs because the gas binds with hemoglobin upon entering the bloodstream, neutralizing its vessel-expanding properties. Head explains, "Our researchers who looked at how nitric oxide binds to hemoglobin found that it had no effect on normal hemoglobin. But I started to wonder if there might be any effect on abnormal hemoglobin -- particularly in sickle cell disease."
To pursue this question, Head entered into a collaboration with several local sickle cell specialists, including Carlo Brugnara, MD, of Children's Hospital and Bridges, as well as MGH investigators specializing in nitric oxide research. They first added low concentrations of nitric oxide -- similar to those used therapeutically -- to normal red blood cells and those from sickle cell disease patients. They found that the gas, while having no effect on the normal blood cells, caused the sickle hemoglobin to hold on to oxygen more avidly than it usually would.
They then took blood samples from nine volunteer patients with sickle cell disease and three normal volunteers before and after the volunteers inhaled low levels of nitric oxide in air for 45 minutes. In eight of the nine sickle cell disease patients, breathing nitric oxide caused their red cells to give up oxygen less readily than before, while the cells from the normal patients showed no change. The increased oxygen retention by the sickle cell patients' red cells persisted for a least an hour after they breathed the nitric oxide gas.
Co-author Brugnara, director of the hematology lab in the Department of Laboratory Medicine at Children's, has conducted research into sickle cell treatment approaches designed to keep the blood cells from dehydrating. He says, "Dr. Head's very novel idea of applying this interesting molecule to sickle cell disease may turn into one of the most significant treatment developments of this decade."
Additional co-authors of the paper include Warren M. Zapol, MD, senior author and chief of the MGH Department of Anesthesia and Critical Care; Ricardo Martinez-Ruiz, MD, Robert Kacmarek, RRT, David Kuter, MD, and Kenneth Bloch, MD, all of the MGH.
The next step the researchers will undertake is a multi-center, randomized double-blind study to determine whether nitric oxide inhalation acutally can decrease symptoms in patients experiencing sickle cell crisis. The earliest stages of such a study have just begin, based at the MGH.
Journal
Journal of Clinical Investigation