Inhaling a small dose of nitric oxide gas may one day help sickle cell patients avoid pain crises and live healthier lives, researchers say. Nitric oxide may help normalize a sickle cell patient’s hemoglobin by restoring the natural charge and shape to the oxygen-carrying component of red blood cells, MCG researchers have found.
“Hemoglobin S plus nitric oxide behaves much like normal adult hemoglobin, which does not sickle,” said Dr. C. Alvin Head, chair of the Department of Anesthesiology and Perioperative Medicine.
In fact, their test-tube studies of human hemoglobin show nitric oxide not only prevents unhealthy clustering of hemoglobin S molecules but can melt existing polymers, leaving more hemoglobin free to do its job of oxygen delivery to the body.
Low concentrations of the short-acting gas, which is found naturally on hemoglobin, reach red blood cells when inhaled, essentially turning the lungs into a hemoglobin repair shop. Sabina Wang, an MCG research associate who performed the studies, presented the findings during the American Society of Anesthesiologists’ annual meeting in Atlanta last October. Dr. Steffen Meiler, vice chair of research in the Department of Anesthesiology and Perioperative Medicine, also was a contributing co-author.
“This is clearly a novel idea,” Dr. Head said of findings that extra nitric oxide normalizes the neutral charge of hemoglobin S to a slightly negative charge. It might also help prevent development of unwanted hemoglobin S polymers in the microcirculation when oxygen levels are lower, once hemoglobin releases its oxygen to the tissues.
Those surface irregularities create puzzle pieces that help hemoglobin S molecules fit together to form the polymer. The neutral charge permits this abnormal bonding that eventually deforms the red blood cells that carry them. “As the polymer gets longer, it binds to the red cell membrane and begins to deform the cell. If you can prevent this from occurring, you won’t get the abnormal-shaped cells [or the resulting pain crises],” he said.
The
negative charge helps hemoglobin molecules repel each other and stay
independent, round and functional. Oxygen also can break apart dangerous
polymers, but the smaller nitric oxide is more agile, has a higher affinity for
hemoglobin and—perhaps most importantly—can normalize the charge of hemoglobin
S, Ms. Wang noted.
Low doses of nitric oxide already are used for conditions including hypoxic respiratory failure in newborns.
“We knew that nitric oxide would bind to hemoglobin very, very rapidly,” said Dr. Head. “In fact, that is the basis of why when you inhale it in very low concentrations, you do not get systemic vascular effects. It rapidly crosses the lungs, binds to the hemoglobin, then circulates in the blood.”
It was when he was giving nitric oxide to lung transplant patients years ago, patients who might end up breathing the gas for days or weeks at a time without apparent ill effects, that he first considered how it also might benefit sickle cell patients.
Previously published studies by Dr. Head and his colleagues in a hypoxic animal model for sickle cell disease showed the animals that breathed nitric oxide gas are the ones that survived.
“This is not a cure, but we think it will get patients out of a crisis earlier or maybe prevent a crisis,” said Dr. Head of the potential therapy that may one day be used by sickle cells patients like inhalers are used by asthmatics.
The MCG researchers already are working with University of Georgia researchers to crystalize hemoglobin S and identify all points of action for nitric oxide. “We know there is a charge change globally,” Dr. Head said, “but we want to identify the exact sites where it’s binding and might have its biggest impact.”
Toni Baker