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Inhaled nitric oxide may help sickle cell disease

October 24, 2005

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, Medical College of Georgia researchers have found.

"Hemoglobin S plus nitric oxide behaves much like normal adult hemoglobin, which does not sickle," says Dr. C. Alvin Head, chair of the Medical College of Georgia 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.

Inhaling the short-acting gas naturally found on hemoglobin allows low concentrations to come in close contact with red blood cells and essentially turns the lungs into a hemoglobin repair shop.

"This is clearly a novel idea," Dr. Head says of findings that show the extra nitric oxide changes the neutral charge of hemoglobin S to the slightly negative charge much like normal hemoglobin. It could also help prevent development of the unwanted hemoglobin S polymers in the microcirculation when oxygen levels are lower, once hemoglobin releases its oxygen to the tissues.

Those surface irregularities create unfortunate 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, Dr. Head says. "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," he says or the resulting pain crises as the sickled cells deprive body tissue of adequate oxygen.

Add nitric oxide to the equation and the newly created negative charge helps hemoglobin molecules repel each other and stay independent, round and functional, he says of findings being presented during the American Society of Anesthesiologists' annual meeting in Atlanta Oct. 22-26. Sabina Wang, a research associate who performed these studies, will present their work. Dr. Steffen Meiler, vice chair of research for the MCG Department of Anesthesiology and Perioperative Medicine, also is a contributing co-author.

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 notes.

Anesthesiologists and other physicians already give low doses of nitric oxide to patients for reasons such as hypoxic respiratory failure in the newborn.

"We knew that nitric oxide would bind to hemoglobin very, very rapidly," says Dr. Head. "That has been very well proven in the medical literature. In fact, that is the basis of why when you inhale it in very low concentrations, you do not get systemic vascular effects," he says of the powerful dilator of blood vessels. "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 who 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," says 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, but we want to identify the exact sites where it's binding and might have its biggest impact," Dr. Head says.

Medical College of Georgia