July 25, 2000 Inhalation of nitric oxide (NO) gas, a therapy that has significantly improved treatment of several life-threatening diseases, also may prevent the development of pulmonary vascular disease, a dangerous condition that can affect about one of every 500 infants: specifically those who are born prematurely or who have congenital heart defects. In the July issue of Circulation Research, investigators from the Massachusetts General Hospital (MGH) report that inhaled NO kept infant rats with lung injury from developing pulmonary vascular disease (PVD) by interfering with the basic process underlying the disorder, an overgrowth of cells in the walls of the pulmonary arteries. There currently is no way to prevent PVD in at-risk infants, and treatments for the condition are not very effective.
"Nitric oxide therapy has the potential to significantly increase the quality of life and in some cases save the lives of infants at risk for pulmonary vascular disease," says Jesse D. Roberts, MD, of the MGH Departments of Anesthesia and Pediatrics, the paper's first author. "With these findings and the knowledge that nitric oxide is a very safe treatment for other lung conditions, the time is right to design clinical trials in human infants."
PVD can develop in infants when damage to the lungs - caused by the use of ventilators to support premature lungs, lung inflammation, or stresses imposed by congenital heart defects - induces the walls of vessels carrying blood between the heart and lungs to thicken. In particular, muscle cells lining the peripheral pulmonary arteries proliferate excessively, leading to increased pressures within those vessels and a reduction in the flow of blood into the lungs. The heart must beat even harder to push blood through the overmuscularized vessels, which can result in heart failure. In infants with a hole between their left and right heart, PVD worsens the mixing of fresh, oxygenated blood with deoxygenated blood, reducing the supply of oxygen to every organ of the body. The outcome can be growth delay, developmental delays or even death.
Research in the past decade has shown that nitric oxide gas - not to be confused with the anesthetic nitrous oxide - plays key roles in many bodily functions, including the relaxation of blood vessels. MGH anesthesiology researchers pioneered the study of inhaled NO and were the first to show that the gas could relax blood vessels in the lungs without affecting the rest of the circulatory system. Roberts and his MGH colleagues previously showed that NO can successfully treat infants with persistent pulmonary hyper-tension of the newborn, a rare but life-threatening condition of full-term babies.
Two clues discovered by researchers elsewhere led to the current investigation of NO's possible role in treating PVD: observations that arterial cell proliferation is key to the development of the condition and studies in cultured cells suggesting that NO could decrease vascular cell proliferation. Since inhaled NO only effects cells in the lungs, it should be able to stop the PVD-associated proliferation without interfering with cell growth in other parts of the body.
To test their hypothesis, the researchers injected a group of newborn rats with monocrotaline, an agent known to cause lung injury and PVD. A control group was injected with an inert substance. Some of the monocrotaline-injected rats continuously breathed mixture of air with a small amount of NO throughout the two-week study.
A week after the study began, a three-fold increase in the muscularization of lung arteries was seen in the rats receiving monocrotaline without NO, confirming that the substance had set off the process underlying PVD. In those rats receiving inhaled NO, however, no overproliferation of muscle cells was seen and symptoms of PVD did not develop.
"Our observations suggest that inhaled NO works directly by decreasing abnormal lung artery cell proliferation," Roberts explains. "The protective effect seen in the rats receiving NO did not depend on the gas's action against conditions such as pulmonary hypertension, lung inflammation, and thrombosis. Instead NO has a fundamental role in regulating cell proliferation in the injured lung. It really gets at the heart of the problem."
Other authors of the study are Kenneth Bloch, MD, of the MGH Division of Cardiology and Cardiovascular Research Center (CVRC); Jean-Daniel Cheche of the CVRC; and Joerg Weimann, MD, Wolfgang Steudel, MD, and Warren Zapol, MD, of the Department of Anesthesia and Critical Care. The study was supported by grants from the Milton Foundation, the Massachusetts Biomedical Research Foundation, the Deutsche Forschungsgemeinschaft, and the National Institutes of Health.
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