A persistent scarcity of oxygen in body tissues - a widespread problem in patients with heart or lung disease - can create a defect of red blood cells that further exacerbates the condition by constricting blood vessels in the lung, Howard Hughes Medical Institute researchers at Duke University Medical Center have found.
What's more, the team demonstrated through studies in people and animals that inhalation of a 'souped up' form of nitric oxide, which targets red blood cells, reverses the blood abnormality to restore normal lung pressure.
The team's findings appear in the online Early Edition of Proceedings of the National Academy of Sciences (October 3-7, 2005). The work was supported by the National Heart, Lung, and Blood Institute and the National Science Foundation. Stamler is a paid consultant for Nitrox LLC, a biotechnology company developing NO-based drugs for disorders of the heart, lung and blood.
The potentially fatal lung condition, pulmonary hypertension, is characterized by high blood pressure in the lungs. The disorder is a common complication of chronic diseases such as emphysema, arthritis, sickle cell disease and heart failure. However, pulmonary hypertension can also arise in otherwise healthy people for unknown reasons. Symptoms include shortness of breath under minimal exertion, fatigue, chest pain, dizzy spells and fainting.
"Many people suffer pulmonary hypertension as a complicating factor of other chronic disease," said study senior author Jonathan Stamler, M.D. "In such cases, the lung condition is often predictive of poorer outcomes. For others, pulmonary hypertension is the primary disease."
"We have now established a molecular defect of the red blood cells as an important contributing cause of hypertension in the lung," added Timothy McMahon, lead author of the study. Physicians had previously considered an abnormality within the lung itself as the primary source of the condition, he explained. Physicians had not considered red blood cells as a cause of lung disease.
"We have found that when red blood cells are exposed to abnormally low oxygen for long periods, they become depleted of an essential substance that they normally release to relax blood vessels in the lung," McMahon continued. "But not only do blood cells, which of course perfuse the lung, cause lung problems, we've also found that inhalation of a new drug designed to correct the blood defect can reverse this condition."
Stamler's group reported in 1996 that hemoglobin in red blood cells acts as a finely tuned biosensor, adjusting blood flow to provide exactly the optimum amount of oxygen to tissues and organs. The blood cell adjusts blood flow by changing shape and releasing a nitric oxide-like molecule called s-nitrosothiol (SNO), which the cell carries through the bloodstream along with oxygen.
When oxygen levels are high, hemoglobin scavenges excess oxygen and NO, constricting blood vessels and reducing blood flow. When oxygen levels drop, the NO is released to relax blood vessels and improve blood flow. The Duke team now finds that with prolonged oxygen shortage, or hypoxia, blood cells become depleted of SNOs, therefore losing their ability to relax blood vessels.
More recent evidence from the Duke group has indicated that other types of SNOs might offer new therapeutic approaches to diseases of the heart, lung and blood. For example, the researchers found that SNOs played a critical role in septic shock, a common cause of death in intensive care units. They later showed that the compounds are lacking in the blood of patients with sickle cell disease and also play a part in preventing asthma. The latest findings extend the role of SNOs in red blood cells to include pulmonary hypertension.