Discovery Links Blood Cell Defect To Common Lung Disorder, Leads To Novel Treatment

The team's findings will appear in theonline Early Edition of Proceedings of the National Academy of Sciencesnext week (October 3-7, 2005). The work was supported by the NationalHeart, Lung, and Blood Institute and the National Science Foundation.Stamler is a paid consultant for Nitrox LLC, a biotechnology companydeveloping NO-based drugs for disorders of the heart, lung and blood.

Thepotentially fatal lung condition, pulmonary hypertension, ischaracterized by high blood pressure in the lungs. The disorder is acommon complication of chronic diseases such as emphysema, arthritis,sickle cell disease and heart failure. However, pulmonary hypertensioncan 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 sufferpulmonary hypertension as a complicating factor of other chronicdisease," said study senior author Jonathan Stamler, M.D. "In suchcases, the lung condition is often predictive of poorer outcomes. Forothers, pulmonary hypertension is the primary disease."

"We havenow established a molecular defect of the red blood cells as animportant contributing cause of hypertension in the lung," addedTimothy McMahon, lead author of the study. Physicians had previouslyconsidered an abnormality within the lung itself as the primary sourceof the condition, he explained. Physicians had not considered red bloodcells as a cause of lung disease.

"We have found that when redblood cells are exposed to abnormally low oxygen for long periods, theybecome depleted of an essential substance that they normally release torelax blood vessels in the lung," McMahon continued. "But not only doblood cells, which of course perfuse the lung, cause lung problems,we've also found that inhalation of a new drug designed to correct theblood defect can reverse this condition."

Stamler's groupreported in 1996 that hemoglobin in red blood cells acts as a finelytuned biosensor, adjusting blood flow to provide exactly the optimumamount of oxygen to tissues and organs. The blood cell adjusts bloodflow by changing shape and releasing a nitric oxide-like moleculecalled s-nitrosothiol (SNO), which the cell carries through thebloodstream along with oxygen.

When oxygen levels are high,hemoglobin scavenges excess oxygen and NO, constricting blood vesselsand reducing blood flow. When oxygen levels drop, the NO is released torelax blood vessels and improve blood flow. The Duke team now findsthat with prolonged oxygen shortage, or hypoxia, blood cells becomedepleted of SNOs, therefore losing their ability to relax blood vessels.

Morerecent evidence from the Duke group has indicated that other types ofSNOs might offer new therapeutic approaches to diseases of the heart,lung and blood. For example, the researchers found that SNOs played acritical role in septic shock, a common cause of death in intensivecare units. They later showed that the compounds are lacking in theblood of patients with sickle cell disease and also play a part inpreventing asthma. The latest findings extend the role of SNOs in redblood cells to include pulmonary hypertension.

A new chemicaltherapy, which replenished SNO levels in the blood of patients,restored the red blood cells' ability to dilate vessels, loweredpressures, and improved the transfer of oxygen to tissues. Similarly,in the lab, exposure of red blood cells to sustained hypoxia led to adeficiency of the SNO vessel relaxant, according to the researchers.The SNO-deficient blood cells failed to relax blood vessels of thelungs in laboratory studies and constricted pulmonary blood vessels inpigs, they reported. Restoration of SNO levels in the animals likewiselowered pressures in the lungs.

The researchers demonstrated thatunder conditions of prolonged oxygen deficiency, which is very commonin sick patients, red cells become deficient for SNO, thereby losingtheir capacity to relax blood vessels and boost blood flow, Stamlersaid. Pressure came down in the lungs of animals given red blood cellsreplete in SNOs, whereas transfusion of red blood cells deficient inSNO raised pressures, the team reported.

To examine the relevanceof the findings to human disease, the researchers compared the level ofSNO in the blood of patients with pulmonary hypertension to that ofhealthy people. Normal individuals had five times more SNO in theirblood than did those with elevated lung pressure. In fact, those withthe lung condition almost completely lacked hemoglobin with bound SNO,a finding consistent with the effects of hypoxia observed in the lab,Stamler said. That SNO-deficiency led to impaired blood vessel dilationby the red cells, they showed.

The researchers reasoned that ifdeficiency of SNO in red blood cells causes the lung condition, thenrestoring SNO levels should reverse the disease. Ten patients treatedwith an inhaled SNO-generating gas exhibited an increase in SNO in thebloodstream, found the researchers. After therapy, patients' red bloodcells again relaxed blood vessels in a manner comparable to that ofnormal red cells. In addition, the pressures came down in the lungs ofthe patients.

"We have followed this process all the way fromcharacterizing the molecular defect of red blood cells through thetranslation of this basic scientific finding into a promising newtherapy," Stamler said. A larger clinical trial effort now underwaywill further examine the therapy's potential to relieve pulmonaryhypertension, he said.

Collaborators on the study include TimothyMcMahon, Gregory Ahearn, Martin Moya, Andrew Gow, Yuh-Chin Huang,Raphael Nudelman, Yun Yan, Abigail Krichman, Thomas Bashore, RobertCaliff, Claude Piantadosi and Victor Tapson, all of Duke. BenjaminLuchsinger and David Singel of Montana State University alsocontributed to the research.