University Times

$13 million awarded for pulmonary research

Pitt has been awarded an estimated $13 million research grant from the National Heart, Lung and Blood Institute to develop novel approaches to increase the understanding of chronic obstructive pulmonary disease (COPD) and improve outcomes for people with the degenerative breathing disorder.

The five-year grant establishes Pitt as a specialized center of clinically oriented research (SCCOR) in COPD.

Frank C. Sciurba is principal investigator of the SCCOR grant, which entails three unique projects. Sciurba is associate professor of medicine at the School of Medicine and director of the Emphysema Research Center in the Division of Pulmonary, Allergy and Critical Care Medicine.

“COPD damages the lung tissue, expanding and breaking down the walls of air sacs and thickening small airways, which hinders air flow into the lungs and transfer of oxygen into the blood,” said Sciurba. “These studies will help us to better understand the disease process and possibly devise better treatment options for patients.”

COPD, commonly related to smoking, diminishes breathing capacity over time and includes conditions such as chronic bronchitis and emphysema.

Each of the research projects capitalizes on findings of basic science and clinical research performed by the Pitt Emphysema Research Center. This SCCOR focuses on advanced cellular and molecular investigations of lung tissue changes involved in COPD to increase understanding of disease progression.

In addition to clinicians and scientists from Pitt, the projects are being undertaken with the collaboration of James Hogg, professor emeritus of pathology at the University of British Columbia.

Center researchers will study peripheral markers of COPD supporting a hypothesis that the disease is not uniform in its presentation. Researchers believe the differences are definable by anatomic, physiological, molecular and cellular processes to determine disease manifestation and progression. Using quantitative computed tomography, researchers will study airway remodeling, emphysema and their associations with other functional and physiological indicators of COPD to define unique clinical subcategories related to the interactions of genetic and environmental characteristics in 800 study subjects.

Center researchers also will continue to study lung tissue for evidence that abnormal immune system responses may contribute to airway injuries that signal COPD progression. Concurrent studies will look at how genetic factors and other molecular mediators affect lung tissue injury by focusing on damage to cellular repair mechanisms related to the inflammatory process.

Another center study will assess the efficacy of inhaled cyclosporine in patients with severe COPD to modify immune response and possibly slow disease progression and improve quality of life.

Tissue changes characterizing COPD and transplant rejection are similar in many ways, and inhaled cyclosporine is effective in treating organ rejection in lung transplant patients. Project leaders are Michael Donahoe, an associate professor of medicine in the Division of Pulmonary, Allergy and Critical Care Medicine, and Robert Branch, a professor of medicine and director of the Center for Clinical Pharmacology at the School of Medicine.

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Low doses of CO protect lung cells

Pitt researchers have demonstrated that low-dose carbon monoxide administered in conjunction with oxygen therapy markedly inhibits oxygen-induced damage to lung cells. These findings, reported in the Jan. 19 issue of the Journal of Biological Chemistry, have significant implications for the treatment of acute respiratory distress syndrome, or ARDS, according to the study’s authors.

ARDS is a life-threatening medical condition in which patients experience severe shortness of breath and oxygen starvation. It is the No. 1 killer of patients in intensive care unit facilities in the United States.

Although ARDS often occurs in people who have lung disease, even people with normal lungs can develop the condition as the result of severe trauma or an infection. Without prompt treatment, the oxygen deprivation resulting from ARDS can be lethal. Even with appropriate treatment, 30-40 percent of people with severe ARDS die.

Treatment for ARDS primarily involves hooking patients up to a mechanical ventilator and giving them almost pure oxygen (95 percent oxygen and 5 percent carbon dioxide). However, recent studies in animals have shown that prolonged exposure to an elevated level of oxygen, or hyperoxia, can cause long-term lung injury that resembles ARDS.

Based on previous research showing that low-dose carbon monoxide (CO) has potent anti-inflammatory effects in a number of tissues, the Pitt researchers cultured lung cells from mice in a medium with a high concentration of oxygen, with and without low levels of CO. They then monitored the cells for hyperoxia-induced toxicity.

They found that the presence of CO significantly inhibited the destruction of lung cells as well as the production of molecules in the cells that are known to induce cell suicide, or apoptosis. In contrast, more than half of the mouse lung cells incubated without CO died within 72 hours — compared to about 25 percent of the CO-treated cells — and produced high levels of apoptotic molecules.

“Giving ARDS patients almost pure oxygen over a prolonged period may be a double-edged sword,” said lead investigator Augustine Choi, professor of medicine and the chief of the Division of Pulmonary, Allergy and Critical Care Medicine at the School of Medicine. “It saves their life in the short term, but long-term exposure appears to cause significant damage to many cell types including the epithelial and endothelial cells of the lung. However, by administering oxygen mixed with a very small amount of carbon monoxide, we may be able to significantly reduce such oxygen-associated damage and cell death.”

Other Pitt researchers involved in the study are Xue Wang, Yong Wang, Hong Pyo Kim, Kiichi Nakahira and Stefan W. Ryter of the Division of Pulmonary, Allergy and Critical Care Medicine.

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Pharmaceutical grant awarded

Bristol-Myers Squibb awarded a $155,000 grant to Kim Coley, associate professor of pharmacy and therapeutics in the School of Pharmacy, in support of the project “Predictors of Successful Aripiprazole Treatment in Psychiatric Patients.” The study will identify patients and treatment factors that predict successful treatment in the inpatient setting.

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Ion channel model may aid in development of drugs

To open the door for better medicines, assistant professor Michael D. Grabe thought he first needed to open the doors, or channels, that allow for passage in and out of cells to see what science is up against when developing new drugs.

A faculty member in the biological sciences department in the School of Arts and Sciences, Grabe created a model of open channels in plant cells to gauge the appearance of closed channels in the human heart and brain, which resemble open plant channels. The results have appeared in the online edition of Nature and will be published in Nature’s Feb. 1 print edition.

Known as ion channels, the passages that Grabe studied are proteins that open and close so that electrically charged atoms, or ions, can pass into cells. The ion’s charge then passes from one cell to the next, allowing the cells to communicate over long distances.

“We wouldn’t have consciousness if it wasn’t for our cells’ ability to hold and pass ions,” he added.

Scientists already know the shape of open channels in human and animal cells. With more knowledge on the shape of closed channels in animal cells, scientists will be better able to understand how to control channels with medicine and restore cell function to treat such conditions as epilepsy and heart arrhythmia, Grabe said.

“Unless we know how these small devices work, it’s really difficult to re-create how they work together in the body,” he said. “It’s hard to fix a door when you don’t have any idea what a hinge looks like or what a hinge is.”

Modern drug developers target ion channels because of their prominent role in molecular harmony. According to Grabe, his model gives scientists another reference when mapping the mechanics of ion channels.

“When developing a drug, researchers need to know what the target of the drug looks like,” he said. “My research focused on what ion channels look like when they’re closed and when they’re open.”

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Medical group practices may offer better care, study says

Many health care consumers might prefer the perceived personal touch of the small neighborhood doctor’s office. But in the first study comparing quality measures to the size and structure of physician groups, researchers found that larger, integrated medical groups generally provide higher-quality care, according to an article in the current issue of the Annals of Internal Medicine.

The study, led by Ateev Mehrotra, of Pitt’s School of Medicine and RAND Health, analyzed data from 119 California physician groups that contracted with PacifiCare, a large health maintenance organization, between July 1999 and June 2000. The researchers examined three preventive-care measures, such as percentage of eligible patients who received mammograms, and three chronic disease-management measures, including percentage of patients with asthma who received a controller medication. The integrated medical groups — with employed physicians practicing together in facilities owned and managed by the group — had higher scores than the independent practices on four of the six quality measures, according to the study.

“Most physicians in this country work in independent, one-, two- or three-person practices,” said Mehrotra. “But the larger systems with employed physicians actually had higher-quality care, and sometimes that difference was substantial. This goes against the perception by some patients that the best care is provided at your small doctor’s office around the corner.”

While the larger groups were far more likely to use electronic medical records and to adopt quality-improvement strategies, such as contacting patients to remind them of missed appointments, these strategies explained little of the quality differences, the study found. The results do not suggest that such strategies are wrong, but “underscore the importance of understanding how organizational setting influences the quality of care provided,” the article noted. While other studies have suggested that the organizational structure of physician groups can affect quality, this is the first to demonstrate this empirically, according to the authors.

The researchers speculated that the centralized decision-making and closer affiliations of the integrated groups might enable them to provide higher-quality care, at least for the types of medical services measured by PacifiCare’s performance reports. And these groups may have more resources to invest in improving care. Younger doctors with the latest training also might be more likely to join these larger, employed-physician groups, Mehrotra noted.

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GSPIA prof to study EU airline emissions law

Martin Staniland of the Graduate School of Public and International Affairs has received a $5,000 grant from the European Union Center at Pitt’s University Center for International Studies to study the impact of emissions from commercial air traffic on global warming.

Staniland plans to examine the background to the recent decision of the European Union to include air transport in the emissions trading system (ETS) set up under the Kyoto protocol on atmospheric pollution. The EU has adopted the protocol; the United States has not.

The decision will require airlines to cap emissions (including carbon dioxide, which is considered a contributor to global warming) from their aircraft. Although the plan is not expected to include the aviation industry until 2010 or 2011, it is unpopular among many of the airlines because they see it as cramping growth.

Staniland notes the plan has caused tension between the EU and non-EU nations including the U.S. because the EU proposes to apply the ETS to non-EU airlines flying to European airports. The issue is likely to create a political debate in the coming decade, Staniland said.

The first phase of the research will examine the timing of the EU’s interest in this topic and the way in which it became an item on the EU’s legislative agenda in comparison with the EU’s agenda-setting on other environmental issues.

Staniland also plans to examine the politics of implementing this policy with reference to existing writing on the European Commission’s regulatory powers over major industries and to competing interpretations of this relationship in economics, political science and economic sociology.