Researchers receive $12.8 million NIH grant to improve diagnosis/treatment of chronic lung disease

Children's Hospital of Pittsburgh of UPMC and University of Pittsburgh School of Medicine researchers have been awarded a $12.8 million grant to improve the diagnosis and predict the therapeutic response of several devastating lung diseases.

This five-year grant from the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) establishes Children's and the University of Pittsburgh as a Specialized Center of Clinically Oriented Research (SCCOR) in Pediatric Pulmonology. This kind of center award is designed to facilitate more rapid translation of basic research findings into effective therapies for specific and troublesome diseases. Jay K. Kolls, MD, principal investigator and a professor of Pediatrics and Immunology at Pitt, and his collaborators not only hope to determine prevention strategies for patients suffering from allergic and fibrotic lung diseases, but also anticipate developing more effective treatments for these patients.

One focus of the research will be to understand why and how Aspergillus (group of molds that are ubiquitous in our environment) causes lung damage in patients with suppressed immune systems. This is particularly important for the health of children because this mold can cause significant lung damage in cystic fibrosis and asthma patients.

Allergic bronchopulmonary aspergillosis (ABPA) is an intense inflammatory reaction to the fungus, Aspergillus fumigatus, and can cause irreversible lung damage in patients with cystic fibrosis (CF) and asthma. Aspergillus, the mold which elicits this immune response, is very common in the environment and found worldwide. Although Aspergillus is not a health problem for most people, it can lead to pneumonia in patients with severely suppressed immune system and cause allergic damage to the airways of patients with CF or asthma. However, scientists do not understand why some patients develop airway damage and others do not.

"Everyone inhales Aspergillus molds. What we need to determine is why and how some develop an allergy to it, and others do not," said Kolls, chief of Pulmonary Medicine, Allergy, and Immunology at Children's. "We don't know why some patients develop this disease and others do not. Ideally we want to be able to predict who is susceptible to the disease and provide better treatments for patients."

Co-investigator Chad Steele, PhD, co-director of the Laboratory of Lung Immunology and Host Defense at Children's and an assistant professor at Pitt, has defined key molecules that initiate the earliest immune responses to Aspergillus. These molecules may be significant in determining which patients develop a protective immune response while others develop an immune response which damages the lung.

This allergic response is developed mostly by CF patients, Kolls said. CF is progressive and attacks the lungs. The disease affects more than 30,000 children and adults in the United States. Currently, the life expectancy of a child born with CF is 32 years. Pennsylvania is one of only 11 states that screens for lung disease. More than 400 patients suffering from the life-shortening and incurable disease are cared for at the Antonia J. and Janet Palumbo CF Center at Children's, under the direction of David Orenstein, MD. Upon review, more than one-third, or 180, of those patients have Aspergillus in their lungs.

Kolls explains that research by co-investigator Anuradha Ray, PhD, of Pitt, has shown that regulatory T cells, also known as the "the gatekeepers," can suppress allergic responses and control allergies in humans. The ability of these cells to control allergic responses may be critical in determining which patients develop allergy and which patients do not develop lung damage.

"Our ultimate goal is to learn if mobilization of these suppressor cells can help control the allergy thereby creating more of an immune response in these patients," Kolls said. " By more clearly defining how this disorder develops through our basic research we will be in a position to develop more effective and specific treatment and prevention strategies and provide a better quality of life for these patients."

David Perlmutter, MD, Children's physician-in-chief and scientific director, says that by "understanding how microbes interact with host immune cells to cause lung disease is absolutely critical and Jay Kolls is one of the world's leaders in this area. This award has permitted him to assemble an outstanding team and will facilitate new discoveries that have the potential to benefit children and their families everywhere."

Another focus of the grant is to improve treatment and diagnosis of patients with a disease called Idiopathic Pulmonary Fibrosis (IPF). IPF is a disease characterized by progressive scarring of the lung without any recognizable reason. The disease affects more than 100,000 patients in the United States, with no proven therapy except lung transplantation. And, there is no good way to diagnose the disease before significant lung damage has occurred or to predict the outcome of the disease.

Co-Investigators from the Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease at Pitt will attempt to design better methods for diagnosis and treatment of IPF. The center provides service and advance research for over 1,000 patients with Interstitial Lung Disease with over a third having IPF. Naftali Kaminski, MD, associate professor at Pitt and the center's director, and Kevin Gibson, MD, associate professor at Pitt, will monitor patients to identify changes in their genes that predict disease progression. These changes may help to understand what causes the disease and to design better drugs.

Steven R. Duncan, MD, associate professor at Pitt, a co-investigator has discovered that many patients with IPF have exaggerated immune response. This new observation may suggest that not all patients will respond to the same therapy and may suggest that some patients will respond to specific drugs that modify the immune system. "This project should allow us what genes are active in a specific patient during disease progression and in the future tailor a therapy," Kaminski said.

Also, Prabir Ray, PhD, associate professor at Pitt, has shown that certain growth factors can protect the lung against the development of fibrosis in mice. He will further study the mechanisms of these protective effects and will examine whether specific therapies could be developed. These experiments are critical because they may help develop approaches not only to halt fibrosis but maybe even to reverse it.


The grant also involves core leaders Joseph Pilewski, MD, who is co-director of the Adult Cystic Fibrosis Program at Children's CF center, and Medical Director of the Lung Transplant Program at UPMC, and Howard Rockette, PhD, who is professor and chair of Pitt's department of Biostatistics.

About Dr. Kolls
Dr. Kolls strives to improve the health of children with lung disease through research, teaching and medical care. Dr. Kolls' lab focuses on lung immunology and host defense to address the fact that, worldwide, respiratory infections are the number one killer of children.

Dr. Kolls' laboratory investigates mechanisms of lung host defenses in normal and immunocompromised hosts as well as lung immunology in disease such as cystic fibrosis and asthma. Additional research interests of Dr. Kolls include gene therapy, lung immunology, lung host defenses, tumor necrosis factor, pneumonia, pneumocytis carinii pneumonia, ethanol, gene expression, polymerase chain reaction and molecular biology.

For more information about Children's or Dr. Kolls, please visit, or the University of Pittsburgh Medical Center at

Last reviewed: By John M. Grohol, Psy.D. on 30 Apr 2016
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