Researchers have identified a highly specific pathway that causes inflammation in lung tissue

Jun 30 2005

Researchers have identified a highly specific pathway that causes inflammation in lung tissue, a discovery that could help in the design of more targeted treatments for patients with various lung diseases, including cystic fibrosis.

Children's Hospital of Pittsburgh and University of Pittsburgh researchers have identified a highly specific pathway that causes inflammation in lung tissue, a discovery that could help in the design of more targeted treatments for patients with various lung diseases, including cystic fibrosis (CF).

Their results, which also confirmed this novel pathway may contribute to lung damage in adult patients with cystic fibrosis (CF), are being published in the July issue of The Journal of Immunology.

Jay K. Kolls, MD, who is the division chief of Pediatric Pulmonology, Laboratory of Lung Immunology and Host Defense at Children's Hospital of Pittsburgh, and professor of Pediatrics and Immunology at the University of Pittsburgh School of Medicine, and his research team measured mediators of inflammation in cystic fibrosis patients, focusing on interleukin 23 (IL-23) and interleukin-17 (IL-17).

"The results show that IL-23 and IL-17 may be good targets for neutralization and blocking the inflammatory response," said Dr. Kolls adding that "this research shows us that with the newly identified pathway of inflammation, it may be possible to treat the patient earlier and more effectively, which could prevent lung disease or give patients a better quality of life and longer lifespan."

Dr. Kolls added, "What's intriguing is that by targeting IL-17 we may also be able to inhibit IL-8, a well-known inflammatory instigator in CF, since our laboratory studies suggest expression of this cytokine is dependant on IL-17. A treatment that focuses on IL-17 instead of IL-8 may be the more rational approach."

Because in CF patients the inflammation is never "shut off" and infections cannot be resolved, researchers have been looking for other ways to treat the inflammation associated with the disease. Throughout most of the world, lung infections are a major cause of death and illness among children. Although death rates are low in the United States, lung infection is the leading reason children visit doctors.

"Studies over the last decade have suggested that an excessive inflammatory response to infection occurs in CF. Clinical trials of non-specific anti-inflammatory therapies have shown some clinical benefit, but significant side effects have limited their utility," said co-author Joseph Pilewski, MD, associate professor of Medicine, Pediatrics and Cell Biology and Physiology at the University of Pittsburgh School of Medicine. "This work identifies a target for more specific regulation of the inflammatory pathways that ultimately contribute to lung damage in CF. Modulating this pathway could lead to a safer and more effective anti-inflammatory therapy for CF and perhaps other inflammatory lung diseases."

Dr. Pilewski also is co-director of the Adult Cystic Fibrosis Program at the Antonio J. and Janet Palumbo Cystic Fibrosis Center at Children's Hospital of Pittsburgh, and Medical Director of the Lung Transplant Program at the University of Pittsburgh Medical Center.

Dr. Kolls' team is investigating gene-based strategies to probe the immune system's ability to fight infection in the T-cell depleted setting. In mice when T-cells are depleted, the mice are able to protect themselves against infections when given an experimental therapy that takes certain proteins secreted by T-cells – the growth factor, IL-17, for example – and reconstitutes them into the system. Such an approach might someday treat infections which do not respond well to antibiotics, such as pneumocystis.

The investigation of cytokines is also leading to better understanding of their role in inflammation in the lungs of patients with cystic fibrosis.

Dr. Kolls said, "I think that if we can understand the inflammation processes, we can make an impact on their lives." Dr. Kolls and his team's discovery could also have applications with Multiple Sclerosis, as well as Inflammatory Bowel Disease.

More than 30,000 patients in the United States have CF, and Pennsylvania is one of only 11 states that screen for lung disease. 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.

"Translational research is very important, especially with regards to young patients who suffer from such a chronic disease like cystic fibrosis," said Dr. Kolls. "Using research to positively impact our young patient's lives is the most rewarding part of what we do as scientists and physicians. Everything we do is really focused on how to apply that understanding and research toward bettering the outcomes and quality of life for our patients."