Could Controlling Inflammation Improve Cystic Fibrosis Therapies?

Today, February 28th, is the 11th annual International Rare Disease Day. This is a day for every member of the rare disease community—patients, caregivers, and researchers—to join together on behalf of all of those suffering with a rare disease. In this blog post we highlight one Massachusetts General Hospital researcher who is tackling rare disease.

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Fifty years ago, a cystic fibrosis (CF) diagnosis was like receiving a death sentence. Most children with CF did not live past the age of 10.

Thanks to heavy investment and advancements in medical research, children diagnosed with CF after the year 2000 are expected to live into their 50s. However, more research is needed to cure this disease, starting with a better understanding of the mechanisms that cause the infection and inflammation associated with CF.

Children born with this rare genetic disease experience a thick, sticky buildup of mucus in the lungs, pancreas and other organs due to a lack of a chloride channel needed to hydrate mucus for effective transport through the body. The non-hydrated mucus clogs airways and traps bacteria, which can cause chronic lung infections and inflammation that eventually lead to permanent lung damage, respiratory failure and death.

Research from Bryan Hurley, PhD, principal investigator within the Mucosal Immunology & Biology Research Center at MassGeneral Hospital for Children, and director of the MGHfC Digestive Disease Summer Research Program, focuses on infectious and inflammatory diseases, such as CF, that disrupt mucosal surfaces of the lung and digestive tract. He is investigating how targeting neutrophils—white blood cells that attack infections—could be the key to developing improved therapies for CF patients.

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Current treatments and limitations

CF is typically treated through inhaled drugs and antibiotics that clear the patients’ airways and help fight infections. However, researchers have yet to find a long-term solution that will stop these chronic lung infections from eventually becoming deadly.

“CF is a complicated chronic condition where patients experience bouts of infection and inflammation, leading to an overabundance of neutrophils in the airways,” says Hurley. “Too many neutrophils in the airways can damage the lungs to the point where they don’t function effectively, eventually leading to end-stage lung failure.”

Potential CF therapeutic strategies

To understand how this works, one needs to understand how neutrophils travel in the body. Neutrophils naturally circulate in the blood stream and lymphatic system.

When an infection occurs, they receive a signal that directs them to the infection site. In many cases, this requires neutrophils to break through mucosal barriers made of tightly woven epithelial cells.

This epithelial barrier is found in several organs, including the lungs and the digestive tract, and is designed to protect the body from harmful substances that are inhaled or ingested.

Breaking through the barrier is sometimes necessary to allow neutrophils to reach the infection site, but it also compromises this defense system.

Hurley says a better understanding of the process behind neutrophil activation and barrier breakthrough could lead to new therapeutic targets. “We’re investigating whether we can develop therapies that specifically reduce the number of neutrophils penetrating the mucosal barrier without hindering neutrophil access to the organ tissue or diminishing their antimicrobial functions.”

“We believe achieving this nuanced balance might allow neutrophils to effectively battle microbes without destroying the surrounding organ tissue environment.”

The model system

Working with Hongmei Mou, PhD, of the Mass General Mucosal Immunology and Biology Research Center, and Lael M. Yonker, MD, co-director of the Mass General Cystic Fibrosis Center, Hurley’s lab has developed a model system of the respiratory tract made from expandable human airway basal stem cells. The process of culturing and expanding airway cells from human cough samples was developed by Mou while working as a postdoctoral fellow in the lab of Jay Rajagopal, MD.

The cells in this model system replicate the structure and function of the cells in the respiratory tract, with beating cilia and the ability to secrete mucus.

In addition, high resolution imaging technology called micro-Optical Coherence Tomography from the lab of  Guillermo (Gary) Tearney, MD, PhD, of the Wellman Center for Photomedicine at Mass General, is providing Hurley and his team with an unprecedented close up view of neutrophil activity in the model system.

In this video: The cells are infected with the bacteria Pseudomonas aeruginosa on the apical (lung airspace tissue) side. Neutrophils are then pipetted onto the basolateral side (vascular tissue) and begin organizing and crossing the barrier in response to multiple chemo-attractant lipid signals produced during infection.

Translation to patients

Hurley’s team has found that once neutrophils cross the infected epithelial barrier in response to epithelial cell release of a lipid signal called hepoxilin A3, they start producing a second lipid signal, leukotriene B4, which prompts other neutrophils to cross the barrier as well.

“We think leukotriene B4 is the workhorse, an amplifying signal that kicks the neutrophil breaching of the epithelial barrier into overdrive,” says Hurley.

Through translational funding from the Cystic Fibrosis Foundation and support from the National Institute of Allergy and Infectious Diseases (NIAID), Hurley’s team is investigating ways to interfere with both hepoxilin A3 and leukotriene B4 signals with the objective of dampening the inflammatory process.

These approaches will be tested in vivo to determine if they can achieve the critical balance of reduced inflammatory damage with sufficient infection containment.

The power of collaboration

Hurley credits the progress he has made in his research to Mass General’s collaborative culture.

“These kinds of projects are impossible to do alone,” says Hurley. “By working with other Mass General researchers, with their willingness to combine forces and leverage individual expertise and technologies towards a specific biomedical research question, we were able to contribute a unique perspective on inflammation that will likely have an impact on future therapeutic options for a variety of perplexing diseases.”

“At a place like Mass General, with the organizational structure the Research Institute provides, you have an unparalleled opportunity to do things that are bigger than what you could possibly do on your own,” says Hurley. “You’re much stronger when you work together.”

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