Oct. 22, 2018

The Paper of the Month for October 2018 is "Eosinophils increase airway sensory nerve density in mice and in human asthma" published in Science Translational Medicine. This project was led by Matthew Drake, M.D., assistant professor of medicine, Division of Pulmonary and Critical Care Medicine, OHSU School of Medicine. Its authors in descending order are Dr. Drake, Dr. Gregory Scott, Emily Blum, Dr. Katherine Lebold, Dr. Zhenying Nie, Dr. James Lee, Dr. Allison Fryer, Dr. Richard Costello and Dr. David Jacoby. 

Asthma is a chronic airway disease affecting about 235 million people worldwide. People with asthma experience periods of increased bronchoconstriction – or airway narrowing – and a heightened sensitivity to environmental irritants such as smoke, perfumes or cold air, resulting in wheezing and shortness of breath.

Because airway nerves control bronchoconstriction, researchers in the OHSU Asthma Lab were interested in determining if the airway nerve structure changes in asthma and, if so, how those changes might contribute to increased asthma symptoms.

Seeing the forest and the trees

It turns out that two-thirds of patients with asthma have an overabundance of immune cells called eosinophils in their airways. Eosinophils affect the function of many cells in the airways, but their effects on airway nerves weren't fully understood. 

"Studying airway nerves and understanding nerve structure in particular has historically been challenging due to the limitations of previous imaging techniques," said Dr. Drake.

Typically, when studying tissues in the body, he said, samples must be cut into thin sections that can be analyzed on a traditional microscope. That's problematic for studying nerves because nerves form complex, three-dimensional structures that span hundreds of tissue sections. 

Think of it like tree branches in a forest. Using sectioned tissues, researchers could only visualize small sections of the branches, which meant never seeing the whole tree or how multiple trees fit together. 

To overcome this challenge, the research team developed a new technique using OHSU's state-of-the-art confocal microscopes to generate three-dimensional imagery.

"With our new method, you can see both the forest and the trees," said Dr. Drake.

A new mechanism

Using this complete picture of airway nerves and their interactions with eosinophils, the research team compared airway nerves in healthy human airways to patients with asthma. 

They found that, in asthma, airway nerves are denser, twice as long and have double the number of branches. Those changes are associated with worse lung function and more asthma symptoms. In addition, nerve density is associated with more eosinophils in the airway. 

To study the interactions of eosinophils and airway nerves, the researchers utilized genetic techniques in a mouse model to demonstrate that eosinophils caused airway nerve growth and that more airway nerves led to increased bronchoconstriction. By identifying a new mechanism in asthma, the researchers opened up opportunities for developing new asthma treatments for the millions of patients with poorly controlled symptoms. 

"This body of work is compelling from a number of perspectives," said Mary Heinricher, Ph.D., associate dean of basic research, OHSU School of Medicine. "First, it is truly interdisciplinary, sitting at the intersection of the nervous and immune systems with physiology. Second, it surprising, at least from a naïve neuroscience point of view, because no one would have predicted altered structure of sensory neurons triggered by an immune activation. And third, it highlights the intriguing and counter-intuitive findings that sometimes result when clinical and basic science come together."

Next steps

The team is investigating several new areas, including whether changes in nerves are preventable or if this process is reversible once it is established. "We are studying whether currently available asthma drugs are beneficial for asthmatics with increased airway nerves, and we are identifying new drug targets that will hopefully lead to therapies in the future," said Dr. Drake.

He added, "This work could not have been done without the outstanding collaboration between our team members and without OHSU's support for research, particularly for early-stage investigators. OHSU's commitment to early career physician-scientists is as an essential part of our team's success."  

Dr. Drake is supported by an NIH K08 career development award and was previously supported by the Pulmonary Divisions T-32 award. He has also received grant support from the Collins Trust and through the EXITO Program (joint PSU-OHSU program headed by Dr. Cindy Morris). He has also been part of the Human Investigators Program and has benefited from early career guidance via OCTRI. Dr. Lebold is a member of the M.D.-Ph.D. program at OHSU and supported by an NIH F Award. Dr. Scott is a graduate of the M.D.-Ph.D. program and was supported by an NIH F Award.

Pictured front row from left: Emily Blum, Becky Proskocil, Allison Fryer, Gina Calco, Jane Nie; back row from left: Matt Drake, Brenda Marsh, Ali Pincus, Lauren Hales-Beck, David Jacoby. 

Citation

Matthew G. Drake, Gregory D. Scott, Emily D. Blum, Katherine M. Lebold, Zhenying Nie, James J. Lee, Allison D. Fryer, Richard W. Costello, David B. Jacoby. Eosinophils increase airway sensory nerve density in mice and in human asthma. Science Translational Medicine, 2018;10 (457): eaar8477 DOI:

Resources

• Read the paper
• View the OHSU news announcement 
• Visit the lab's website
• Previous Papers of the Month