Suspect protein found to play protective role in chronic lung disease

A cell surface protein regarded as a potential troublemaker in the lungs plays an unexpected protective role mitigating the damage caused by chronic pulmonary diseases such as asthma, University of Texas Medical School at Houston scientists report in the January edition of The Journal of Clinical Investigation (JCI).

Genetically knocking the protein out of a specialized strain of mouse that models chronic lung disease resulted in higher levels of inflammation, mucus, and tissue damage in the lungs as well as early death in the mice lacking the protein, researchers found.

A separate commentary by University of North Carolina researchers in the same issue of the journal calls the finding “surprising and important” in light of the fact that suppressing the protein is being investigated as a potential treatment for asthma. “Some believe this receptor protein plays a detrimental role and if you block it, you could improve asthma. This study shows that if you remove this protein from a diseased lung, you’ll make lung inflammation and damage worse,” said senior author Michael R. Blackburn, Ph.D., associate professor of biochemistry and molecular biology at the UT Medical School at Houston. By completely removing the protein, known as the A1 adenosine receptor, from a diseased line of mice, “we can be sure that what we are dealing with are A1 receptor responses,” Blackburn said. “In our model of adenosine dependent lung disease, it appears that the A1 receptor plays an important role turning on anti-inflammatory and tissue protective pathways.”

The A1 receptor also has been associated with bronchoconstriction in asthmatic airways by other researchers. The receptor, A1AR for short, is one of four proteins found on cell surfaces that connect with the signaling molecule adenosine. Adenosine, a byproduct of stress and tissue damage, is found in elevated amounts in the lungs of asthmatics, Blackburn said.

Earlier work by Blackburn and others indicates adenosine itself causes damage in the lung that resembles that seen in chronic lung diseases such as asthma, chronic obstructive pulmonary disease (emphysema, for example) and pulmonary fibrosis. Understanding adenosine and its interaction with the four types of receptor is critical to determining its role in disease. “We believe if you could control specific aspects of the adenosine signaling pathway, you could control all three of these diseases,” Blackburn noted “It will be important to examine the interplay of adenosine receptor signaling in other model systems as well as in the lungs of people suffering chronic lung disease to determine how these pathways might be manipulated to treat the progression of asthma and COPD.”

Blackburn and UT Medical School at Houston Department of Biochemistry and Molecular Biology Chairman Rod Kellems, Ph.D., earlier developed a strain of mice lacking the protein that normally clears excess adenosine. These knockout mice have elevated levels of the signaling molecule and swiftly develop a lethal respiratory disease that combines the features of asthma, COPD, and pulmonary fibrosis.

The mice provide a research model for understanding the adenosine signaling pathway because they permit researchers to knock out one of the four receptors at a time and observe the effects of the knocked out receptor on the severity of pulmonary disease in an environment of elevated adenosine. This double-knockout approach was employed in the JCI paper.

Blackburn’s team, including Chun-Xiao Sun, Ph.D., lead author of the JCI paper and a senior research associate in biochemistry, is examining the receptors’ roles one by one.

JCI paper co-authors were Jurgen Schnermann, Ph.D., of the National Institute of Digestive Disorders and Kidneys at the National Institutes of Health, who produced the original A1AR knockout mice; Jose Molina, a research assistant in biochemistry, and Hays Young and Jonathon Volmer, graduate students in the UT Graduate School of Biomedical Sciences at Houston (GSBS).

Blackburn also is on the GSBS faculty.

Media Contact

Scott Merville EurekAlert!

More Information:

http://www.uth.tmc.edu

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