(Press-News.org) BIRMINGHAM, Ala. – Cigarette smoke shuts off a key enzyme in airways that regulates the body's response to inflammation, according to findings from the University of Alabama at Birmingham published online today at Science Express.
The UAB researchers say smoke inhibits the enzyme, called Leukotriene A4 Hydrolase (LTA4H), causing it to fail in its job of shutting down white blood cells following a successful response to inflammation.
The team says the research study identified a previously unknown substrate of LTA4H called proline-glycine-proline (PGP). In a normal response to inflammation, PGP's role is to recruit neutrophils – white blood cells – that rush to the scene and attack the cause of the inflammation. When the job is over, LTA4H steps in to shut off PGP, in turn halting the recruitment of neutrophils and ending the body's defensive stand.
"We found, however, that cigarette smoke inhibited LTA4H, preventing it from shutting down PGP," said J. Edwin Blalock, Ph.D., senior author and professor in the UAB Division of Pulmonary, Allergy and Critical Care Medicine. "A continued presence of PGP means a continued response of neutrophils, a never-ending cycle that supports chronic inflammation."
Blalock said PGP is a biomarker for several lung diseases that feature chronic inflammation, such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis.
The study also details a dual role played by LTA4H in suppressing or encouraging inflammation. When contained within a cell, LTA4H has a pro-inflammatory job, generating an agent know as Leukotriene B4 (LTB4), which, much like PGP, calls in the neutrophils when required. However, when LTA4H is found outside of the cell (when the cell it resides in dies, for example) its role switches to an anti-inflammatory one, as it works to suppress PGP and end the body's inflammatory response.
"This dual role was poorly understood until we identified PGP," said Blalock. "This could have important ramifications for the design of new anti-inflammatory drugs that target LTA4H."
Blalock said that because too much LTB4 can contribute to chronic inflammation, pharmaceutical manufacturers are examining potential drugs to inhibit LTA4H, thus reducing the amount of LTB4. Blalock said he believes that approach needs revision.
"Drugs are in design that would reduce LTB4 by shutting down LTA4H," he said. "But we now know that LTA4H has a beneficial role to play in the reduction of PGP.
"While inhibiting LTB4 might be a good thing, to simultaneously block LTA4H's ability to degrade PGP defeats the purpose, and may make the situation worse."
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This study was supported by grants from the National Heart, Lung and Blood Institute, one of the National Institutes of Health.
Blalock collaborated with Robert Snelgrove, Ph.D., of the Imperial College London, along with colleagues at the University of Montevallo (Montevallo, Ala.), the Birmingham Veterans Affairs Medical Center and the UAB Lung Health Center, Gregory Fleming James Cystic Fibrosis Center and Department of Pediatrics.
About UAB
Known for its innovative and interdisciplinary approach to education at both the graduate and undergraduate levels, the University of Alabama at Birmingham (UAB) is the state of Alabama's largest employer and an internationally renowned research university and academic health center whose professional schools and specialty patient care programs are consistently ranked as among the nation's top 50; find more information at www.uab.edu and www.uabmedicine.org.
EDITOR'S NOTE: The University of Alabama at Birmingham (UAB) is a separate, independent institution from the University of Alabama, which is located in Tuscaloosa. Please use University of Alabama at Birmingham on first reference and UAB on second reference.
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