image: Mice missing the gene for LTA4 showed heightened airway resistance and remodeling (top right) compared to controls. This effect was mitigated by neutralizing PGP with a compound named RTR (bottom right). This material relates to a paper that appeared in the Aug. 22, 2018, issue of <i>Science Translational Medicine</i>, published by AAAS. The paper, by D.F Patel at Imperial College London in London, UK; and colleagues was titled, "An extracellular matrix fragment drives epithelial remodeling and airway hyperresponsiveness." view more
Credit: D.F. Patel <i>et al., Science Translational Medicine</i> (2018)
Dhiren Patel and colleagues have found that leftover fragments of the body's support structure for cells can promote inflammation and harmful changes in the airways in a mouse model of asthma. These remnants were also detected in samples from asthma patients, suggesting they play a critical role as a mediator of airway remodeling and could be a fruitful therapeutic target for researchers seeking new treatments for chronic lung diseases such as asthma and COPD. One area of interest for these scientists is the fact that the extracellular matrix (ECM) - the noncellular parts of tissues that provide support to surrounding cells - can release small fragments named matrikines when it degrades. The enzyme LTA4H, which has been investigated as a potential target for asthma therapies, acts as both a promoter and a restraint on inflammatory responses by degrading matrikines, including one called PGP. This degradation pathway is impaired in chronic lung disease, which motivated Patel et al. to research the role of LTA4H and the ECM in the development of asthma. The scientists used a mouse model of allergic asthma and found rodents deficient in LTA4H displayed less inflammation but a marked increase in airway sensitivity due to accumulation of PGP. Furthermore, a structural relative of PGP named AcPGP enhanced mucus production and induced airway remodeling when administered to human bronchial cells in culture. The authors examined sputum samples from two patient groups (50 patients total) with either moderate or severe asthma and found they harbored elevated AcPGP levels compared to controls. They conclude by saying accumulation of PGP could help explain why LTA4H inhibitors have often failed in clinical trials, and a more targeted approach for one side of this pathway may be more productive.
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Journal
Science Translational Medicine