Matrikines are key regulators in modulating the amplitude of lung inflammation in acute pulmonary infection
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Updated: Apr 3, 2026
Assessment of Respiratory Function in Conscious Mice by Double-chamber Plethysmography
Published on: July 10, 2018
Samia Akthar1, Dhiren F Patel1, Rebecca C Beale1
1Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
Abstract:
Bioactive matrix fragments (matrikines) have been identified in a myriad of disorders, but their impact on the evolution of airway inflammation has not been demonstrated. We recently described a pathway where the matrikine and neutrophil chemoattractant proline-glycine-proline (PGP) could be degraded by the enzyme leukotriene A4 hydrolase (LTA4H). LTA4H classically functions in the generation of pro-inflammatory leukotriene B4, thus LTA4H exhibits opposing pro- and anti-inflammatory activities. The physiological significance of this secondary anti-inflammatory activity remains unknown. Here we show, using readily resolving pulmonary inflammation models, that loss of this secondary activity leads to more pronounced and sustained inflammation and illness owing to PGP accumulation. PGP elicits an exacerbated neutrophilic inflammation and protease imbalance that further degrades the extracellular matrix, generating fragments that perpetuate inflammation. This highlights a critical role for the secondary anti-inflammatory activity of LTA4H and thus has consequences for the generation of global LTA4H inhibitors currently being developed.
Insights
Leukotriene A4 hydrolase (LTA4H) has a lesser-known anti-inflammatory role in degrading proline-glycine-proline (PGP). Loss of this function causes prolonged airway inflammation due to PGP accumulation.
Area of Science:
- Biochemistry
- Immunology
- Pulmonary Medicine
Background:
- Bioactive matrix fragments, or matrikines, are implicated in various disorders.
- The enzyme leukotriene A4 hydrolase (LTA4H) degrades the matrikine proline-glycine-proline (PGP), a neutrophil chemoattractant.
- LTA4H possesses both pro-inflammatory and anti-inflammatory functions, the latter being poorly understood.
Purpose of the Study:
- To investigate the physiological significance of LTA4H's anti-inflammatory activity.
- To determine the impact of LTA4H's PGP-degrading function on airway inflammation.
Main Methods:
- Utilized pulmonary inflammation models.
- Assessed the consequences of impaired LTA4H anti-inflammatory activity.
Main Results:
- Loss of LTA4H's secondary anti-inflammatory activity resulted in more severe and persistent pulmonary inflammation.
- Accumulation of PGP exacerbated neutrophilic inflammation and protease imbalance.
- Sustained inflammation led to further extracellular matrix degradation, creating a cycle of inflammation.
Conclusions:
- The anti-inflammatory activity of LTA4H in degrading PGP is crucial for resolving pulmonary inflammation.
- Impairment of this function leads to chronic inflammation and disease progression.
- Findings have implications for the development of LTA4H inhibitors.
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