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Published on: June 7, 2018
Effects of MR889, a cyclic thiolic neutrophil elastase inhibitor, on rheologic properties of mucus
M Moretti1, M Gorrini, A M Donnetta
1Istituto di Tisiologia e Malattie dell'Apparato Respiratorio, Università di Modena, Italy.
Abstract:
MR889 is a synthetic inhibitor of human neutrophil elastase with potential in clinical conditions characterized by a high load of this proteolytic enzyme, mainly chronic obstructive pulmonary disease. On the basis of its mechanism of inhibition, it has been suggested that MR889, upon reaction with elastase, would generate new free thiol groups. The aim of this study was to investigate whether MR889, upon reaction with elastase, may modify rheologic properties, i.e. apparent viscosity and elasticity, of both human sputum and porcine stomach mucus, in ex-vivo and in vitro experiments. MR889 10(-4) M alone had no effect on rheologic properties of samples, whereas an agent with free thiol group, n-acetylcysteine 10(-4) M reduced both viscosity and elasticity. MR889 10(-4) M upon reaction with elastase 0.03 nMol (giving 83% of elastase inhibition) had no effect on rheologic properties of samples, whereas upon reaction with elastase 0.15 nMol (49% inhibition) yielded a marked decrease in viscosity. This result would suggest that MR889, in the presence of a high load of elastase, may acquire direct mucus modifying capacity, likely because of its greater utilization upon reaction with the enzyme.
Insights
MR889, an inhibitor of human neutrophil elastase, may alter mucus rheology at high enzyme concentrations. This suggests a potential role in managing conditions like COPD by modifying mucus properties.
Area of Science:
- Biochemistry
- Pulmonary Medicine
- Rheology
Background:
- Human neutrophil elastase (HNE) is implicated in diseases like COPD.
- MR889 is a synthetic HNE inhibitor.
- HNE activity can degrade lung tissue and affect mucus properties.
Purpose of the Study:
- To investigate if MR889 modifies rheologic properties of human sputum and porcine mucus.
- To determine if MR889's interaction with elastase alters mucus viscosity and elasticity.
- To explore MR889's potential direct mucus-modifying capacity.
Main Methods:
- Ex-vivo and in vitro experiments were conducted.
- Rheologic properties (apparent viscosity, elasticity) of mucus samples were measured.
- MR889 was tested alone, with n-acetylcysteine, and in combination with varying concentrations of elastase.
Main Results:
- MR889 alone did not affect mucus rheology.
- N-acetylcysteine, a thiol-containing agent, reduced viscosity and elasticity.
- MR889 showed a marked decrease in viscosity when reacting with a higher concentration of elastase (0.15 nMol).
Conclusions:
- MR889 may gain mucus-modifying capacity at high elastase loads.
- This effect is likely due to increased utilization of MR889 upon reaction with elastase.
- MR889's potential therapeutic application in elastase-mediated diseases warrants further investigation.
