Abstract
ScopeInhibiting human neutrophil elastase (HNE) is a promising strategy for treating inflammatory lung diseases, such as H1N1 and SARS virus infections. The use of sivelestat, the only clinically registered synthesized HNE inhibitor, is largely limited by its risk of organ toxicity because it irreversibly inhibits HNE. Therefore, potent reversible HNE inhibitors are promising alternatives to sivelestat.Methods and ResultsAn in vitro HNE inhibition assay was employed to screen a series of triterpenes. Six pentacyclic triterpenes, but not tetracyclic triterpenes, significantly inhibited HNE. Of these pentacyclic triterpenes, ursolic acid exhibited the highest inhibitory potency (IC50 = 5.51 µM). The HNE inhibitory activity of ursolic acid was further verified using a mouse model of acute smoke-induced lung inflammation. The results of nuclear magnetic resonance and HNE inhibition kinetic analysis showed that the pentacyclic triterpenes competitively and reversibly inhibited HNE. Molecular docking experiments indicated that the molecular scaffold, 28-COOH, and a double bond at an appropriate location in the pentacyclic triterpenes are important for their inhibitory activity.ConclusionOur results provide insights into the effects of pentacyclic triterpenes on lung inflammatory actions through reversible inhibition of HNE activity.
Highlights
IntroductionThey are involved in the pathogenesis of various lung inflammatory diseases, including acute lung injury (ALI), acute respiratory distress syndrome (ARDS), bronchiectasis, pulmonary emphysema, and chronic obstructive pulmonary disease (COPD) [1]
Neutrophils are major mediators of inflammation. They are involved in the pathogenesis of various lung inflammatory diseases, including acute lung injury (ALI), acute respiratory distress syndrome (ARDS), bronchiectasis, pulmonary emphysema, and chronic obstructive pulmonary disease (COPD) [1]
Active human neutrophil elastase (HNE) is detectable in the bronchoalveolar lavage fluid (BALF) of COPD patients and its activity corresponds to the level of inflammation [6]
Summary
They are involved in the pathogenesis of various lung inflammatory diseases, including acute lung injury (ALI), acute respiratory distress syndrome (ARDS), bronchiectasis, pulmonary emphysema, and chronic obstructive pulmonary disease (COPD) [1]. The number of airway neutrophils is an important indicator for ALI and ARDS [2]. Active HNE is detectable at inflammation sites even though endogenous inhibitors are present in the plasma. Active HNE is detectable in the bronchoalveolar lavage fluid (BALF) of COPD patients and its activity corresponds to the level of inflammation [6]. Inflammatory cytokines, such as tumor necrosis factor-a (TNF-a), interleukin-1b (IL-1b), IL-2, IL-6, and IL-8, activate neutrophils, causing excessive HNE release [7,8]
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