Anti-Contractile and Anti-Inflammatory Effects of Diacerein on Isolated Mouse Airways Smooth Muscle and Mouse Asthma Model.

Shunbo Shi,Lu Xue,Haiting Qiu,Jinhua Shen,Yongbo Peng,Qing-Hua Liu,Ping Zhao,Shuhui Han

doi:10.3389/fphar.2020.560361

Abstract

Characterized by abnormal smooth muscle contractility and airway inflammation, asthma is one of the most common airway diseases worldwide. Diacerein is a well-known anti-inflammatory drug, widely used in osteoarthritis. In current study, the innovative usage of diacerein in anti-contractile and anti-inflammatory treatment of asthma was studied. In vitro experiments including tension measurement and patch-clamp technique and in vivo experiments including establishment of mice model and measurement of respiratory resistance were applied to explore the role of diacerein in asthma. It turned out that agonist-precontracted mouse airway smooth muscle could be relaxed by diacerein via intracellular and extracellular calcium mobilization which was mediated by switched voltage-dependent L-type Ca2+ channels, non-selective cation channels, large-conductance Ca2+-activated K+ channel, and Na+/Ca2+ exchangers. Furthermore, diacerein could relieve bronchospasm and control airway inflammation in asthmatic mice via reduction of several inflammatory factors. Our studies elucidated the potential therapeutic property of diacerein in asthma treatment and the possible underlying mechanism. It also confirmed that new uses for already-approved drugs could be an important form of innovation.

Highlights

Asthma is a heterogeneous and chronic inflammatory disease mainly characterized by reversible bronchial obstruction, expiratory airflow limitation, airway hyperresponsiveness, remodeling, and inflammation (Holgate, 2012; Wenzel, 2012; Nieto-Fontarigo et al, 2019)
To confirm the participation of voltage-dependent L-type Ca2+ channels (VDLCCs) in relaxant activity of diacerein on precontracted mouse tracheal rings (mTRs) induced by high K+, a selective blocker of VDLCCs, 10 mM nifedipine (Darnell and Peters, 1982) was employed and a similar inhibitory activity on high K+‐induced steady state contraction was observed in mTRs (Figure 1C), which implied that blockade of VDLCCs might be involved in diacerein-induced relaxation on mTRs
These results indicated that diacerein inhibited high K+-induced pre-contraction in a dose-dependent way and VDLCCs might participate in the process

Summary

Introduction

Asthma is a heterogeneous and chronic inflammatory disease mainly characterized by reversible bronchial obstruction, expiratory airflow limitation, airway hyperresponsiveness, remodeling, and inflammation (Holgate, 2012; Wenzel, 2012; Nieto-Fontarigo et al, 2019). Increasing prevalence, reduced quality of life, and extra economic burden made asthma an expensive and challenging concern for individuals and whole society (Bahadori et al, 2009; Moorman et al, 2012; Chen et al, 2018). As the mainstay of asthma therapy, the conventional use of bronchodilators or inhaled corticosteroids might be limited on partly severe asthma patients (Fajt and Wenzel, 2017). Long-term usage of high-dose inhaled corticosteroids might increase the risk of pneumonia (McKeever et al, 2013), nontuberculous mycobacterial pulmonary disease (Brode et al, 2017), cataracts, osteoporosis in elderly patients (Heffler et al, 2018), and hypothalamic-pituitary-adrenal (HPA) axis suppression in children (Kapadia et al, 2016). The development of more effective drugs for asthma with less side effects are urgently needed (Fajt and Wenzel, 2017)

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Results

Conclusion