Protective effects of tiotropium alone or combined with budesonide against cadmium inhalation induced acute neutrophilic pulmonary inflammation in rats.

Shiwei Zhao,You Lv,Zhixi Yu,Wenhui Zhang,Pascal Gustin,Qi Yang,Jianming Zhi,Bernhard Ryffel

doi:10.1371/journal.pone.0193610

Shiwei Zhao, You Lv + Show 6 more

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https://doi.org/10.1371/journal.pone.0193610

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Journal: PloS one	Publication Date: Feb 28, 2018
Citations: 7	License type: CC BY 4.0

Affiliation: Shanghai Jiao Tong University, University of Liège

Abstract

As a potent bronchodilator, the anti-inflammatory effects of tiotropium and its interaction with budesonide against cadmium-induced acute pulmonary inflammation were investigated. Compared to values obtained in rats exposed to cadmium, cytological analysis indicated a significant decrease of total cell and neutrophil counts and protein concentration in bronchoalveolar lavage fluid (BALF) in rats pretreated with tiotropium (70μg/15ml or 350μg/15ml). Zymographic tests showed a decrease of MMP-2 activity in BALF in rats pretreated only with high concentration of tiotropium. Histological examination revealed a significant decrease of the severity and extent of inflammatory lung injuries in rats pretreated with both tested concentrations of tiotropium. Though tiotropium (70μg/15ml) or budesonide (250μg/15ml) could not reduce cadmium-induced bronchial hyper-responsiveness, their combination significantly decreased bronchial contractile response to methacholine. These two drugs separately decreased the neutrophil number and protein concentration in BALF but no significant interaction was observed when both drugs were combined. Although no inhibitory effects on MMP-2 and MMP-9 was observed in rats pretreated with budesonide alone, the combination with the ineffective dose of tiotropium induced a significant reduction on these parameters. The inhibitory effect of tiotropium on lung injuries was not influenced by budesonide which alone induced a limited action on the severity and extent of inflammatory sites. Our findings show that tiotropium exerts anti-inflammatory effects on cadmium-induced acute neutrophilic pulmonary inflammation. The combination of tiotropium with budesonide inhibits cadmium-induced inflammatory injuries with a synergistic interaction on MMP-2 and MMP-9 activity and airway hyper-responsiveness.

Highlights

Chronic Obstructive Pulmonary Disease (COPD) is characterized by persistent airflow restriction, resulting a progressive irreversible decline in lung function [1]
By using the model of acute pulmonary inflammation induced by a single inhalation of Cd in rats, the aim of this study was to investigate whether tiotropium could exert its anti-inflammatory effect and restore budesonide insensitivity against Cd-induced acute neutrophilic inflammation
The aim of the present study being to investigate whether tiotropium can interact with glucocorticoid to better control Cd-induced acute neutrophilic pulmonary inflammation, a low concentration of budesonide (250μg/15ml of nebulized solution) demonstrating a very limited anti-inflammatory effect has been selected during preliminary assays

Summary

Introduction

Chronic Obstructive Pulmonary Disease (COPD) is characterized by persistent airflow restriction, resulting a progressive irreversible decline in lung function [1]. Lung function and life quality become dramatically impaired in case of acute exacerbations of COPD (AECOPD) which become the main cause of high mortality and morbidity [2]. Neutrophil recruitment is highly increased accompanied with bronchoconstriction during COPD exacerbations [3]. Seeking out the effective treatment to suppress neutrophilic infiltration will be helpful to control AECOPD. According to GOLD, bronchodilators are recommended as the first line therapy in COPD [1]. Whether tiotropium could reduce the severity and frequency of AECOPD by inhibiting neutrophilic infiltration remains to be clarified

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