Potentiated interaction between ineffective doses of budesonide and formoterol to control the inhaled cadmium-induced up-regulation of metalloproteinases and acute pulmonary inflammation in rats.

Wenhui Zhang,Yongyao Cui,Jianming Zhi,Carole Cambier,Pascal Gustin,Fan Zhang,Adélite Habyarimana

doi:10.1371/journal.pone.0109136

Wenhui Zhang, Yongyao Cui + Show 5 more

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https://doi.org/10.1371/journal.pone.0109136

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Journal: PloS one	Publication Date: Oct 14, 2014
Citations: 41	License type: CC BY 4.0

Affiliation: Shanghai Jiao Tong University, University of Liège

Abstract

The anti-inflammatory properties of glucocorticoids are well known but their protective effects exerted with a low potency against heavy metals-induced pulmonary inflammation remain unclear. In this study, a model of acute pulmonary inflammation induced by a single inhalation of cadmium in male Sprague-Dawley rats was used to investigate whether formoterol can improve the anti-inflammatory effects of budesonide. The cadmium-related inflammatory responses, including matrix metalloproteinase-9 (MMP-9) activity, were evaluated. Compared to the values obtained in rats exposed to cadmium, pretreatment of inhaled budesonide (0.5 mg/15 ml) elicited a significant decrease in total cell and neutrophil counts in bronchoalveolar lavage fluid (BALF) associated with a significant reduction of MMP-9 activity which was highly correlated with the number of inflammatory cells in BALF. Additionally, cadmium-induced lung injuries characterized by inflammatory cell infiltration within alveoli and the interstitium were attenuated by the pre-treatment of budesonide. Though the low concentration of budesonide (0.25 mg/15 ml) exerted a very limited inhibitory effects in the present rat model, its combination with an inefficient concentration of formoterol (0.5 mg/30 ml) showed an enhanced inhibitory effect on neutrophil and total cell counts as well as on the histological lung injuries associated with a potentiation of inhibition on the MMP-9 activity. In conclusion, high concentration of budesonide alone could partially protect the lungs against cadmium exposure induced-acute neutrophilic pulmonary inflammation via the inhibition of MMP-9 activity. The combination with formoterol could enhance the protective effects of both drugs, suggesting a new therapeutic strategy for the treatment of heavy metals-induced lung diseases.

Highlights

Cadmium is listed by the Agency for Toxic Substances and Disease Registry as the world’s seventh largest hazardous substance
While being very potent anti-inflammatory drugs, GCs are known to be sometimes poorly active against neutrophilic pulmonary inflammation as that occurring in chronic obstructive pulmonary disease (COPD) patients especially during exacerbations [24]
The aim of this paper was to investigate whether their activity can be enhanced when associated with a long acting b2-adrenergic receptor agonists (LABAs) in rats exposed to a single inhalation of cadmium through a down-regulation of matrix metalloproteinase-9 (MMP-9) which has been shown to play a key role in this model [10]

Summary

Introduction

Cadmium is listed by the Agency for Toxic Substances and Disease Registry as the world’s seventh largest hazardous substance. It is classified as a Group 1 carcinogen by International Agency for Research on Cancer (IARC) [1]. Lungs became a toxicological target as illustrated by the marked deficit in lung function correlated with an increase in urinary cadmium concentration which has been found in workers exposed to cadmium in jewelry workshops [4]. Acute exposure to cadmium induces deterioration in lung function and neutrophilic infiltration which is a dominant component of COPD especially during acute exacerbations of this chronic inflammatory process [9]

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Conclusion