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

PLoS One. 2014 Oct 14;9(10):e109136. doi: 10.1371/journal.pone.0109136. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Administration, Inhalation
  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use
  • Bronchoalveolar Lavage Fluid / cytology
  • Budesonide / pharmacology*
  • Budesonide / therapeutic use*
  • Cadmium / toxicity
  • Chemokines / metabolism
  • Cytokines / metabolism
  • Ethanolamines / pharmacology*
  • Ethanolamines / therapeutic use*
  • Formoterol Fumarate
  • Leukocyte Count
  • Lung / pathology
  • Male
  • Matrix Metalloproteinase 9 / chemistry
  • Matrix Metalloproteinase 9 / metabolism*
  • Neutrophils / cytology
  • Pneumonia / drug therapy*
  • Rats
  • Rats, Sprague-Dawley
  • Up-Regulation / drug effects*

Substances

  • Anti-Inflammatory Agents
  • Chemokines
  • Cytokines
  • Ethanolamines
  • Cadmium
  • Budesonide
  • Matrix Metalloproteinase 9
  • Formoterol Fumarate

Grants and funding

This study was supported by Innovation Program of Shanghai Municipal Education Commission (No. 12YZ051, China); the National Natural Science Foundation of China (No. 81373468); and Wallonie Bruxelles International grant (Belgium). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.