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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.

Zhang W, Zhi J, Cui Y, Zhang F, Habyarimana A, Cambier C, Gustin P - PLoS ONE (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.

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.

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Protective effects of formoterol and budesonide on the concentrations of total cells (A), neutrophils (B) and macrophages (C) in bronchoalveolar lavage fluid in rats exposed to cadmium.CdCl2: 0.1% CdCl2 cadmium group; FMT 0.5+Cd and FMT 1+Cd: animals pretreated with increasing concentrations of formoterol (0.5 mg/30 ml; 1 mg/30 ml respectively) before cadmium inhalation; BUD 0.25+Cd and BUD 0.5+Cd: animals exposed to budesonide (0.25 mg/15 ml and 0.5 mg/15 ml respectively) followed by cadmium exposure; * Indicates a significant difference in comparison with sham group (* P<0.05, ** P<0.01, *** P<0.001); # indicates a significant difference in comparison with cadmium-exposed group (# P<0.05, ## P<0.01, ###P<0.001).
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pone-0109136-g001: Protective effects of formoterol and budesonide on the concentrations of total cells (A), neutrophils (B) and macrophages (C) in bronchoalveolar lavage fluid in rats exposed to cadmium.CdCl2: 0.1% CdCl2 cadmium group; FMT 0.5+Cd and FMT 1+Cd: animals pretreated with increasing concentrations of formoterol (0.5 mg/30 ml; 1 mg/30 ml respectively) before cadmium inhalation; BUD 0.25+Cd and BUD 0.5+Cd: animals exposed to budesonide (0.25 mg/15 ml and 0.5 mg/15 ml respectively) followed by cadmium exposure; * Indicates a significant difference in comparison with sham group (* P<0.05, ** P<0.01, *** P<0.001); # indicates a significant difference in comparison with cadmium-exposed group (# P<0.05, ## P<0.01, ###P<0.001).

Mentions: A single cadmium exposure induced a significant increase in total cell number in BALF which was attributed to a marked increase in neutrophil and macrophage concentrations in BALF (Fig. 1A–C). Pretreatment of healthy rats with formoterol and/or budesonide had no effect on BALF cell counts as compared to sham group (data not shown).


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.

Zhang W, Zhi J, Cui Y, Zhang F, Habyarimana A, Cambier C, Gustin P - PLoS ONE (2014)

Protective effects of formoterol and budesonide on the concentrations of total cells (A), neutrophils (B) and macrophages (C) in bronchoalveolar lavage fluid in rats exposed to cadmium.CdCl2: 0.1% CdCl2 cadmium group; FMT 0.5+Cd and FMT 1+Cd: animals pretreated with increasing concentrations of formoterol (0.5 mg/30 ml; 1 mg/30 ml respectively) before cadmium inhalation; BUD 0.25+Cd and BUD 0.5+Cd: animals exposed to budesonide (0.25 mg/15 ml and 0.5 mg/15 ml respectively) followed by cadmium exposure; * Indicates a significant difference in comparison with sham group (* P<0.05, ** P<0.01, *** P<0.001); # indicates a significant difference in comparison with cadmium-exposed group (# P<0.05, ## P<0.01, ###P<0.001).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4196767&req=5

pone-0109136-g001: Protective effects of formoterol and budesonide on the concentrations of total cells (A), neutrophils (B) and macrophages (C) in bronchoalveolar lavage fluid in rats exposed to cadmium.CdCl2: 0.1% CdCl2 cadmium group; FMT 0.5+Cd and FMT 1+Cd: animals pretreated with increasing concentrations of formoterol (0.5 mg/30 ml; 1 mg/30 ml respectively) before cadmium inhalation; BUD 0.25+Cd and BUD 0.5+Cd: animals exposed to budesonide (0.25 mg/15 ml and 0.5 mg/15 ml respectively) followed by cadmium exposure; * Indicates a significant difference in comparison with sham group (* P<0.05, ** P<0.01, *** P<0.001); # indicates a significant difference in comparison with cadmium-exposed group (# P<0.05, ## P<0.01, ###P<0.001).
Mentions: A single cadmium exposure induced a significant increase in total cell number in BALF which was attributed to a marked increase in neutrophil and macrophage concentrations in BALF (Fig. 1A–C). Pretreatment of healthy rats with formoterol and/or budesonide had no effect on BALF cell counts as compared to sham group (data not shown).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.

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.

Show MeSH
Related in: MedlinePlus