title: 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.
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.
authors.affiliation: Department of Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Wenhui
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Jianming
authors.initials: J
authors.lastname: Zhi
authors.affiliation: Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Yongyao
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Department of Pathology, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department for Functional Sciences B41, Faculty of Veterinary Medicine, University of Liège, Liège, Belgium.
authors.forename: Adélite
authors.initials: A
authors.lastname: Habyarimana
authors.affiliation: Department for Functional Sciences B41, Faculty of Veterinary Medicine, University of Liège, Liège, Belgium.
authors.forename: Carole
authors.initials: C
authors.lastname: Cambier
authors.affiliation: Department for Functional Sciences B41, Faculty of Veterinary Medicine, University of Liège, Liège, Belgium.
authors.forename: Pascal
authors.initials: P
authors.lastname: Gustin
mesh_terms: D000208:Acute Disease; D000280:Administration, Inhalation; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D019819:Budesonide / Q000494:pharmacology* / Q000627:therapeutic use*; D002104:Cadmium / Q000633:toxicity; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004983:Ethanolamines / Q000494:pharmacology* / Q000627:therapeutic use*; D000068759:Formoterol Fumarate; D007958:Leukocyte Count; D008168:Lung / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology; D011014:Pneumonia / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000893:Anti-Inflammatory Agents; D018925:Chemokines; D016207:Cytokines; D004983:Ethanolamines; D002104:Cadmium; D019819:Budesonide; D020780:Matrix Metalloproteinase 9; D000068759:Formoterol Fumarate