title: Effects of formoterol and ipratropium bromide on repeated cadmium inhalation-induced pulmonary inflammation and emphysema in rats.
abstract: The anti-inflammatory properties of inhaled formoterol and ipratropium bromide, alone or in combination, were investigated in a rat model of chronic pulmonary inflammation with airspace enlargement induced by cadmium inhalation. At the end of the protocol, cadmium-induced increase of airway resistance was prevented by formoterol (4 mg/30 ml) or ipratropium (0.20 mg/20 ml). Formoterol elicited a significant decrease in total cell and neutrophil counts in bronchoalveolar lavage fluid as well as on the activity of gelatinase B (MMP-9), an enzyme strongly expressed in alveolar macrophages and epithelial cells. Additionally, a significant attenuation of the lung lesions characterized by inflammatory cell infiltration within the alveoli and the interstitium and a decrease in mean linear intercept were observed. Although ipratropium alone had no effects on the cadmium-induced pulmonary inflammation and emphysema, its combination with an inefficient concentration of formoterol (1 mg/30 ml) showed a synergistic inhibitory effect on neutrophil and total cell counts as well as on the mean linear intercept associated with a synergistic inhibition on the MMP-9 activity. Gelatinase A (MMP-2) activity was not influenced by drug pretreatments. Neither macrophage metalloelastase (MMP-12) activity nor levels of cytokines IL-1β, TNF-α and GM-CSF in bronchoalveolar lavage fluid were modified in rats chronically exposed to cadmium. No desensitization of β(2)-adrenoceptors or cholinergic receptors on airway smooth muscles and inflammatory cells during the protocol was observed. In conclusion, formoterol alone or combined with ipratropium bromide partially protects the lungs against the chronic inflammation and airspace enlargement by reducing neutrophilic infiltration possibly via the inhibition of MMP-9 activity.
authors.affiliation: Department of Physiology, School of Medicine, Shanghai Jiaotong University, Shanghai, China. i_zhangwenhui@yahoo.com.cn
authors.forename: WenHui
authors.initials: W
authors.lastname: Zhang
authors.forename: Laurence
authors.initials: L
authors.lastname: Fievez
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.forename: Esteban
authors.initials: E
authors.lastname: Cheu
authors.forename: Nadine
authors.initials: N
authors.lastname: Antoine
authors.forename: Catherine
authors.initials: C
authors.lastname: Delguste
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: WeiFang
authors.initials: W
authors.lastname: Rong
authors.forename: Fabrice
authors.initials: F
authors.lastname: Bureau
authors.forename: Charles
authors.initials: C
authors.lastname: Advenier
authors.forename: Pascal
authors.initials: P
authors.lastname: Gustin
mesh_terms: D000280:Administration, Inhalation; D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D001993:Bronchodilator Agents / Q000378:metabolism / Q000494:pharmacology*; D002104:Cadmium / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D018925:Chemokines / Q000032:analysis; D016207:Cytokines / Q000032:analysis; D004983:Ethanolamines / Q000378:metabolism / Q000494:pharmacology*; D000068759:Formoterol Fumarate; D009241:Ipratropium / Q000378:metabolism / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology; D016210:Methacholine Chloride / Q000378:metabolism / Q000494:pharmacology; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011656:Pulmonary Emphysema / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019714:Tissue Inhibitor of Metalloproteinases / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology
chemical_list: D001993:Bronchodilator Agents; D018925:Chemokines; D016207:Cytokines; D004983:Ethanolamines; D019714:Tissue Inhibitor of Metalloproteinases; D002104:Cadmium; D016210:Methacholine Chloride; D053508:Matrix Metalloproteinase 12; D009241:Ipratropium; D000068759:Formoterol Fumarate