Effects of formoterol and ipratropium bromide on repeated cadmium inhalation-induced pulmonary inflammation and emphysema in rats.
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.
Zhang
WenHui
W
Department of Physiology, School of Medicine, Shanghai Jiaotong University, Shanghai, China. i_zhangwenhui@yahoo.com.cn
Fievez
Laurence
L
Zhang
Fan
F
Cheu
Esteban
E
Antoine
Nadine
N
Delguste
Catherine
C
Zhang
Yong
Y
Rong
WeiFang
W
Bureau
Fabrice
F
Advenier
Charles
C
Gustin
Pascal
P
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
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