Repeated cadmium nebulizations induce pulmonary MMP-2 and MMP-9 production and emphysema in rats.
This study describes induction of pulmonary inflammation, production of matrix metalloprotease of type 2 (MMP-2) and type 9 (MMP-9), and emphysema in cadmium (Cd)-exposed rats. Sprague-Dawley rats were randomly distributed into two groups: one placebo-exposed group undergoing saline (NaCl 0.9%) inhalation (n=30) and one Cd-exposed group undergoing cadmium (CdCl(2) 0.1%) inhalation (n=30). The animals of the placebo- and Cd-exposed groups were divided in five subgroups (n=6). Subgroups underwent either a single exposure of 1h or repeated exposures three times weekly for 1h during 3 weeks (3W), 5 weeks (5W), 5 weeks followed by 2 weeks without exposure (5W+2) or 5 weeks followed by 4 weeks without exposure (5W+4). Each animal underwent determination of enhanced pause (Penh) as index of airflow limitation prior to the first exposure as well as before sacrifice. The animals were sacrificed the day after their last exposure. The left lung was fixed for histomorphometric analysis (determination of median interwall distance (MIWD)), whilst bronchoalveolar lavage fluid (BALF) was collected from the right lung. BALF was analyzed cytologically, and MMP-2 and MMP-9 levels were determined by gelatine zymography. Twelve rats previously instilled with pancreatic elastase were used as positive emphysema controls and underwent the same investigations. Cd-exposure induced a significant increase of BALF macrophages, neutrophils and MMP-9 up to 5W+4, whereas MMP-2 gelatinolytic activity returned to baseline levels within 5W. MIWD was significantly increased in all repeatedly Cd-exposed groups and elastase-treated rats. Penh was increased in Cd-exposed rats after a single exposure and after 3W. MMP gelatinolytic activity was significantly correlated with macrophages, neutrophils and Penh. In repeatedly exposed rats, MIWD was positively and significantly correlated with MMP gelatinolytic activity, suggesting that increased MMP-2 and MMP-9 production favours the development of emphysema.
Kirschvink
Nathalie
N
Department for Functional Sciences B41, Section of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Veterinary Medicine, University of Liège, Liège 4000, Belgium. nathalie.kirschvink@ulg.ac.be
Vincke
Grégoire
G
Fiévez
Laurence
L
Onclinx
Cécile
C
Wirth
Delphine
D
Belleflamme
Michèle
M
Louis
Renaud
R
Cataldo
Didier
D
Peck
Michael J
MJ
Gustin
Pascal
P
D000280:Administration, Inhalation; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002104:Cadmium / Q000008:administration & dosage; D002105:Cadmium Poisoning / Q000378:metabolism* / Q000473:pathology*; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D010196:Pancreatic Elastase / Q000008:administration & dosage / Q000494:pharmacology; D010993:Plethysmography, Whole Body; D011014:Pneumonia / Q000139:chemically induced / Q000473:pathology; D011656:Pulmonary Emphysema / Q000139:chemically induced* / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D002104:Cadmium; D010196:Pancreatic Elastase; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9