Matrix Metalloproteinases Inhibition Attenuates Tobacco Smoke-Induced Emphysema in Guinea Pigs

摘要: Study objective: To evaluate the effect of CP-471,474 (Pfizer Global Research and Development; Groton, CT), a broad-spectrum inhibitor matrix metalloproteinases (MMPs) in an experimental model emphysema. Design: Randomized, double-blinded, controlled experiment. Setting: Biochemistry morphology laboratories animal research facility. Methods: Guinea pigs were exposed to cigarette smoke over 1 month, 2 months, 4 half animals received CP-471,474. Age-matched guinea room air used as control animals. After death, lungs lavaged with saline solution, MMPs lavage fluid determined by zymography immunoblot. Lungs fixed for histology, immunohistochemistry, morphometry. Results: Following 1-month exposure tobacco smoke, semiquantitative histologic assessment showed moderate lung inflammation, which progressed extent severity reached peak at months. significantly reduced both (p < 0.002) 0.05) inflammation At spontaneous reduction inflammatory response was observed treated untreated animals, consequently no difference between both. Emphysematous changes, revealed significant increase average size alveoli, detected months exposure. The decreased destructive lesions mainly 0.0001) also 0.02). Smoking increased MMP-9 MMP-1 activities shown Immunoreactive localized alveolar bronchiolar epithelial cells, macrophages, airways smooth-muscle cells. Conclusion: These findings support role early emphysematous provoked smoking. (CHEST 2003; 123:1633–1641)