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

^* From the Instituto Nacional de Enfermedades Respiratorias (Drs. Selman and Gaxiola, and Mr. Cisneros-Lira), Tlalpan, Mexico; Pfizer Global Research and Development (Drs. Kudlacz and Mitchell), Groton, CT; and Facultad de Ciencias (Mr. Ramírez and Dr. Pardo), Universidad Nacional Autónoma de México, Ciudad Universitaria, México, México.

Correspondence to: Annie Pardo, PhD, Facultad de Ciencias, UNAM, Apartado Postal 21-630, Coyoacan, México DF, 04000, México; e-mail: aps{at}hp.fciencias.unam.mx

Study objective: To evaluate the effect of CP-471,474 (Pfizer Global Research and Development; Groton, CT), a broad-spectrum inhibitor of matrix metalloproteinases (MMPs) in an experimental model of emphysema.

Design: Randomized, double-blinded, controlled experiment.

Setting: Biochemistry and morphology laboratories and animal research facility.

Methods: Guinea pigs were exposed to cigarette smoke over 1 month, 2 months, and 4 months, and half of the animals received CP-471,474. Age-matched guinea pigs exposed to room air were used as control animals. After death, the lungs were lavaged with saline solution, and MMPs in the lavage fluid were determined by zymography and immunoblot. Lungs were fixed for histology, immunohistochemistry, and morphometry.

Results: Following a 1-month exposure to tobacco smoke, semiquantitative histologic assessment showed moderate lung inflammation, which progressed in extent and severity and reached a peak at 2 months. CP-471,474 significantly reduced both the extent (p < 0.002) and severity (p < 0.05) of inflammation at 2 months. At 4 months, a spontaneous reduction of the inflammatory response was observed in both treated and untreated animals, and consequently no difference was observed between both. Emphysematous changes, revealed by a significant increase in the average size of alveoli, were detected at 2 months and 4 months of tobacco smoke exposure. The inhibitor significantly decreased the destructive lesions mainly at 2 months (p < 0.0001) and also at 4 months (p < 0.02). Smoking increased MMP-9 and MMP-1 activities as shown by zymography and immunoblot. Immunoreactive MMP-9 was mainly localized in alveolar and bronchiolar epithelial cells, macrophages, and airways smooth-muscle cells.

Conclusion: These findings support a role for MMPs in the early inflammatory response and in the emphysematous lesions provoked by cigarette smoking.

Key Words: collagenases • COPD • gelatinases • pulmonary emphysema

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