Matrix metalloproteinases inhibition attenuates tobacco smoke-induced emphysema in Guinea pigs.
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.


METHODS
Randomized, double-blinded, controlled experiment.


METHODS
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.


CONCLUSIONS
These findings support a role for MMPs in the early inflammatory response and in the emphysematous lesions provoked by cigarette smoking.
Selman
Moisés
M
Instituto Nacional de Enfermedades Respiratorias, Tlalpan, Mexico.
Cisneros-Lira
José
J
Gaxiola
Miguel
M
Ramírez
Remedios
R
Kudlacz
Elizabeth M
EM
Mitchell
Peter G
PG
Pardo
Annie
A
D000818:Animals; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D006168:Guinea Pigs; D055768:Halogenated Diphenyl Ethers; D007150:Immunohistochemistry; D008168:Lung / Q000201:enzymology / Q000473:pathology*; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D010647:Phenyl Ethers / Q000627:therapeutic use*; D011656:Pulmonary Emphysema / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
C119912:CP 471,474; D055768:Halogenated Diphenyl Ethers; D061965:Matrix Metalloproteinase Inhibitors; D010647:Phenyl Ethers; D014028:Tobacco Smoke Pollution; D020782:Matrix Metalloproteinases; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1