Synthetic Serine Elastase Inhibitor Reduces Cigarette Smoke-induced Emphysema in Guinea Pigs

• Published in: American journal of respiratory and critical care medicine Vol. 166; no. 7; pp. 954 - 960
• Main Authors: Wright, Joanne L, Farmer, Stephen G, Churg, Andrew
• Format: Journal Article
• Language: English
• Published: New York, NY Am Thoracic Soc 01-10-2002; American Lung Association
• Subjects: Animals; Biological and medical sciences; Bronchoalveolar Lavage Fluid - cytology; Chemokine CCL8; Chemokine CXCL2; Desmosine - metabolism; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression Regulation - drug effects; Guinea Pigs; Hydroxyproline - drug effects; Hydroxyproline - metabolism; Male; Medical sciences; Mice; Mice, Inbred C57BL; Monocyte Chemoattractant Proteins - genetics; Monocyte Chemoattractant Proteins - metabolism; Monokines - drug effects; Monokines - genetics; Monokines - metabolism; Neutrophils - drug effects; Pharmacology. Drug treatments; Pulmonary Emphysema - blood; Pulmonary Emphysema - drug therapy; Pulmonary Emphysema - etiology; Respiratory system; Serpins - administration & dosage; Time Factors; Tobacco Smoke Pollution - adverse effects; Transcription, Genetic - drug effects; Tumor Necrosis Factor-alpha - drug effects; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Leukocyte elastase; Lung disease; Serine endopeptidases; Respiratory disease; Enzyme; Lung; Rodentia; Tobacco smoking; Exploration; Peptidases; Chemotherapy; Vertebrata; Mammalia; Guinea pig; Treatment; Animal; Hydrolases; Emphysema; Protease inhibitor
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.200202-098OC

To test whether a serine elastase inhibitor could prevent or reduce emphysema, we exposed guinea pigs to cigarette smoke acutely, or daily for 6 months, and treated some animals with the neutrophil elastase inhibitor ZD0892. Acute smoke exposure increased lavage neutrophils and increased desmosine and hydroxyproline, measures of elastin and collagen breakdown; all these measures were reduced by ZD0892. Long-term smoke exposure produced emphysema and increases in lavage neutrophils, desmosine, hydroxyproline, and plasma tumor necrosis factor alpha (TNF-alpha). ZD0892 treatment returned lavage neutrophils, desmosine, and hydroxyproline levels to control values, and decreased airspace enlargement by 45% and TNF-alpha by 30%. Animals exposed to smoke for 4 months and then to smoke plus ZD0892 for 2 months were not protected against emphysema. Mice exposed to smoke showed increases in gene expression of neutrophil chemoattractant macrophage inflammatory protein-2, macrophage chemoattractant protein-1, and TNF-alpha at 2 hours along with increased plasma TNF-alpha; ZD0892 prevented the increases in macrophage inflammatory protein-2 and macrophage chemoattractant protein-1 expression and reduced plasma TNF-alpha levels to baseline. These data demonstrate that a serine elastase inhibitor ameliorates the inflammatory and destructive effects of cigarette smoke, and that these effects are mediated in part by neutrophils and by smoke-driven TNF-alpha production.