Synthetic serine elastase inhibitor reduces cigarette smoke-induced emphysema in guinea pigs.

Abstract

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.

• Authors: Joanne L Wright, Stephen G Farmer, Andrew Churg
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 166 Issue 7 Pg. 954-60 (Oct 01 2002) ISSN: 1073-449X [Print] United States
• PMID: 12359653 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ccl8 protein, mouse
• Chemokine CCL8
• Chemokine CXCL2
• Monocyte Chemoattractant Proteins
• Monokines
• Serpins
• Tobacco Smoke Pollution
• Tumor Necrosis Factor-alpha
• Desmosine
• Hydroxyproline

Topics

• Animals
• 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, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Monocyte Chemoattractant Proteins (genetics, metabolism)
• Monokines (drug effects, genetics, metabolism)
• Neutrophils (drug effects)
• Pulmonary Emphysema (blood, drug therapy, etiology)
• Serpins (administration & dosage)
• Time Factors
• Tobacco Smoke Pollution (adverse effects)
• Transcription, Genetic (drug effects)
• Tumor Necrosis Factor-alpha (drug effects, genetics, metabolism)