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

Am J Respir Crit Care Med. 2002 Oct 1;166(7):954-60. 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Hydroxyproline / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Monocyte Chemoattractant Proteins / genetics
  • Monocyte Chemoattractant Proteins / metabolism
  • Monokines / drug effects
  • Monokines / genetics
  • Monokines / metabolism
  • Neutrophils / drug effects
  • Pulmonary Emphysema / blood
  • Pulmonary Emphysema / drug therapy*
  • Pulmonary Emphysema / etiology*
  • 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


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