Synthetic serine elastase inhibitor reduces cigarette smoke-induced emphysema in guinea pigs.
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.
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D054412:Chemokine CCL8; D054426:Chemokine CXCL2; D003895:Desmosine / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006168:Guinea Pigs; D006909:Hydroxyproline / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018945:Monocyte Chemoattractant Proteins / Q000235:genetics / Q000378:metabolism; D015846:Monokines / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects; D011656:Pulmonary Emphysema / Q000097:blood / Q000188:drug therapy* / Q000209:etiology*; D015843:Serpins / Q000008:administration & dosage*; D013997:Time Factors; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
C515454:Ccl8 protein, mouse; D054412:Chemokine CCL8; D054426:Chemokine CXCL2; D018945:Monocyte Chemoattractant Proteins; D015846:Monokines; D015843:Serpins; D014028:Tobacco Smoke Pollution; D014409:Tumor Necrosis Factor-alpha; D003895:Desmosine; D006909:Hydroxyproline