Amelioration of human neutrophil elastase-induced emphysema in hamsters by pretreatment with an oligopeptide chloromethyl ketone.
Human neutrophils are a likely source of elastase in the pathogenesis of human pulmonary emphysema. A study was undertaken to determine whether emphysema, induced in hamsters by intratracheal treatment with human neutrophil elastase (HNE), could be ameliorated by intratracheal instillation of succinyl-alanyl-alanyl-prolyl-valine-chloromethyl ketone (CMK). One mg of CMK was given to hamsters 1 h before 300 or 360 micrograms HNE or 1 h or 4 h after 360 micrograms HNE. The animals were studied eight weeks after treatment. The CMK given 4 h after HNE did not ameliorate the emphysema. The CMK given 1 h before HNE, ameliorated the development of emphysema but not bronchial secretory cell metaplasia. A molar ratio of instilled CMK to HNE of 128 was required for 50% in vivo effectiveness in ameliorating emphysema. Clearance studies indicated that 6.9% of the instilled CMK could be lavaged from the lungs 1 h after instillation. Therefore, an 8.9 to 1 molar ratio of lavageable CMK to HNE, at the time of HNE instillation, resulted in 50% protection. Using an in vitro assay with 3H-elastin as substrate, a 3 to 1 molar ratio of CMK to HNE was required to inhibit 50% of the elastolytic activity; 14% of the activity remained with an 18 to 1 molar ratio of CMK to HNE. Study of the in vivo effectiveness of anti-elastases, given as pretreatment in ameliorating HNE-induced emphysema and secretory cell metaplasia, is a reasonable bioassay, which may be used as a step in evaluating such agents for possible use in the prevention of human disease.
Pulmonary Center, Boston University School of Medicine, Massachusetts.
E C
EC
Lucey
P J
PJ
Stone
J C
JC
Powers
G L
GL
Snider
D000818:Animals; D001681:Biological Assay; D006224:Cricetinae; D004646:Emphysema / Q000139:chemically induced / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008647:Mesocricetus; D009504:Neutrophils / Q000201:enzymology; D010196:Pancreatic Elastase
D010196:Pancreatic Elastase