Cathepsin B inhibition improves lung injury associated to D-galactosamine/tumor necrosis factor-alpha-induced liver injury in mice.
The present study was designed to investigate the effects of benzyloxicarbonyl-L-phenylalanyl-alanine-fluoromethylketone (Z-FA.FMK), an inhibitor of cathepsin B on lung injury that occurs concurrently with liver injury induced by D-galactosamine/tumor necrosis factor-alpha (D-GalN/TNF-alpha). Four groups of BALB/c male mice were treated as follows: Group 1--mice receiving intravenous (iv) injections of physiological saline; Group 2--administered with 8 mg/kg Z-FA.FMK by iv injection; Group 3--mice treated with 700 mg/kg D-GalN and 15 microg/kg TNF-alpha by sequential intraperitoneal (ip) injection; Group 4--treated with 700 mg/kg D-GalN and 15 microg/kg TNF-alpha by sequential ip injection 1 h after administration with 8 mg/kg Z-FA.FMK. Mice from Groups 3 and 4 were sacrificed 4 h after D-GalN/TNF-alpha injections. The mice treated with D-GalN/TNF-alpha showed lung damage; increased TNF receptor-associated factor immunoreactivity, lipid peroxidation, protein carbonyl content, and lactate dehydrogenase activity; decreased catalase, superoxide dismutase, and paraoxonase activities. Treatment with Z-FA.FMK resulted in an improvement of these alterations in D-GalN/TNF-alpha-administered mice. The apoptotic index of type-II pneumocytes was the almost same in the four study groups, but pneumocytes labeled with proliferating cell nuclear antigen antibody was more numerous in Group 4 mice. Our results show that D-GalN/TNF-alpha results in lung damage without induction of apoptosis. Treatment with Z-FA.FMK stimulates proliferation of type-II pneumocytes and improves degenerative alterations in injured lung occurred with liver injury induced by D-GalN/TNF-alpha.
Oztay
Fusun
F
Department of Biology, Faculty of Science, Istanbul University, Vezneciler, 34459, Istanbul, Turkey. fusoztay@istanbul.edu.tr
Gezginci-Oktayoglu
Selda
S
Bayrak
Bertan Boran
BB
Yanardag
Refiye
R
Bolkent
Sehnaz
S
D000818:Animals; D017209:Apoptosis; D002401:Cathepsin B / Q000037:antagonists & inhibitors*; D049109:Cell Proliferation; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D003978:Diazomethane / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D005688:Galactosamine / Q000633:toxicity*; D055370:Lung Injury / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*
D015853:Cysteine Proteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; C024918:benzyloxycarbonylphenylalanylalanine diazomethyl ketone; D003978:Diazomethane; D005688:Galactosamine; D002401:Cathepsin B