Cathepsin B inhibition improves lung injury associated to D-galactosamine/tumor necrosis factor-alpha-induced liver injury in mice.

Abstract

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.

• Authors: Fusun Oztay, Selda Gezginci-Oktayoglu, Bertan Boran Bayrak, Refiye Yanardag, Sehnaz Bolkent
• Journal: Molecular and cellular biochemistry (Mol Cell Biochem) Vol. 333 Issue 1-2 Pg. 65-72 (Jan 2010) ISSN: 1573-4919 [Electronic] Netherlands
• PMID: 19629648 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cysteine Proteinase Inhibitors
• Tumor Necrosis Factor-alpha
• benzyloxycarbonylphenylalanylalanine diazomethyl ketone
• Diazomethane
• Galactosamine
• Cathepsin B

Topics

• Animals
• Apoptosis
• Cathepsin B (antagonists & inhibitors)
• Cell Proliferation
• Chemical and Drug Induced Liver Injury (drug therapy)
• Cysteine Proteinase Inhibitors (pharmacology, therapeutic use)
• Diazomethane (analogs & derivatives, pharmacology, therapeutic use)
• Galactosamine (toxicity)
• Lung Injury (chemically induced, drug therapy)
• Male
• Mice
• Mice, Inbred BALB C
• Tumor Necrosis Factor-alpha (toxicity)