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.