Attenuation of bleomycin-induced pneumopathy in mice by a caspase inhibitor.
Caspases have been implicated in the effector process of apoptosis in several systems including the Fas-Fas ligand pathway. We previously demonstrated that excessive apoptosis of lung epithelial cells and the Fas-Fas ligand pathway were essential in the pathogenesis of bleomycin-induced pneumopathy in mice. Therefore, the purpose of this study was to investigate whether a caspase inhibitor could prevent the development of this model. The expression of caspase-1 and caspase-3 was upregulated on lung epithelial cells, alveolar macrophages, and infiltrating inflammatory cells in this model. We demonstrated that a broad-spectrum caspase inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, decreased the caspase-1- and caspase-3-like activity, the number of apoptotic cells, the pathological grade of lung inflammation and fibrosis, and the hydroxyproline content in lung tissues in this model. We conclude that caspase inhibitors could be a new therapeutic approach against lung injury and pulmonary fibrosis.
Kuwano
K
K
Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Higashiku, Fukuoka 812-8582, Japan. kkuwano@kokyu.med.kyushu-u.ac.jp
Kunitake
R
R
Maeyama
T
T
Hagimoto
N
N
Kawasaki
M
M
Matsuba
T
T
Yoshimi
M
M
Inoshima
I
I
Yoshida
K
K
Hara
N
N
D000280:Administration, Inhalation; D000590:Amino Acid Chloromethyl Ketones / Q000008:administration & dosage*; D000818:Animals; D001761:Bleomycin / Q000633:toxicity*; D015153:Blotting, Western; D020170:Caspase 1 / Q000378:metabolism; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage; D053938:DNA Fragmentation / Q000187:drug effects; D006909:Hydroxyproline / Q000032:analysis / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D001761:Bleomycin; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D020170:Caspase 1; D006909:Hydroxyproline