Therapeutic effect of lecithinized superoxide dismutase on bleomycin-induced pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is thought to involve inflammatory infiltration of leukocytes, lung injury induced by reactive oxygen species (ROS), in particular superoxide anion, and fibrosis (collagen deposition). No treatment has been shown to improve definitively the prognosis for IPF patients. Superoxide dismutase (SOD) catalyzes the dismutation of superoxide anion to hydrogen peroxide, which is subsequently detoxified by catalase. Lecithinized SOD (PC-SOD) has overcome clinical limitations of SOD, including low tissue affinity and low stability in plasma. In this study, we examined the effect of PC-SOD on bleomycin-induced pulmonary fibrosis. Severity of the bleomycin-induced fibrosis in mice was assessed by various methods, including determination of hydroxyproline levels in lung tissue. Intravenous administration of PC-SOD suppressed the bleomycin-induced increase in the number of leukocytes in bronchoalveolar lavage fluid. Bleomycin-induced collagen deposition and increased hydroxyproline levels in the lung were also suppressed in animals treated with PC-SOD, suggesting that PC-SOD suppresses bleomycin-induced pulmonary fibrosis. The dose-response profile of PC-SOD was bell-shaped, but concurrent administration of catalase restored the ameliorative effect at high doses of PC-SOD. Intratracheal administration or inhalation of PC-SOD also attenuated the bleomycin-induced inflammatory response and fibrosis. The bell-shaped dose-response profile of PC-SOD was not observed for these routes of administration. We consider that, compared with intravenous administration, inhalation of PC-SOD may be a more therapeutically beneficial route of administration due to the higher safety and quality of life of the patient treated with this drug.
Tanaka
Ken-Ichiro
K
Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto, Japan.
Ishihara
Tomoaki
T
Azuma
Arata
A
Kudoh
Shoji
S
Ebina
Masahito
M
Nukiwa
Toshihiro
T
Sugiyama
Yukihiko
Y
Tasaka
Yuichi
Y
Namba
Takushi
T
Ishihara
Tsutomu
T
Sato
Keizo
K
Mizushima
Yutaka
Y
Mizushima
Tohru
T
D000280:Administration, Inhalation; D000818:Animals; D001761:Bleomycin; D002374:Catalase / Q000008:administration & dosage; D016923:Cell Death / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004848:Epithelium / Q000187:drug effects / Q000473:pathology; D006861:Hydrogen Peroxide / Q000378:metabolism; D007275:Injections, Intravenous; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008648:Mesoderm / Q000187:drug effects / Q000473:pathology; D051379:Mice; D010713:Phosphatidylcholines / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D011014:Pneumonia / Q000188:drug therapy; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy*; D013482:Superoxide Dismutase / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*
D010713:Phosphatidylcholines; D001761:Bleomycin; D003094:Collagen; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase; C434045:lecithinized superoxide dismutase