Aggravation of bleomycin-induced pulmonary inflammation and fibrosis in mice lacking peroxiredoxin I.
Oxidative stress plays an important role in the pathogenesis of acute lung injury and pulmonary fibrosis. Peroxiredoxin (Prx) I is a cellular antioxidant enzyme induced under stress conditions. In the present study, the protective effects of Prx I on the development of bleomycin-induced acute pulmonary inflammation and pulmonary fibrosis were investigated using Prx I-deficient mice. Survival of Prx I-deficient mice after bleomycin administration was significantly lower than that of wild-type mice, corresponding with enhanced acute pulmonary inflammation and fibrosis. The level of inflammatory cytokines and chemokines, such as TNF-α, macrophage inflammatory protein-2, and monocyte chemotactic protein-1, was significantly elevated in the bronchoalveolar lavage fluid of Prx I-deficient mice after bleomycin administration. Furthermore, the level of 8-isoprostane, an oxidative stress marker, and the concentration and alveolar macrophage expression of macrophage migration inhibitory factor were elevated in the lungs of Prx I-deficient mice after bleomycin administration. The exacerbation of bleomycin-induced pulmonary inflammation and fibrosis in Prx I-deficient mice was inhibited by treatment with N-acetyl-L-cysteine, a radical scavenger, or with (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester, a tautomerase inhibitor of macrophage migration inhibitory factor. These findings suggest that mice lacking Prx I are highly susceptible to bleomycin-induced pulmonary inflammation and fibrosis because of increases in pulmonary oxidant levels and macrophage migration inhibitory factor activity in response to bleomycin.
Department of Respiratory Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
Norihiro
N
Kikuchi
Yukio
Y
Ishii
Yuko
Y
Morishima
Yuichi
Y
Yageta
Norihiro
N
Haraguchi
Tadahiro
T
Yamadori
Hironori
H
Masuko
Tohru
T
Sakamoto
Toru
T
Yanagawa
Eiji
E
Warabi
Tetsuro
T
Ishii
Nobuyuki
N
Hizawa
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects; D017209:Apoptosis; D001761:Bleomycin / Q000009:adverse effects*; D018893:Bronchoalveolar Lavage; D002478:Cells, Cultured; D015237:Dinoprost / Q000031:analogs & derivatives / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced*; D008168:Lung / Q000473:pathology; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress; D054464:Peroxiredoxins / Q000235:genetics* / Q000502:physiology*; D011658:Pulmonary Fibrosis / Q000473:pathology*
D000903:Antibiotics, Antineoplastic; D016166:Free Radical Scavengers; D008263:Macrophage Migration-Inhibitory Factors; D001761:Bleomycin; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost; D054464:Peroxiredoxins; D000111:Acetylcysteine