Expression of 150-kDa oxygen-regulated protein (ORP150) stimulates bleomycin-induced pulmonary fibrosis and dysfunction in mice.
Idiopathic pulmonary fibrosis (IPF) involves pulmonary injury associated with inflammatory responses, fibrosis and dysfunction. Myofibroblasts and transforming growth factor (TGF)-β1 play major roles in the pathogenesis of this disease. Endoplasmic reticulum (ER) stress response is induced in the lungs of IPF patients. One of ER chaperones, the 150-kDa oxygen-regulated protein (ORP150), is essential for the maintenance of cellular viability under stress conditions. In this study, we used heterozygous ORP150-deficient mice (ORP150(+/-) mice) to examine the role of ORP150 in bleomycin-induced pulmonary fibrosis. Treatment of mice with bleomycin induced the expression of ORP150 in the lung. Bleomycin-induced inflammatory responses were slightly exacerbated in ORP150(+/-) mice compared to wild-type mice. On the other hand, bleomycin-induced pulmonary fibrosis, alteration of lung mechanics and respiratory dysfunction was clearly ameliorated in the ORP150(+/-) mice. Bleomycin-induced increases in pulmonary levels of both active TGF-β1 and myofibroblasts were suppressed in ORP150(+/-) mice. These results suggest that although ORP150 is protective against bleomycin-induced lung injury, this protein could stimulate bleomycin-induced pulmonary fibrosis by increasing pulmonary levels of TGF-β1 and myofibroblasts.
Department of Analytical Chemistry, Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
Ken-Ichiro
K
Tanaka
Ayano
A
Shirai
Yosuke
Y
Ito
Takushi
T
Namba
Kayoko
K
Tahara
Naoki
N
Yamakawa
Tohru
T
Mizushima
D000818:Animals; D001761:Bleomycin / Q000494:pharmacology; D018840:HSP70 Heat-Shock Proteins; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D058628:Myofibroblasts / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
D018840:HSP70 Heat-Shock Proteins; D011506:Proteins; D016212:Transforming Growth Factor beta; C050087:oxygen-regulated proteins; D001761:Bleomycin