Decreased proteasomal function accelerates cigarette smoke-induced pulmonary emphysema in mice.
Chronic obstructive pulmonary disease (COPD) is a disease common in elderly people, characterized by progressive destruction of lung parenchyma and chronic inflammation of the airways. The pathogenesis of COPD remains unclear, but recent studies suggest that oxidative stress-induced apoptosis in alveolar cells contributes to emphysematous lung destruction. The proteasome is a multicatalytic enzyme complex that plays a critical role in proteostasis by rapidly destroying misfolded and modified proteins generated by oxidative and other stresses. Proteasome activity decreases with aging in many organs including lungs, and an age-related decline in proteasomal function has been implicated in various age-related pathologies. However, the role of the proteasome system in the pathogenesis of COPD has not been investigated. Recently, we have established a transgenic (Tg) mouse model with decreased proteasomal chymotrypsin-like activity, showing age-related phenotypes. Using this model, we demonstrate here that decreased proteasomal function accelerates cigarette smoke (CS)-induced pulmonary emphysema. CS-exposed Tg mice showed remarkable airspace enlargement and increased foci of inflammation compared with wild-type controls. Importantly, apoptotic cells were found in the alveolar walls of the affected lungs. Impaired proteasomal activity also enhanced apoptosis in cigarette smoke extract (CSE)-exposed fibroblastic cells derived from mice and humans in vitro. Notably, aggresome formation and prominent nuclear translocation of apoptosis-inducing factor were observed in CSE-exposed fibroblastic cells isolated from Tg mice. Collective evidence suggests that CS exposure and impaired proteasomal activity coordinately enhance apoptotic cell death in the alveolar walls that may be involved in the development and progression of emphysema in susceptible individuals such as the elderly.
1] Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan [2] Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan.
Yosuke
Y
Yamada
Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Utano
U
Tomaru
Faculty of Health Sciences, Hokkaido University, Sapporo, Japan.
Akihiro
A
Ishizu
Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Tomoki
T
Ito
Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Takayuki
T
Kiuchi
Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Ayako
A
Ono
Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Syota
S
Miyajima
First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
Katsura
K
Nagai
Department of Cellular Pharmacology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Tsunehito
T
Higashi
Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan.
Yoshihiro
Y
Matsuno
Department of Medical Oncology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Hirotoshi
H
Dosaka-Akita
First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
Masaharu
M
Nishimura
Department of Cellular Pharmacology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Soichi
S
Miwa
Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Masanori
M
Kasahara
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011656:Pulmonary Emphysema / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana
D012906:Smoke; D046988:Proteasome Endopeptidase Complex