Mitochondria-mediated apoptosis of lung epithelial cells in idiopathic interstitial pneumonias.
We previously demonstrated that the up-regulation of p53, Fas, and DNA damage are present in lung epithelial cells from patients with idiopathic interstitial pneumonias (IIP). Fas ligation induces apoptosis of lung epithelial cells predominantly through the direct activation of the caspase cascade via caspase-8 activation, whereas the up-regulation of p53 and other cellular stresses can induce mitochondria-mediated apoptosis. In this study, we investigated the incidence of mitochondria-mediated apoptosis of epithelial cells in IIP. We performed TUNEL staining to detect apoptotic cells and western blot analysis and immunohistochemistry to assess the expression and activation of caspases and the cytochrome c release from mitochondria in lung tissues from eight patients with usual interstitial pneumonia, five patients with nonspecific interstitial pneumonia, and eight patients with normal lung parenchyma. The expressions of pro- and cleaved caspase-8, 9, 3, and cytochrome c release from the mitochondria were all significantly increased in the lung tissues of IIP compared with normal lung parenchyma. The positive signals for caspases in epithelial cells were increased in IIP compared with normal lung parenchyma by immunohistochemistry. The results of TUNEL and electron microscopy suggested that apoptotic cells were predominantly epithelial cells. TUNEL-positive cells in % of epithelial cells were significantly increased in IIP compared with normal lung parenchyma, and significantly correlated with cytochrome c release from the mitochondria and with the expression of cleaved caspase-3 in epithelial cells. We conclude that mitochondria-mediated apoptosis may be involved in the pathophysiology of IIP.
Kuwano
Kazuyoshi
K
Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. kkuwano@kokyu.med.kyushu-u.ac.jp
Hagimoto
Naoki
N
Maeyama
Takashige
T
Fujita
Masaki
M
Yoshimi
Michihiro
M
Inoshima
Ichiro
I
Nakashima
Nobutaka
N
Hamada
Naoki
N
Watanabe
Kentaro
K
Hara
Nobuyuki
N
D000368:Aged; D017209:Apoptosis; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002452:Cell Count; D003574:Cytochrome c Group / Q000378:metabolism; D004847:Epithelial Cells / Q000201:enzymology / Q000473:pathology; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D008168:Lung / Q000201:enzymology / Q000473:pathology*; D017563:Lung Diseases, Interstitial / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000201:enzymology / Q000473:pathology*
D003574:Cytochrome c Group; D020169:Caspases