Thioredoxin-1 protects against hyperoxia-induced apoptosis in cells of the alveolar walls.
BACKGROUND
The mechanisms of hyperoxia-induced lung injury remain poorly defined. Thioredoxin-1 (TRX-1) is a small ubiquitous protein that acts as an important radical scavenger. We investigated the effect of TRX-1 on apoptosis in hyperoxia-induced lung injury.


METHODS
Mice were exposed to 98% O(2) to produce a model of hyperoxia-induced lung injury. Using transgenic mice overexpressing human TRX-1 (hTRX-1), we assessed lung structure (n=4 per group), immunohistochemical staining for 8-hydroxy-deoxyguanosine (n=4 per group), TUNEL staining (n=5 per group), cytokine (n=5 per group) of IL-1beta and IL-6, and protein (n=6 per group) and m-RNA levels (n=4 per group) (or both) of cytochrome c, Bcl-2, Bax, p21, and p53 in the lungs.


RESULTS
After exposure to hyperoxia, hTRX-1 transgenic mice had significantly decreased alveolar damage. The apoptotic index was significantly lower in hTRX-1 transgenic mice than in wild-type (WT) mice after exposure to hyperoxia. Protein expression of cytochrome c in the lung was significantly lower in hTRX-1 transgenic mice than in WT mice after exposure to hyperoxia. Protein expression and m-RNA levels of Bcl-2 in the lung were significantly higher in hTRX-1 transgenic mice than in WT mice after exposure to hyperoxia. TRX-1 had no effect on the protein and m-RNA levels of Bax and p21. The protein and m-RNA levels of p53 was unaffected by hyperoxia in hTRX-1 transgenic mice. The cytokine level of IL-6 was significantly higher in hTRX-1 transgenic mice than in WT mice after exposure to hyperoxia. TRX-1 had no effect on cytokine level of IL-1beta.


CONCLUSIONS
These findings suggest that overexpression of hTRX-1 protects against hyperoxia-induced apoptosis in cells of the alveolar walls. The up-regulating Bcl-2 protein is considered to be one of antiapoptotic effects of TRX-1 in hyperoxia-induced lung injury.
Yamada
Tadaaki
T
Department of Respiratory Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan. tadaaki-y@muc.biglobe.ne.jp
Iwasaki
Yoshinobu
Y
Nagata
Kazuhiro
K
Fushiki
Shinji
S
Nakamura
Hajime
H
Marunaka
Yoshinori
Y
Yodoi
Junji
J
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology*; D045304:Cytochromes c / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D016158:Genes, p53 / Q000235:genetics; D018496:Hyperoxia / Q000473:pathology; D008168:Lung / Q000473:pathology; D008171:Lung Diseases / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D011650:Pulmonary Alveoli / Q000166:cytology / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism*; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
D000975:Antioxidants; C494827:Bax protein, mouse; D016207:Cytokines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; C491203:TXN protein, human; D051028:bcl-2-Associated X Protein; C052617:Bcl2 protein, mouse; D013879:Thioredoxins; D045304:Cytochromes c