TY - JOUR
T1 - Inhibition of Src and forkhead box O1 signaling by induced pluripotent stem-cell therapy attenuates hyperoxia-augmented ventilator-induced diaphragm dysfunction
AU - Li, Li Fu
AU - Chang, Yuh Lih
AU - Chen, Ning Hung
AU - Wang, Chien Ying
AU - Chang, Gwo Jyh
AU - Lin, Meng Chih
AU - Chang, Chih Hao
AU - Huang, Chung Chi
AU - Chuang, Jen Hua
AU - Yang, Yi Pin
AU - Chiou, Shih Hwa
AU - Liu, Yung Yang
N1 - Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/7/1
Y1 - 2016/7/1
N2 - Mechanical ventilation (MV) with hyperoxia is required for providing life support to patients with acute lung injury (ALI). However, MV may cause diaphragm weakness through muscle injury and atrophy, an effect termed ventilator-induced diaphragm dysfunction (VIDD). Src protein tyrosine kinase and class O of forkhead box 1 (FoxO1) mediate acute inflammatory responses and muscle protein degradation induced by oxidative stress. Induced pluripotent stem cells (iPSCs) have been reported to improve hyperoxia-augmented ALI; however, the mechanisms regulating the interactions among VIDD, hyperoxia, and iPSCs are unclear. In this study, we hypothesized that iPSC therapy can ameliorate hyperoxia-augmented VIDD by suppressing the Src-FoxO1 pathway. Male C57BL/6 mice, either wild-type or Src-deficient, aged between 6 and 8 weeks were exposed to MV (6 or 10 mL/kg) with or without hyperoxia for 2–8 h after the administration of 5 × 107 cells/kg Oct4/Sox2/Parp1 mouse iPSCs or iPSC-derived conditioned medium (iPSC-CM). Nonventilated mice were used as controls. MV during hyperoxia aggravated VIDD, as demonstrated by the increases in Src activation, FoxO1 dephosphorylation, malondialdehyde, caspase-3, atrogin-1 and muscle ring finger-1 production, microtubule-associated protein light chain 3-II, disorganized myofibrils, disrupted mitochondria, autophagy, and myonuclear apoptosis; however, MV with hyperoxia reduced mitochondrial cytochrome C, diaphragm muscle fiber size, and contractility (P < 0.05). Hyperoxia-exacerbated VIDD was attenuated in Src-deficient mice and by iPSCs and iPSC-CM (P < 0.05). Our data indicate that iPSC therapy attenuates MV-induced diaphragmatic injury that occurs during hyperoxia-augmented VIDD by inhibiting the Src-FoxO1 signaling pathway.
AB - Mechanical ventilation (MV) with hyperoxia is required for providing life support to patients with acute lung injury (ALI). However, MV may cause diaphragm weakness through muscle injury and atrophy, an effect termed ventilator-induced diaphragm dysfunction (VIDD). Src protein tyrosine kinase and class O of forkhead box 1 (FoxO1) mediate acute inflammatory responses and muscle protein degradation induced by oxidative stress. Induced pluripotent stem cells (iPSCs) have been reported to improve hyperoxia-augmented ALI; however, the mechanisms regulating the interactions among VIDD, hyperoxia, and iPSCs are unclear. In this study, we hypothesized that iPSC therapy can ameliorate hyperoxia-augmented VIDD by suppressing the Src-FoxO1 pathway. Male C57BL/6 mice, either wild-type or Src-deficient, aged between 6 and 8 weeks were exposed to MV (6 or 10 mL/kg) with or without hyperoxia for 2–8 h after the administration of 5 × 107 cells/kg Oct4/Sox2/Parp1 mouse iPSCs or iPSC-derived conditioned medium (iPSC-CM). Nonventilated mice were used as controls. MV during hyperoxia aggravated VIDD, as demonstrated by the increases in Src activation, FoxO1 dephosphorylation, malondialdehyde, caspase-3, atrogin-1 and muscle ring finger-1 production, microtubule-associated protein light chain 3-II, disorganized myofibrils, disrupted mitochondria, autophagy, and myonuclear apoptosis; however, MV with hyperoxia reduced mitochondrial cytochrome C, diaphragm muscle fiber size, and contractility (P < 0.05). Hyperoxia-exacerbated VIDD was attenuated in Src-deficient mice and by iPSCs and iPSC-CM (P < 0.05). Our data indicate that iPSC therapy attenuates MV-induced diaphragmatic injury that occurs during hyperoxia-augmented VIDD by inhibiting the Src-FoxO1 signaling pathway.
UR - http://www.scopus.com/inward/record.url?scp=84962821186&partnerID=8YFLogxK
U2 - 10.1016/j.trsl.2016.03.011
DO - 10.1016/j.trsl.2016.03.011
M3 - 文章
C2 - 27055225
AN - SCOPUS:84962821186
SN - 1931-5244
VL - 173
SP - 131-147.e1
JO - Translational Research
JF - Translational Research
ER -