title: Induced pluripotent stem cell therapy ameliorates hyperoxia-augmented ventilator-induced lung injury through suppressing the Src pathway.
abstract: BACKGROUND
  High tidal volume (VT) mechanical ventilation (MV) can induce the recruitment of neutrophils, release of inflammatory cytokines and free radicals, and disruption of alveolar epithelial and endothelial barriers. It is proposed to be the triggering factor that initiates ventilator-induced lung injury (VILI) and concomitant hyperoxia further aggravates the progression of VILI. The Src protein tyrosine kinase (PTK) family is one of the most critical families to intracellular signal transduction related to acute inflammatory responses. The anti-inflammatory abilities of induced pluripotent stem cells (iPSCs) have been shown to improve acute lung injuries (ALIs); however, the mechanisms regulating the interactions between MV, hyperoxia, and iPSCs have not been fully elucidated. In this study, we hypothesize that Src PTK plays a critical role in the regulation of oxidants and inflammation-induced VILI during hyperoxia. iPSC therapy can ameliorate acute hyperoxic VILI by suppressing the Src pathway.
  
  
  METHODS
  Male C57BL/6 mice, either wild-type or Src-deficient, aged between 2 and 3 months were exposed to high VT (30 mL/kg) ventilation with or without hyperoxia for 1 to 4 h after the administration of Oct4/Sox2/Parp1 iPSCs at a dose of 5×10(7) cells/kg of mouse. Nonventilated mice were used for the control groups.
  
  
  RESULTS
  High VT ventilation during hyperoxia further aggravated VILI, as demonstrated by the increases in microvascular permeability, neutrophil infiltration, macrophage inflammatory protein-2 (MIP-2) and plasminogen activator inhibitor-1 (PAI-1) production, Src activation, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, and malaldehyde (MDA) level. Administering iPSCs attenuated ALI induced by MV during hyperoxia, which benefited from the suppression of Src activation, oxidative stress, acute inflammation, and apoptosis, as indicated by the Src-deficient mice.
  
  
  CONCLUSIONS
  The data suggest that iPSC-based therapy is capable of partially suppressing acute inflammatory and oxidant responses that occur during hyperoxia-augmented VILI through the inhibition of Src-dependent signaling pathway.
authors.affiliation: Chest Department, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yung-Yang
authors.initials: YY
authors.lastname: Liu
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan; Department of Respiratory Therapy, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Li-Fu
authors.initials: LF
authors.lastname: Li
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
authors.forename: Jui-Ying
authors.initials: JY
authors.lastname: Fu
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan; Department of Respiratory Therapy, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Kuo-Chin
authors.initials: KC
authors.lastname: Kao
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan; Department of Respiratory Therapy, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Chung-Chi
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Department of Medical Research & Education, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yueh
authors.initials: Y
authors.lastname: Chien
authors.affiliation: Department of Medical Research & Education, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Liao
authors.affiliation: Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Medical Research & Education, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Shih-Hwa
authors.initials: SH
authors.lastname: Chiou
authors.affiliation: Department of Medical Research & Education, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yuh-Lih
authors.initials: YL
authors.lastname: Chang
mesh_terms: D000818:Animals; D017209:Apoptosis; D065150:Cellular Reprogramming; D054426:Chemokine CXCL2 / Q000378:metabolism; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism; D018496:Hyperoxia / Q000150:complications* / Q000503:physiopathology; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000637:transplantation*; D007249:Inflammation / Q000473:pathology; D008168:Lung / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D018384:Oxidative Stress; D010766:Phosphorylation; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012121:Respiration, Artificial / Q000009:adverse effects; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D033581:Stem Cell Transplantation; D013990:Tidal Volume; D055397:Ventilator-Induced Lung Injury / Q000209:etiology* / Q000503:physiopathology / Q000628:therapy*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*
chemical_list: D054426:Chemokine CXCL2; D008562:Membrane Glycoproteins; D050814:Octamer Transcription Factor-3; D017395:Plasminogen Activator Inhibitor 1; C494174:Pou5f1 protein, mouse; D017382:Reactive Oxygen Species; D055748:SOXB1 Transcription Factors; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D011065:Poly(ADP-ribose) Polymerases; D019061:src-Family Kinases