Improvement of ventilator-induced lung injury by IPS cell-derived conditioned medium via inhibition of PI3K/Akt pathway and IP-10-dependent paracrine regulation

Li Fu Li, Yung Yang Liu, Cheng Ta Yang, Yueh Chien, Nae Fang Twu, Mong Lien Wang, Chien Ying Wang, Chung Chi Huang, Kuo Chin Kao, Han Shui Hsu, Cheng-Wen Wu Lee, Shih Hwa Chiou*

*Corresponding author for this work

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Mechanical ventilation in patients may increase the risk of an acute lung injury (ALI), termed ventilator-induced lung injury (VILI). Induced pluripotent stem cells (iPSCs) have previously been shown to improve tissue repair in different disease models, including ALI. However, the therapeutic efficacy of iPSCs-derived conditioned medium (iPSC-CM) on ALI or VILI remains unknown. Here, we demonstrated that both iPSCs and iPSC-CM effectively decrease high-tidal-volume-induced VILI-related inflammatory processes and HMGB1 and PAI-1 production, predominantly through suppressing PI3K/Akt signaling. Notably, iPSC-CM suppressed production of macrophage inflammatory protein-2, malondialdehyde, and increased total glutathione content. Transmission electron microscopy revealed that iPSC-CM potentially restored the bronchial microstructure. This iPSC-CM efficacy could be mimicked by PI3K inhibitor LY294002 or Akt heterozygous knockout, and either treatment showed no further improvement on VILI in iPSC-CM recipients. Furthermore, iPSC-CM increased interferon gamma-induced protein 10 (IP-10) production in injured lungs. Administration of IP-10-neutralizing antibodies increased neutrophil infiltration, impaired lung oxygenation and deteriorated the protective effects mediated by iPSC-CM. Our data provide a preclinical indication regarding the therapeutic potential of iPSC-CM in VILI and suggest that inhibiting PI3K/Akt pathway or increasing IP-10 is a prospective diagnostic and therapeutic target for VILI patients.

Original languageEnglish
Pages (from-to)78-91
Number of pages14
JournalBiomaterials
Volume34
Issue number1
DOIs
StatePublished - 1 Jan 2013

Keywords

  • Akt
  • IP-10
  • Induced pluripotent stem cell
  • Ventilator-induced lung injury

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    Li, L. F., Liu, Y. Y., Yang, C. T., Chien, Y., Twu, N. F., Wang, M. L., Wang, C. Y., Huang, C. C., Kao, K. C., Hsu, H. S., Wu Lee, C-W., & Chiou, S. H. (2013). Improvement of ventilator-induced lung injury by IPS cell-derived conditioned medium via inhibition of PI3K/Akt pathway and IP-10-dependent paracrine regulation. Biomaterials, 34(1), 78-91. https://doi.org/10.1016/j.biomaterials.2012.09.042