Journal
BIOMATERIALS
Volume 34, Issue 1, Pages 78-91Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2012.09.042
Keywords
Induced pluripotent stem cell; Ventilator-induced lung injury; Akt; IP-10
Funding
- National Science Council [100-2120-M-002-011, 100-2325-B-010-010, 100-2321-B-010-020, 101-2314-B-182A-088-MY3]
- Taipei Veterans General Hospital [E99-101]
- Yen-Tjing-Ling Medical Foundation [CI-99/100]
- Department of Health Cancer Center Research of Excellence [DOH101-TD-C-111-007]
- Genomic Center Project of National Yang-Ming University
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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. (C) 2012 Elsevier Ltd. All rights reserved.
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