• 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, and Shih-Hwa Chiou.
• Department of Medicine, Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan.
• Biomaterials. 2013 Jan 1; 34 (1): 78-91.

AbstractMechanical 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.Copyright © 2012 Elsevier Ltd. All rights reserved.

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