Improvement of ventilator-induced lung injury by IPS cell-derived conditioned medium via inhibition of PI3K/Akt pathway and IP-10-dependent paracrine regulation.
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.
Department of Medicine, Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan.
Li-Fu
LF
Li
Yung-Yang
YY
Liu
Cheng-Ta
CT
Yang
Yueh
Y
Chien
Nae-Fang
NF
Twu
Mong-Lien
ML
Wang
Chien-Ying
CY
Wang
Chung-Chi
CC
Huang
Kuo-Chin
KC
Kao
Han-Shui
HS
Hsu
Cheng-Wen
CW
Wu
Shih-Hwa
SH
Chiou
D000818:Animals; D054370:Chemokine CXCL9 / Q000378:metabolism*; D017077:Culture Media, Conditioned / Q000494:pharmacology*; D006579:Heterozygote; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism*; D007249:Inflammation / Q000473:pathology / Q000503:physiopathology; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects; D019899:Paracrine Communication / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D033581:Stem Cell Transplantation; D013990:Tidal Volume / Q000187:drug effects; D016896:Treatment Outcome; D055397:Ventilator-Induced Lung Injury / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*
D054370:Chemokine CXCL9; D017077:Culture Media, Conditioned; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt