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Original Research: CRITICAL CARE |

IV Delivery of Induced Pluripotent Stem Cells Attenuates Endotoxin-Induced Acute Lung Injury in MiceInduced Pluripotent Stem Cells and Lung Injury

Kuang-Yao Yang, MD, PhD; Hsin-Chin Shih, MD, PhD; Chorng-Kuang How, MD; Cheng-Yu Chen, MD, PhD; Han-Shui Hsu, MD, PhD; Ching-Wen Yang, BS; Yu-Chin Lee, MD, FCCP; Reury-Perng Perng, MD, PhD, FCCP; Chi-Hsien Peng, MD; Hsin-Yang Li, MD, PhD; Chia-Ming Chang, MD; Chung-Yuan Mou, PhD; Shih-Hwa Chiou, MD, PhD
Author and Funding Information

From the Department of Chest Medicine (Drs K.-Y. Yang, Lee, and Perng), the Department of Emergency Medicine (Drs Shih and How), the Department of Surgery (Dr Hsu), the Department of Medical Research and Education (Ms C.-W. Yang and Dr Chiou), the Department of Obstetrics and Gynecology (Drs Li and Chang), Taipei Veterans General Hospital; Institute of Clinical Medicine (Drs K.-Y. Yang, Shih, How, Chen, Peng, Li, and Chiou), Institute of Emergency and Critical Care Meicine (Drs Shih and How), Institute of Oral Biology (Dr Chang), and Institute of Pharmacology (Dr Chiou), School of Medicine (Drs K.-Y. Yang, Chen, Hsu, Lee, Perng, Li, Chang, and Chiou), National Yang-Ming University; and the Department of Medical Research and Education (Dr Chen), National Yang-Ming University Hospital; Shin Kong Wu Ho-Su Memorial Hospital and Fu-Jen Catholic University (Dr Peng); and the Department of Chemistry, College of Science (Dr Mou), National Taiwan University, Taipei, Taiwan, China.

Correspondence to: Shih-Hwa Chiou, MD, PhD, Department of Medical Research and Education, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Rd, Taipei, 11217, Taiwan; e-mail: kyyang@vghtpe.gov.tw


Drs K.-Y. Yang and Chiou contributed equally to this work.

Funding/Support: This work was supported, in part, by Taiwan National Science Council Research Grants [NSC 97-3111-B-075-001-MY3, NSC 97-2314-B-075-046, NSC 100-2325-B-010-010, NSC 100-2314-B-075-047-MY3], Department of Health [DOH100-TD-C-111-007], Taipei Veterans General Hospital [V97C1-143, V98C1-072, V99C1-167, V100C-159, V97B1-006, E1-008, and F-001], the Joint Projects of UTVGH [VGHUST 98-G6-6], Yen-Tjing-Ling Medical Foundation, and National Yang-Ming University (Ministry of Education, Aim for the Top University Plan).

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).


© 2011 American College of Chest Physicians


Chest. 2011;140(5):1243-1253. doi:10.1378/chest.11-0539
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Background:  Induced pluripotent stem (iPS) cells are novel stem cell populations, but the role of iPS cells in acute lung injury (ALI) is not currently known. We investigated the effect of iPS cells in modifying the pathophysiology of endotoxin-induced ALI.

Methods:  Male C57BL/6 8- to 12-week-old mice were enrolled in this study. Mouse iPS cells were delivered through the tail veins of mice 4 h after intratracheal instillation of endotoxin. Lung histopathologic findings, the pulmonary levels of cytokines, and functional parameters were analyzed after either 24 h or 48 h.

Results:  More iPS cells integrated into the lungs of mice with ALI than those of the control mice, as demonstrated by in vivo radionuclide imaging and in vitro Hoechst-labeled fluorescent staining. iPS cells significantly diminished the histopathologic changes of ALI and the lung injury score. There was also a significant reduction in the activity of nuclear factor-κB (NF-κB) and neutrophil accumulation in the lung, confirmed by immunostaining, electrophoretic mobility shift assays, and the decrease of myeloperoxidase activity, in the iPS-cell-treated mice with ALI. These protective effects were not replicated by the control cell therapy with fibroblasts. iPS cells mediated a downregulation of the proinflammatory response to endotoxin (reducing tumor necrosis factor-α, IL-6, and macrophage inflammatory peptide-2). In addition, iPS cells rescued the hypoxemia and pulmonary function of ALI. Treatment with a conditioned medium of iPS cells showed effects similar to those of iPS cells, which may suggest the therapeutic benefits of iPS mediated by paracrine factors.

Conclusions:  IV delivery of iPS cells provides a beneficial effect to attenuate the severity of endotoxin-induced ALI and improve physiologic impairment, which is partly mediated by a reduction in NF-κB activity and neutrophils accumulation. The conditioned medium of iPS cells demonstrated effects equal to those of iPS cells.

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