title: Intratracheal transplantation of human umbilical cord blood-derived mesenchymal stem cells dose-dependently attenuates hyperoxia-induced lung injury in neonatal rats.
abstract: Intratracheal transplantation of human umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) attenuates the hyperoxia-induced neonatal lung injury. The aim of this preclinical translation study was to optimize the dose of human UCB-derived MSCs in attenuating hyperoxia-induced  lung injury in newborn rats. Newborn Sprague-Dawley rats were randomly exposed to hyperoxia (95% oxygen) or normoxia after birth for 14 days. Three different doses of human UCB-derived MSCs, 5 × 10(3) (HT1), 5 × 10(4) (HT2), and 5 × 10(5) (HT3),  were delivered intratracheally at postnatal day (P) 5. At P14, lungs were harvested for analyses including morphometry for alveolarization, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) staining, myeoloperoxidase activity, mRNA level of  tumor necross factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, and transforming growth factor-β (TGF-β), human glyceradehyde-3-phosphate dehydrogenase (GAPDH), and p47(phox), and collagen levels. Increases in TUNEL-positive cells were attenuated  in all transplantation groups. However, hyperoxia-induced lung injuries, such as reduced alveolarization, as evidenced by increased mean linear intercept and mean alveolar volume, and increased collagen levels were significantly attenuated in both HT2 and HT3, but not in HT1, with better attenuation  in HT3 than in HT2. Dose-dependent human GAPDH expression, indicative of the presence of human RNA in lung tissue, was observed only in the transplantation groups, with higher expression in HT3 than in HT2, and higher expression in HT2 than in HT1. Hyperoxia-induced inflammatory responses  such as increased myeloperoxidase acitivity, mRNA levels of TNF-α, IL-1β, IL-6, and TGF-β of the lung tissue, and upregulation of both cytosolic and membrane p47(phox), indicative of oxidative stress, were significantly attenuated in both HT2 and HT3 but not  in HT1. These results demonstrate that intratracheal transplantation of human UCB-derived MSCs with appropriate doses may attenuate hyperoxia-induced lung injury through active involvement of these cells in modulating host inflammatory responses and oxidative stress in neonatal rats.
authors.affiliation: Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul, Korea.
authors.forename: Yun Sil
authors.initials: YS
authors.lastname: Chang
authors.forename: Soo Jin
authors.initials: SJ
authors.lastname: Choi
authors.forename: Dong Kyung
authors.initials: DK
authors.lastname: Sung
authors.forename: Soo Yoon
authors.initials: SY
authors.lastname: Kim
authors.forename: Wonil
authors.initials: W
authors.lastname: Oh
authors.forename: Yoon Sun
authors.initials: YS
authors.lastname: Yang
authors.forename: Won Soon
authors.initials: WS
authors.lastname: Park
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005312:Fetal Blood / Q000166:cytology*; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000378:metabolism; D006801:Humans; D018496:Hyperoxia; D053208:Kaplan-Meier Estimate; D055370:Lung Injury / Q000378:metabolism / Q000401:mortality / Q000628:therapy*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D019255:NADPH Oxidases / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016207:Cytokines; D003094:Collagen; D009195:Peroxidase; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1