Recent evidence suggests mesenchymal stem cells (MSCs) can downmodulate bleomycin-induced lung injury, and umbilical cord blood (UCB) is a promising source for human MSCs. This study examined whether intratracheal or intraperitoneal transplantation of human UCB-derived MSCs can attenuate hyperoxia-induced lung injury in immunocompetent newborn rats. Wild-type Sprague-Dawley rats were randomly exposed to 95% oxygen or air from birth. In the transplantation groups, a single dose of PKH26-labeled human UCBderived MSCs was administered either intratracheally (2 × 10 6 cells) or intraperitoneally (5 × 10 5 cells) at postnatal day (P) 5. At P14, the harvested lungs were examined for morphometric analyses of alveolarization and TUNEL staining, as well as the myeoloperoxidase activity, the level of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and transforming growth factor (TGF)-β mRNA, α-smooth muscle actin (SMA) protein, and collagen levels. Differentiation of MSCs to the respiratory epithelium was also evaluated both in vitro before transplantation and in vivo after transplantation. Despite one fourth dosage of MSCs, significantly more PKH26-labeled donor cells were recovered with intratracheal administration than with intraperitoneal administration both during normoxia and hyperoxia. The hyperoxia-induced increase in the number of TUNELpositive cells, myeloperoixdase activity, and the level of IL-6 mRNA were significantly attenuated with both intratracheal and intraperitoneal MSCs transplantation. However, the hyperoxia-induced impaired alveolarization and increased the level of TNF-α and TGF-β mRNA, α-SMA protein, and collagen were significantly attenuated only with intratracheal MSCs transplantation. MSCs differentiated into respiratory epithelium in vitro and a few PKH26-positive donor cells were colocalized with pro surfactant protein C in the damaged lungs. In conclusion, intratracheal transplantation of human UCB-derived MSCs is more effective than intraperitoneal transplantation in attenuating the hyperoxia-induced lung injury in neonatal rats.Key words: Hyperoxic lung injury; Transplantation; Animal; Newborn; Inflammation; Cell differentiation INTRODUCTION development of hyperoxic neonatal lung injury and BPD (42).Recently, the exogenous administration of bone marBronchopulmonary dysplasia (BPD) is a chronic pulmonary disease that usually occurs in premature infants row (BM)-derived mesenchymal stem cells (MSCs) significantly attenuated the bleomycin-induced lung injury receiving prolonged ventilatory support and oxygen supplementation. It is also an important cause of mortality by downmodulating the inflammatory responses and ameliorating their fibrotic effects (33). In addition, the transand long-term respiratory morbidity with few effective treatments (3,6). The histopathological characteristics of planted cells assumed the lung parenchymal cell phenotypes (34). The anti-inflammatory effect of MSCs has BPD include impaired alveolarization and interstitial fibrosis (30). Prolonged exposure of neonata...
This study was done to determine the neuroprotective effect of cycloheximide on neonatal hypoxic-ischemic brain injury. Seven day-old newborn rat pups were subjected to 90 min of 8% oxygen following a unilateral carotid artery ligation. The extent of cerebral infarction was evaluated at 1 and 4 week of recovery. Apoptosis was identified by performing terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining and flow cytometry with a combination of fluoresceinated annexin V and propidium iodide. Brain infarction area was significantly increased at 4 week compared to 1 week after hypoxia-ischemia in the control group. With cycloheximide treatment, the number of TUNEL positive cells in the ipsilateral cerebral cortex at 48 hr and peri-infarct area at 1 and 4 week of recovery was significantly reduced, both apoptotic and necrotic cells by flow cytometry 48 hr after the injury were significantly reduced, and the extent of cerebral infarction at 1 and 4 week of recovery was also significantly attenuated compared to the hypoxia-ischemia control group. In summary, our data suggest that apoptosis plays an important role in the development of delayed infarction, and inhibition of apoptosis with cycloheximide significantly reduces the ensuing cerebral infarction in a newborn rat pup model of cerebral hypoxia-ischemia.
We have previously shown that cycloheximide significantly inhibited apoptosis, and reduced ensuing cerebral infarction in a newborn rat model of cerebral hypoxia-ischemia. This study was performed to determine the therapeutic window for cycloheximide therapy. Seven day-old newborn rat pups were subjected to 100 min of 8% oxygen following a unilateral carotid artery ligation, and cycloheximide was given at 0, 6, 12 and 24 hr after hypoxia-ischemia (HI). Apoptosis or necrosis was identified by performing flow cytometry with a combination of fluorescinated annexin V and propidium iodide, and the extent of cerebral infarction was evaluated with triphenyl tetrazolium chloride (TTC) at 48 hr and 72 hr after HI, respectively. With cycloheximide treatment at 0 hr after HI, both apoptotic and necrotic cells by flow cytometry were significantly reduced, only necrotic cells were significantly reduced at 6 and 12 hr, and no protective effect was seen if administration was delayed until 24 hr after HI compared to the HI control group. Infarct volume, measured by TTC, was significantly reduced by 92% and 61% when cycloheximide was given at 0 or 6 hr after HI respectively; however, there was an insignificant trend in infarct reduction if cycloheximide was administered 12 hr after HI, and no protective effect was observed when administration was delayed until 24 hr after HI. In summary, cycloheximide was neuroprotective when given within 6 hr after HI in the developing newborn rat brain.
This study was done to determine whether alpha -phenyl-N-tert-butylnitrone (PBN), a spin-trapping agent possessing significant anti-inflammatory capabilities, could attenuate hyperoxia-induced lung injury, and if so, whether this protective effect is mediated by the down-modulation of inflammation in neonatal rats. Newborn Sprague-Dawley rat pups were subjected to 14 days of hyperoxia (> 90% oxygen) within 10 hours after birth. PBN treatment, given 100 mg/kg intraperitoneally daily throughout the experiment, significantly attenuated hyperoxia-induced lung pathology, such as decreased radial alveolar count, increased mean linear intercept, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling-positive cells. Hyperoxia-induced activation of nicotinamide adenine dinucleotide phosphate oxidase that is responsible for superoxide anion production, as evidenced by up-regulation and membrane translocation of p67phox, and the inflammatory responses, such as increased mRNA expression of tumor necrosis factor-alpha, interleukin-6, and transforming growth factor-beta, were also significantly attenuated with PBN treatment. In summary, a spin-trapping agent PBN significantly attenuated hyperoxia-induced lung injury by down-regulating the inflammatory responses in neonatal rats.
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