Hypoxia pretreatment enhances the therapeutic potential of mesenchymal stem cells (BMSCs) on ozone-induced lung injury in rats (original) (raw)
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Ozone induces oxidative stress in rat alveolar type II and type I-like cells
Free Radical Biology …, 2006
Ozone is a highly reactive gas present in urban air, which penetrates deep into the lung and causes lung injury. The alveolar epithelial cells are among the first cell barriers encountered by ozone. To define the molecular basis of the cellular response to ozone, primary cultures of rat alveolar type II and type I-like cells were exposed to 100 ppb ozone or air for 1 h. The mRNA from both phenotypes was collected at 4 and 24 h after exposure for gene expression profiling. Ozone produced extensive alterations in gene expression involved in stress and inflammatory responses, transcription factors, antioxidant defenses, extracellular matrix, fluid transport, and enzymes of lipid metabolism and cell differentiation. Real-time reverse transcription-polymerase chain reaction and Western blot analysis verified changes in mRNA and protein levels of selected genes. Besides the increased stress response, ozone exposure downregulated genes of cellular differentiation. The changes were more prominent at 4 h in the type I-like phenotype and at 24 h in the type II phenotype. The type I-like cells were more sensitive to ozone than type II cells. The genome-wide changes observed provide insight into signal pathways activated by ozone and how cellular protection mechanisms are initiated.
2018
Hyperoxia induces activation of the renin-angiotensin system (RAS) in newborn rat lungs. This study investigated the therapeutic effects of human mesenchymal stem cells (MSCs) on lung development and RAS expression in neonatal rats exposed to hyperoxia. Sprague-Dawley rat pups were exposed to either room air (RA) or oxygen-enriched atmosphere (O2) treatment from postnatal days 1 to 14. Human MSCs (1 × 105 cells) in 0.03 mL of normal saline (NS) were administered intratracheally on postnatal day 5, and four study groups were obtained: RA + NS, RA + MSCs, O2 + NS, and O2 + MSCs. The lungs were excised for cytokine, expression of RAS components, and histological analyses on postnatal day 14. Body and lung weights were significantly lower in rats reared in hyperoxia than in those reared in RA. The rats reared in hyperoxia and treated with NS exhibited significantly higher tumor necrosis factor (TNF)-α and interleukin (IL)-6 levels, mean linear intercept (MLI), and expression of angioten...
Toxicology and Applied Pharmacology, 2006
Mice lacking inducible nitric oxide synthase (NOS2−/−) are more susceptible to ozone-induced lung inflammation and injury than their isogenic wild-type (NOS2+/+) counterparts, demonstrating an apparent protective effect for NOS2 in murine lungs. We hypothesized that nitric oxide (NO) generated from either NOS2 in the airway epithelial cells or the bone marrow-derived inflammatory cells was responsible for the protective effect of NOS2. To test this hypothesis, we prepared chimeric mice by killing their endogenous bone marrow cells by whole body irradiation, followed by bone marrow transplantation from a heterologous donor mouse. We exposed C57BL/6 (NOS2+/+), NOS2 −/−, and chimeric NOS2 mice (NOS2−/+, NOS2+/−) to 1 ppm of ozone for 3 consecutive nights. NOS2−/− mice were more severely injured after exposure to ozone than C57BL/6 mice, including a more robust inflammatory cell influx (4.14×10 5 ±2.19×10 5 vs. 2.78 ×10 5 ± 1.36×10 5 cells respectively; p=0.036) and greater oxidation of total protein sulfhydryls (R-SH) in their blood plasma. Chimeric NOS2 −/+ mice, which had bone marrow from NOS2−/− mice transplanted into C57BL/ 6 recipients, had a significantly greater response to ozone (increased numbers of neutrophils in lung lavage and decreased concentrations of exhaled NO) as compared to the reciprocal chimeric strain (NOS2+/−). We conclude that NOS2 has a protective effect against acute lung injury caused by ozone inhalation, which may be mediated, in part, by NO generated by NOS2 from inflammatory cells, predominantly neutrophils, recruited into the lung.
A model of chronic inflammation and pulmonary emphysema after multiple ozone exposures in mice
AJP: Lung Cellular and Molecular Physiology, 2011
Oxidative stress plays a role in the pathophysiology of emphysema through the activation of tissue proteases and apoptosis. We examined the effects of ozone exposure by exposing BALB/c mice to either a single 3-h exposure or multiple exposures over 3 or 6 wk, with two 3-h exposures per week. Compared with air-exposed mice, the increase in neutrophils in bronchoalveolar lavage fluid and lung inflammation index was greatest in mice exposed for 3 and 6 wk. Lung volumes were increased in 3- and 6-wk-exposed mice but not in single-exposed. Alveolar space and mean linear intercept were increased in 6- but not 3-wk-exposed mice. Caspase-3 and apoptosis protease activating factor-1 immunoreactivity was increased in the airway and alveolar epithelium and macrophages of 3- and 6-wk-exposed mice. Interleukin-13, keratinocyte chemoattractant, caspase-3, and IFN-γ mRNA were increased in the 6-wk-exposed group, but heme oxygenase-1 (HO-1) mRNA decreased. matrix metalloproteinase-12 (MMP-12) and c...
Cell Transplantation, 2000
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.
American Journal of Respiratory Cell and Molecular Biology, 2012
Surfactant protein-D (Sftpd) is a pulmonary collectin important in down-regulating macrophage inflammatory responses. In these experiments, we analyzed the effects of chronic macrophage inflammation attributable to loss of Sftpd on the persistence of ozoneinduced injury, macrophage activation, and altered functioning in the lung. Wild-type (Sftpd 1/1) and Sftpd 2/2 mice (aged 8 wk) were exposed to air or ozone (0.8 parts per million, 3 h). Bronchoalveolar lavage (BAL) fluid and tissue were collected 72 hours later. In Sftpd 2/2 mice, but not Sftpd 1/1 mice, increased BAL protein and nitrogen oxides were observed after ozone inhalation, indicating prolonged lung injury and oxidative stress. Increased numbers of macrophages were also present in BAL fluid and in histologic sections from Sftpd 2/2 mice. These cells were enlarged and foamy, suggesting that they were activated. This conclusion was supported by findings of increased BAL chemotactic activity, and increased expression of inducible nitric oxide synthase in lung macrophages. In both Sftpd 1/1 and Sftpd 2/2 mice, inhalation of ozone was associated with functional alterations in the lung. Although these alterations were limited to central airway mechanics in Sftpd 1/1 mice, both central airway and parenchymal mechanics were modified by ozone exposure in Sftpd 2/2 mice. The most notable changes were evident in resistance and elastance spectra and baseline lung function, and in lung responsiveness to changes in positive endexpiratory pressure. These data demonstrate that a loss of Sftpd is associated with prolonged lung injury, oxidative stress, and macrophage accumulation and activation in response to ozone, and with more extensive functional changes consistent with the loss of parenchymal integrity.