α-PHENYL-<i>N</i>-tert-BUTYLNITRONE ATTENUATES HYPEROXIA-INDUCED LUNG INJURY BY DOWN-MODULATING INFLAMMATION IN NEONATAL RATS

Chang, Yun Sil; Kim, Yu Jin; Yoo, Hye Soo; Sung, Dong Kyung; Kim, Soo Yoon; Kang, Saem; Park, Won Soon

doi:10.1080/01902140802573007

Cited by 15 publications

(16 citation statements)

References 49 publications

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“…The rationale for the prevention and treatment of BPD is unclear [4,40]. Recently, preclinical studies have been performed to assess MSC injection for the treatment of hyperoxia-induced animal models of BPD [41,42,43,44,45]. The therapeutic effects of UCB-MSCs in BPD have been confirmed in ongoing clinical trials worldwide [15,16,46].…”

Section: Discussionmentioning

confidence: 99%

“…MSCs (1 × 10 5 , p6) were washed with saline after washing twice with pre-warmed MEM-α without phenol red. After saline washing, MSC suspensions were prepared in saline and injected intratracheally at P5, as described previously [42]. The survival rates and health conditions of all rat pups were monitored daily.…”

Section: Methodsmentioning

confidence: 99%

“…Fixed lung tissues were embedded in paraffin, sectioned, and then stained with hematoxylin and eosin (H&E). MLI was used to measure the level of alveolarization by dividing the total length of lines drawn across the lung section by the number of intercepts encountered, as reported previously [42]. Randomly selected sections (>3) per rat and 100 fields per section were assessed.…”

Section: Methodsmentioning

confidence: 99%

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Decorin Secreted by Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Induces Macrophage Polarization via CD44 to Repair Hyperoxic Lung Injury

Kwon

Kim

Bae

et al. 2019

IJMS

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Bronchopulmonary dysplasia (BPD), caused by hyperoxia in newborns and infants, results in lung damage and abnormal pulmonary function. However, the current treatments for BPD are steroidal and pharmacological therapies, which cause neurodevelopmental impairment. Treatment with umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) is an efficient alternative approach. To prevent pulmonary inflammation in BPD, this study investigated the hypothesis that a key regulator was secreted by MSCs to polarize inflammatory macrophages into anti-inflammatory macrophages at inflammation sites. Lipopolysaccharide-induced macrophages co-cultured with MSCs secreted low levels of the inflammatory cytokines, IL-8 and IL-6, but high levels of the anti-inflammatory cytokine, IL-10. Silencing decorin in MSCs suppressed the expression of CD44, which mediates anti-inflammatory activity in macrophages. The effects of MSCs were examined in a rat model of hyperoxic lung damage. Macrophage polarization differed depending on the levels of decorin secreted by MSCs. Moreover, intratracheal injection of decorin-silenced MSCs or MSCs secreting low levels of decorin confirmed impaired alveolarization of damaged lung tissues by down-regulation of decorin. In tissues, a decrease in the anti-inflammatory macrophage marker, CD163, was observed via CD44. Thus, we identified decorin as a key paracrine factor, inducing macrophage polarization via CD44, a master immunoregulator in mesenchymal stem cells.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Decorin Secreted by Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Induces Macrophage Polarization via CD44 to Repair Hyperoxic Lung Injury

Kwon

Kim

Bae

et al. 2019

IJMS

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“…NADPH oxidase is responsible for superoxide anion production (O 2 - ), which generates other ROS such as hydrogen peroxide, hydroxyl radical and hypochlorous acid 20. As the cytoplasmic subunits p47 phox , p67 phox , p40 phox and Rac translocate to membrane-bound cytochrome upon activation of this multicomponent enzyme complex NADPH oxidase,37 membrane translocation of the p67 phox can be served as an in vivo indicator of NADPH oxidase activation as shown in our previous study 38…”

Section: Discussionmentioning

confidence: 89%

Granulocyte Colony Stimulating Factor Attenuates Hyperoxia-Induced Lung Injury by Down-Modulating Inflammatory Responses in Neonatal Rats

et al. 2011

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PurposeGranulocyte colony stimulating factor (G-CSF) has been known to increase neutrophil production and have anti-inflammatory properties, but the effect of G-CSF on pulmonary system is in controversy. We investigated whether G-CSF treatment could attenuate hyperoxia-induced lung injury, and whether this protective effect is mediated by the down-modulation of inflammatory responses in a neonatal rat model.Materials and MethodsNewborn Sprague-Dawley rats (Orient Co., Seoul, Korea) were subjected to 14 days of hyperoxia (90% oxygen) beginning within 10 h after birth. G-CSF (20 µg/kg) was administered intraperitoneally on the fourth, fifth, and sixth postnatal days.ResultsThis treatment significantly improved hyperoxia-induced reduction in body weight gain and lung pathology such as increased mean linear intercept, mean alveolar volume, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling positive cells. Hyperoxia-induced activation of nicotinamide adenine dinucleotide phosphate oxidase, which is responsible for superoxide anion production, as evidenced by upregulation and membrane translocation of p67phox was significantly attenuated after G-CSF treatment, as were inflammatory responses such as increased myeloperoxidase activity and mRNA expression of transforming growth factor-β. However, the attenuation of other proinflammatory cytokines such as tumor necrosis factor-α and interleukin-6 was not significant.ConclusionIn sum, G-CSF treatment significantly attenuated hyperoxia-induced lung injury by down-modulating the inflammatory responses in neonatal rats.

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“…Under deep pentobarbital anesthesia (50 mg/kg, intraperitoneal), a midline incision was made through the sternum and abdomen, and whole-lung tissue was obtained. Lung and body weights were recorded at the time of sacrifice (12)(13)(14).…”

Section: Animalmentioning

confidence: 99%

Upregulation of Shh and Ptc1 in hyperoxia‑induced acute lung injury in neonatal rats

et al. 2012

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Abstract. The aim of the present study was to observe the expression of sonic hedgehog (Shh) and Ptc signaling molecules in the lungs of newborn rats exposed to prolonged hyperoxia, and to explore the role of the SHH signaling pathway in hyperoxia-induced lung injury. Newborn Sprague-Dawley rat pups were placed in chambers containing room air or oxygen above 95% for 14 days following birth. The rats were sacrificed after 3, 7 or 14 days and their lungs were removed. Sections were fixed and subjected to hematoxylin and eosin (H&E) staining. Shh and Ptc1 were quantitated by immunohistochemistry. The total RNA and protein were also extracted from lung tissue; realtime PCR (RT-PCR) and western blot analysis were utilized to assess the mRNA and protein expression of Shh and Ptc1. H&E staining demonstrated significant histomorphological changes in the hyperoxia-exposed lungs at 3, 7 and 14 days of age. The results of the immunohistochemistry, RT-PCR and western blot analysis demonstrated that the expression of Shh was significantly higher in the hyperoxia-exposed lungs at 3, 7 and 14 days, while Ptc1 was significantly elevated at 7 and 14 days. Exposure of the neonatal rat lung to prolonged hyperoxia resulted in acute lung injury and histomorphological changes. Shh and Ptc1 were upregulated in a time-dependent manner in the course of hyperoxia-induced lung injury. The SHH signal pathway may be involved in the pathogenesis of hyperoxia-induced lung injury. This is the first evidence that in vivo hyperoxia induces activation of the SHH signal transduction pathway in newborn lung. IntroductionAs an important therapeutic intervention, high supplemental oxygen concentrations are often administered to neonates with respiratory diseases, including hyaline membrane disease, persistent pulmonary hypertension and others. High concentrations of oxygen are known to cause acute lung injury (ALI) and bronchopulmonary dysplasia (BPD). Prolonged exposure to hyperoxia can also result in severe epithelial and endothelial damage (1). Oxidative stress plays a role in the pathogenesis of ALI. Despite major advances in our understanding of the mechanisms leading to ALI, this condition remains a problem.Lung alveolar interstitial fibroblasts and their communication with adjacent epithelial cells are important in lung development and injury/repair (2). The molecular mechanisms responsible for alterations of ALI have been extensively studied and a number of signaling pathways, including the JAK/STAT (3,4), PI3 kinase/Akt (5,6) and mitogen-activated protein kinase pathways (7-9), have been demonstrated to be important under a number of conditions.The SHH signaling pathway consists chiefly of Shh, Ptc1, Smo, Gli1, Gli2 and Gli3 molecules. It has long been recognized that this pathway is essential for embryonic development, and has been revealed to regulate cell migration, proliferation and apoptosis (10). This cascade is crucial for the patterning of early lung morphogenesis (11). However, its role in acute lung injury/repair remains to be dete...

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α-PHENYL-N-tert-BUTYLNITRONE ATTENUATES HYPEROXIA-INDUCED LUNG INJURY BY DOWN-MODULATING INFLAMMATION IN NEONATAL RATS

Cited by 15 publications

References 49 publications

Decorin Secreted by Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Induces Macrophage Polarization via CD44 to Repair Hyperoxic Lung Injury

Decorin Secreted by Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Induces Macrophage Polarization via CD44 to Repair Hyperoxic Lung Injury

Granulocyte Colony Stimulating Factor Attenuates Hyperoxia-Induced Lung Injury by Down-Modulating Inflammatory Responses in Neonatal Rats

Upregulation of Shh and Ptc1 in hyperoxia‑induced acute lung injury in neonatal rats

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