Role of 15-DeoxyΔ<sup>12,14</sup> Prostaglandin J<sub>2</sub> and Nrf2 Pathways in Protection against Acute Lung Injury

Mochizuki, M.; Ishii, Yukio; Itoh, Ken; Iizuka, Takashi; Morishima, Yuko; Kimura, Tōru; Kiwamoto, Takumi; Matsuno, Yosuke; Hegab, Ahamed E.; Nomura, Akihiro; Sakamoto, Tohru; Uchida, Koji; Yamamoto, Masayuki; Sekizawa, Kiyohisa

doi:10.1164/rccm.200406-755oc

Cited by 114 publications

(92 citation statements)

References 39 publications

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“…However, after treatment with 15d-PGJ2, the expression of NF-κBp65 and IL-8 decreased, suggesting that 15d-PGJ2 can reduce inflammation in HBE cells with increased levels of Nrf2. Moreover, in previous studies, it has been speculated that 15d-PGJ2 reduces inflammation by increasing the levels of Nrf2 Mochizuki et al, 2005). In this study, in keeping with this speculation, we demonstrated that pretreatment with Nrf2 siRNA and CSE can also stimulate the inflammatory response, and the levels of NF-κBp65 and IL-8 did not decrease even following treatment with 15d-PGJ2.…”

Section: Discussionsupporting

confidence: 89%

15-Deoxy-prostaglandin J2 anti-inflammation in a rat model of chronic obstructive pulmonary disease and human bronchial epithelial cells via Nrf2 activation

Luo

Wang

et al. 2015

Genet. Mol. Res.

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ABSTRACT. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates antioxidant and anti-inflammatory genes, and it plays a crucial role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Moreover, 15-deoxy-delta12,14-prostaglandin J2 (15d-PGJ2) plays a protective role against oxidative stress and inflammation both in vivo and in vitro. In a previous study, we found that 15d-PGJ2 increased the expression of Nrf2 in a COPD rat model. This study aims to elucidate the role of 15d-PGJ2 in COPD pathogenesis and the relationship between Nrf2 and human bronchial epithelial (HBE) cells. Normal HBE (HBE) cells were cultured. Following cigarette smoke extract (CSE) stimulation, pre-incubation with or without small interfering RNA (siRNA) Nrf2, and stimulation with or without 15d-PGJ2, the expression levels of Nrf2, NF-κBp65, and IL-8 were detected by reverse transcriptionpolymerase chain reaction and western blot, respectively. The expression of NF-κBp65 and IL-8 in CSE-stimulated normal HBE cells was inhibited by 15d-PGJ2 at both the mRNA level and the protein level. Moreover, the expression of Nrf2 in normal HBE cells was improved by 15d-PGJ2 at both the mRNA level and the protein level. However, the inhibitory or improving effects of 15d-PGJ2 were disengaged by siRNA Nrf2 at both the mRNA level and the protein level. 15d-PGJ2 possesses anti-inflammatory properties in the pathogenesis of COPD, and HBE cells stimulated by CSE via Nrf2 activation.

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Section: Discussionsupporting

confidence: 89%

15-Deoxy-prostaglandin J2 anti-inflammation in a rat model of chronic obstructive pulmonary disease and human bronchial epithelial cells via Nrf2 activation

Luo

Wang

et al. 2015

Genet. Mol. Res.

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“…Nrf2 signaling plays a critical protective role in pulmonary diseases such as carrageenin-induced acute lung injury (31), COPD (30), elastase-induced lung emphysema (17), and asthma (42). In several models, Nrf2-deficient mice exhibited more severe outcomes than their wild-type counterparts (17,31,42). Nrf2 is also an important determinant of susceptibility to hyperoxic lung injury (11).…”

Section: L651mentioning

confidence: 99%

Hydrogen gas reduces hyperoxic lung injury via the Nrf2 pathway in vivo

Kawamura

Wakabayashi

Shigemura

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

146

113

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lung injury is a major concern in critically ill patients who receive high concentrations of oxygen to treat lung diseases. Successful abrogation of hyperoxic lung injury would have a huge impact on respiratory and critical care medicine. Hydrogen can be administered as a therapeutic medical gas. We recently demonstrated that inhaled hydrogen reduced transplant-induced lung injury and induced heme oxygenase (HO)-1. To determine whether hydrogen could reduce hyperoxic lung injury and investigate the underlying mechanisms, we randomly assigned rats to four experimental groups and administered the following gas mixtures for 60 h: 98% oxygen (hyperoxia), 2% nitrogen; 98% oxygen (hyperoxia), 2% hydrogen; 98% balanced air (normoxia), 2% nitrogen; and 98% balanced air (normoxia), 2% hydrogen. We examined lung function by blood gas analysis, extent of lung injury, and expression of HO-1. We also investigated the role of NF-E2-related factor (Nrf) 2, which regulates HO-1 expression, by examining the expression of Nrf2-dependent genes and the ability of hydrogen to reduce hyperoxic lung injury in Nrf2-deficient mice. Hydrogen treatment during exposure to hyperoxia significantly improved blood oxygenation, reduced inflammatory events, and induced HO-1 expression. Hydrogen did not mitigate hyperoxic lung injury or induce HO-1 in Nrf2-deficient mice. These findings indicate that hydrogen gas can ameliorate hyperoxic lung injury through induction of Nrf2-dependent genes, such as HO-1. The findings suggest a potentially novel and applicable solution to hyperoxic lung injury and provide new insight into the molecular mechanisms and actions of hydrogen.

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“…The dose of PGD 2 was chosen based on the published dose of 15-deoxy-⌬ 12,14 -PGJ 2 (15d-PGJ 2 ) administered i.t. (39). The neck wound was closed with sterile sutures under aseptic conditions.…”

Section: Lps and Pgd 2 Administrationmentioning

confidence: 99%

Induction and Function of Lipocalin Prostaglandin D Synthase in Host Immunity

Joo

Kwon

Sadikot

et al. 2007

The Journal of Immunology

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Although mainly expressed in neuronal cells, lipocalin-type PGD synthase (L-PGDS) is detected in the macrophages infiltrated to atherosclerotic plaques. However, the regulation and significance of L-PGDS expression in macrophages are unknown. Here, we found that treatment of macrophages with bacterial endotoxin (LPS) or Pseudomonas induced L-PGDS expression. Epigenetic suppression of L-PGDS expression in macrophages blunted a majority of PGD2 produced after LPS treatment. Chromatin immunoprecipitation assays show that L-PGDS induction was regulated positively by AP-1, but negatively by p53. L-PGDS expression was detected in whole lung and alveolar macrophages treated with LPS or Pseudomonas. L-PGDS overexpressing transgenic mice improved clearance of Pseudomonas from the lung compared with nontransgenic mice. Similarly, intratracheal instillation of PGD2 enhanced removal of Pseudomonas from the lung in mice. In contrast, L-PGDS knockout mice were impaired in their ability to remove Pseudomonas from the lung. Together, our results identify induction of L-PGDS expression by inflammatory stimuli or bacterial infection, the regulatory mechanism of L-PGDS induction, and the protective role of L-PGDS expression in host immune response. Our study suggests a potential therapeutic usage of L-PGDS or PGD2 against Pseudomonas pneumonia.

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Role of 15-DeoxyΔ^12,14 Prostaglandin J₂ and Nrf2 Pathways in Protection against Acute Lung Injury

Abstract: These results demonstrated in vivo that 15d-PGJ2 plays a protective role against ALI by exploiting the Nrf2-mediated transcriptional pathway.

Cited by 114 publications

References 39 publications

15-Deoxy-prostaglandin J2 anti-inflammation in a rat model of chronic obstructive pulmonary disease and human bronchial epithelial cells via Nrf2 activation

15-Deoxy-prostaglandin J2 anti-inflammation in a rat model of chronic obstructive pulmonary disease and human bronchial epithelial cells via Nrf2 activation

Hydrogen gas reduces hyperoxic lung injury via the Nrf2 pathway in vivo

Induction and Function of Lipocalin Prostaglandin D Synthase in Host Immunity

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Role of 15-DeoxyΔ12,14 Prostaglandin J2 and Nrf2 Pathways in Protection against Acute Lung Injury

Abstract: These results demonstrated in vivo that 15d-PGJ2 plays a protective role against ALI by exploiting the Nrf2-mediated transcriptional pathway.

Cited by 114 publications

References 39 publications

15-Deoxy-prostaglandin J2 anti-inflammation in a rat model of chronic obstructive pulmonary disease and human bronchial epithelial cells via Nrf2 activation

15-Deoxy-prostaglandin J2 anti-inflammation in a rat model of chronic obstructive pulmonary disease and human bronchial epithelial cells via Nrf2 activation

Hydrogen gas reduces hyperoxic lung injury via the Nrf2 pathway in vivo

Induction and Function of Lipocalin Prostaglandin D Synthase in Host Immunity

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Role of 15-DeoxyΔ^12,14 Prostaglandin J₂ and Nrf2 Pathways in Protection against Acute Lung Injury