Role of the Nrf2/HO-1 axis in bronchopulmonary dysplasia and hyperoxic lung injuries

Amata, Emanuele; Pittalà, Valeria; Marrazzo, Agostino; Parenti, Carmela; Prezzavento, Orazio; Arena, Elena; Nabavi, Seyed Mohammad; Salerno, Loredana

doi:10.1042/cs20170157

Cited by 60 publications

(35 citation statements)

References 98 publications

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“…HO‐1 expression is enhanced by transcription factors, Nrf2, and is suppressed by transcriptional repressor, Bach1 . The present study revealed that LIR induced Nrf2 upregulation but Bach1 downregulation.…”

Section: Discussionsupporting

confidence: 51%

Protective effects of HO‐1 pathway on lung injury subsequent to limb ischemia reperfusion

Liu

et al. 2019

The Kaohsiung J of Med Scie

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Limb ischemia reperfusion (LIR) can activate endogenous cytoprotective mechanisms by generating specific proteins against reperfusion injury in remote organs. The present study investigated the roles of heme oxygenase‐1 (HO‐1) pathway and the molecular mechanisms underlying the regulation of this pathway on lung injury following LIR. LIR was induced by ischemia for 4 hours followed by reperfusion for 6 hours (LIR 6 hours) or 16 hours (LIR 16 hours) in male Sprague‐Dawley rats. HO‐1 inducer cobalt protoporphyrin (Copp) or HO‐1 inhibitor zinc protoporphyrin (Znpp) was intravenously injected 24 hours before ischemia. The animals were randomly divided into nine groups, including normal control, LIR 6 hours, LIR 16 hours, Copp, Copp + LIR 6 hours, Copp + LIR 16 hours, and Znpp, Znpp+ LIR 6 hours, and Znpp + LIR 16 hours groups (each group included four samples). Lung injury was examined through histopathology. Quantitative real‐time PCR, immunohistochemistry and Western blot were applied to detect the mRNA and protein levels of HO‐1, Nrf2, and Bach1. Our study showed that LIR induced Nrf2 upregulation but Bach1 downregulation to promote HO‐1 expression in lung tissues. Activation of HO‐1 pathway by Copp potentially enhanced Nrf2 expression but inhibition of the pathway by Znpp promoted Bach1 expression. Inducer of HO‐1 pathway, Copp injection improved the lung injury. Nevertheless, Znpp injection aggravated the lung injury following LIR. Our findings suggested that activated HO‐1 pathway might exert protective effects on the lung injury following LIR.

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Section: Discussionsupporting

confidence: 51%

Protective effects of HO‐1 pathway on lung injury subsequent to limb ischemia reperfusion

Liu

et al. 2019

The Kaohsiung J of Med Scie

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“…Moreover, a higher percentage of PBMΦ-IL10 upregulated HO-1 after EL challenge, suggesting a CD163 driven signaling to anti-inflammatory polarisation in adults, which is diminished in newborns. CD163 dependent HO-1 regulation could be a target for therapeutic strategies, since HO-1 reduces oxidative stress, which is one of the main triggers for bronchopulmonary disease (BPD) 41 .…”

Section: Discussionmentioning

confidence: 99%

Impaired functional capacity of polarised neonatal macrophages

Dreschers

Ohl

Schulte

et al. 2020

Sci Rep

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neonatal sepsis is accompanied by impaired apoptotic depletion of monocytes and macrophages (MΦ), aberrant cytokine production, impaired cell metabolism, and sustained inflammation. Macrophage-colony stimulating factor (M-CSF) triggers the differentiation from monocytes into MΦ (MΦ-0). Interleukin-10 (IL10) and Interferon-gamma (IFNy) further differentiate MΦ subpopulations, the anti-inflammatory MΦ-IL10 and the pro-inflammatory MΦ-ifny subtype. We previously have shown significant differences between adult (PBMΦ) and cord blood (CBMΦ) in the metabolism of all subtypes. To test the hypothesis whether the competence to differentiate monocytes into MΦ-0 and to polarise into MΦ-ifny and MΦ-IL10 was diminished in CBMΦ as compared to PBMΦ, we polarised monocytes by cultivation with M-CSF for 72 h, followed by stimulation with IFNy or IL10, for 48 h. After flow cytometry based immunotyping, we tested four functions: Phagocytosis of GFP-E. coli, uptake of erythrocytes, t-cell proliferation, induction of regulatory t-cells as well as phosphorylation analysis of AKT and STAT1/STAT3. Phosphorylation of STAT-1 and STAT-3, obligatory to differentiate into MΦifnγ, MΦ-0 and MΦ-IL10, was found to be aberrant in CBMΦ. Whereas infected MΦ-0 showed identical phagocytic indices and intracellular degradation, TLR4-expression, NFkB up-regulation, IL10-, IL6-, and tnfα production of CBMΦ-0 were reduced. In addition, the capacity to bind aged erythrocytes and the consecutive IL10 production was lower in CBMΦ-IL10. Polarised PBMΦ-IFNy and PBMΦ-IL10 expressed higher levels of co-stimulatory receptors (CD80, CD86), had a higher capacity to stimulate T-cells and induced higher amounts of regulatory t-cells (all p < 0.05 vs. corresponding CBMΦ). Hypoxia-induciblefactor-1α (HIF-1α) was stronger expressed in CBMΦ-IFNy and upregulated in infected CBMΦ-0, whereas heme-oxygenase 1 (HO-1) expression was similar to adult PBMΦ. neonatal MΦ-0, MΦ-ifny and MΦ-IL10 polarisation is impaired with respect to phenotype and functions tested which may contribute to sustained inflammation in neonatal sepsis. Macrophages (MФ) have an extremely broad spectrum of functions in both the induction and resolution of inflammation due to their heterogeneity and plasticity. They are involved in a range of processes, including tissue homeostasis, clearance or pulmonary surfactant as well as inflammation. Deriving from monocytes, they develop into different populations of circulating inflammatory or resident macrophages (MФ) recruited to various tissues. These processes occur in response to inflammation or infection but also in homeostasis in order to replace apoptotic (MФ) 1. The migration of monocytes to the site of infection is crucial 2. After infiltrating the infected tissue they polarise into functional distinguishable MФ. The term "polarisation" instead of differentiation became accepted, since this process depends on the local cytokine milieu and specific microenvironmental cues, and therefore is reversible 3,4. By analogy to T helper cell (Th) nomenclature, MФ ...

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“…Among these enzymes, HO‐1 is an important enzyme involved in a variety of pathologies . The Nrf2/HO‐1 signalling is one of the most promising therapeutic targets for several diseases, including renal I/R injury . Our results showed that AR induced the activation of Nrf2/HO‐1 pathway in H/R‐stimulated HK‐2 cells, and knockdown of Nrf2 reversed the renal‐protective effects of AR on HK‐2 cells.…”

Section: Discussionmentioning

confidence: 99%

Clemaichinenoside protects renal tubular epithelial cells from hypoxia/reoxygenation injury in vitro through activating the Nrf2/HO‐1 signalling pathway

Feng

Kong

Xie

et al. 2019

Clin Exp Pharma Physio

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Renal ischaemia/reperfusion (I/R) is a major cause of acute renal failure with increased morbidity, mortality, and prolonged hospitalizations. Clematichinenoside (AR), a triterpenoid saponin isolated from the roots of Clematis chinensis, was reported to possess a protective effect against I/R injury. However, the effect of AR on renal I/R injury has not been evaluated. This study aims to examine the effect of AR on an in vitro I/R model in human proximal tubular epithelial cells HK‐2. HK‐2 cells were subjected to hypoxia/reoxygenation (H/R) stimulation to mimic I/R in vitro. The results showed that AR improved cell viability of H/R‐stimulated HK‐2 cells. AR pretreatment resulted in decreased production of reactive oxygen species (ROS) and malondialdehyde (MDA), as well as increased in superoxide dismutase (SOD) activity in H/R‐stimulated HK‐2 cells. In addition, AR also presented an anti‐inflammatory activity, as evidenced by decreased secretion of pro‐inflammatory cytokines including IL‐6, IL‐1β, and TNF‐α. Moreover, apoptotic rate was markedly decreased in HK‐2 cells pretreated with AR. The bax expression was decreased, while bcl‐2 expression was increased by AR pretreatment. Furthermore, AR enhanced the H/R‐stimulated activation of the Nrf2/HO‐1 signalling pathway in HK‐2 cells. In conclusion, these findings indicated that AR protected HK‐2 cells from H/R‐induced cell injury via regulating the Nrf2/HO‐1 signalling pathway.

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Role of the Nrf2/HO-1 axis in bronchopulmonary dysplasia and hyperoxic lung injuries

Cited by 60 publications

References 98 publications

Protective effects of HO‐1 pathway on lung injury subsequent to limb ischemia reperfusion

Protective effects of HO‐1 pathway on lung injury subsequent to limb ischemia reperfusion

Impaired functional capacity of polarised neonatal macrophages

Clemaichinenoside protects renal tubular epithelial cells from hypoxia/reoxygenation injury in vitro through activating the Nrf2/HO‐1 signalling pathway

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