TLR4/TRAF6/NOX2 signaling pathway is involved in ventilation-induced lung injury via endoplasmic reticulum stress in murine model

Zeng, Qi; Liu, Ye; Ling, Maoyao; Ma, Riliang; Li, Junda; Chen, Haishao; Pan, Linghui

doi:10.1016/j.intimp.2021.107774

Cited by 16 publications

(9 citation statements)

References 27 publications

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“…Secondly, we did not set up the group that MV with low tidal volume (LTV). Although in our previous studies (8,49), no histological differences and inflammation were noted between non-ventilated mice and LTV mice. But we still cannot exclude MV with LTV affects IP3R/Ca2+ dysregulation, then to make sure that these adverse reactions are completely due to overstretch.…”

Section: Limitationscontrasting

confidence: 54%

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Inhibition of IP3R/Ca2+ Dysregulation Protects Mice From Ventilator-Induced Lung Injury via Endoplasmic Reticulum and Mitochondrial Pathways

et al. 2021

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RationaleDisruption of intracellular calcium (Ca2+) homeostasis is implicated in inflammatory responses. Here we investigated endoplasmic reticulum (ER) Ca2+ efflux through the Inositol 1,4,5-trisphosphate receptor (IP3R) as a potential mechanism of inflammatory pathophysiology in a ventilator-induced lung injury (VILI) mouse model.MethodsC57BL/6 mice were exposed to mechanical ventilation using high tidal volume (HTV). Mice were pretreated with the IP3R agonist carbachol, IP3R inhibitor 2-aminoethoxydiphenyl borate (2-APB) or the Ca2+ chelator BAPTA-AM. Lung tissues and bronchoalveolar lavage fluid (BALF) were collected to measure Ca2+ concentrations, inflammatory responses and mRNA/protein expression associated with ER stress, NLRP3 inflammasome activation and inflammation. Analyses were conducted in concert with cultured murine lung cell lines.ResultsLungs from mice subjected to HTV displayed upregulated IP3R expression in ER and mitochondrial-associated-membranes (MAMs), with enhanced formation of MAMs. Moreover, HTV disrupted Ca2+ homeostasis, with increased flux from the ER to the cytoplasm and mitochondria. Administration of carbachol aggravated HTV-induced lung injury and inflammation while pretreatment with 2-APB or BAPTA-AM largely prevented these effects. HTV activated the IRE1α and PERK arms of the ER stress signaling response and induced mitochondrial dysfunction-NLRP3 inflammasome activation in an IP3R-dependent manner. Similarly, disruption of IP3R/Ca2+ in MLE12 and RAW264.7 cells using carbachol lead to inflammatory responses, and stimulated ER stress and mitochondrial dysfunction.ConclusionIncrease in IP3R-mediated Ca2+ release is involved in the inflammatory pathophysiology of VILI via ER stress and mitochondrial dysfunction. Antagonizing IP3R/Ca2+ and/or maintaining Ca2+ homeostasis in lung tissue represents a prospective treatment approach for VILI.

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Section: Limitationscontrasting

confidence: 54%

“…However, the mechanism of activation of IP3R in VILI remains unclear. In our previous research (49,50), Toll-like Receptor 4 (TLR4), which is a member of the TLR family located on the membrane of cells. TLR4 activates when alveolar cells are overstretched.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of IP3R/Ca2+ Dysregulation Protects Mice From Ventilator-Induced Lung Injury via Endoplasmic Reticulum and Mitochondrial Pathways

et al. 2021

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“… 26 Moreover, NOX2 expression was shown elevated in a mouse model following injurious mechanical ventilation; it was proposed that the Toll-like receptor 4 (TLR4)/Tumor necrosis factor receptor–associated factor (TRAF)/NOX2 pathway was activated after ventilation with high tidal volumes, resulting in excessive ROS production, endoplasmic reticulum stress, and inflammation via the nuclear factor kappa B (NF-κB) pathway. 27 On the other hand, it has been demonstrated that administration of NOX2 inhibitors or substances that prevent NOX2 activation prior to mechanical ventilation had a protective effect on mouse lung injury. 27 , 28 The protective role of NRF2 has been suggested in many in vitro and in vivo VILI models.…”

Section: Experimental Lung Injury - Acute Lung Inflammatory Modelsmentioning

confidence: 99%

“… 27 On the other hand, it has been demonstrated that administration of NOX2 inhibitors or substances that prevent NOX2 activation prior to mechanical ventilation had a protective effect on mouse lung injury. 27 , 28 The protective role of NRF2 has been suggested in many in vitro and in vivo VILI models. Specifically, the first study to demonstrate the protective role of NRF2 in VILI was in NRF2-deficient (NRF2 −/− ) mice.…”

Section: Experimental Lung Injury - Acute Lung Inflammatory Modelsmentioning

confidence: 99%

Mechanistic Understanding of Lung Inflammation: Recent Advances and Emerging Techniques

Keskinidou¹,

Vassiliou²,

Dimopoulou³

et al. 2022

JIR

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Acute respiratory distress syndrome (ARDS) is a life-threatening lung injury characterized by an acute inflammatory response in the lung parenchyma. Hence, it is considered as the most appropriate clinical syndrome to study pathogenic mechanisms of lung inflammation. ARDS is associated with increased morbidity and mortality in the intensive care unit (ICU), while no effective pharmacological treatment exists. It is very important therefore to fully characterize the underlying pathobiology and the related mechanisms, in order to develop novel therapeutic approaches. In vivo and in vitro models are important pre-clinical tools in biological and medical research in the mechanistic and pathological understanding of the majority of diseases. In this review, we will present data from selected experimental models of lung injury/acute lung inflammation, which have been based on clinical disorders that can lead to the development of ARDS and related inflammatory lung processes in humans, including ventilation-induced lung injury (VILI), sepsis, ischemia/reperfusion, smoke, acid aspiration, radiation, transfusion-related acute lung injury (TRALI), influenza, Streptococcus ( S .) pneumoniae and coronaviruses infection. Data from the corresponding clinical conditions will also be presented. The mechanisms related to lung inflammation that will be covered are oxidative stress, neutrophil extracellular traps, mitogen-activated protein kinase (MAPK) pathways, surfactant, and water and ion channels. Finally, we will present a brief overview of emerging techniques in the field of omics research that have been applied to ARDS research, encompassing genomics, transcriptomics, proteomics, and metabolomics, which may recognize factors to help stratify ICU patients at risk, predict their prognosis, and possibly, serve as more specific therapeutic targets.

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“…However, the overexpression of HSP60 during aging could promote ER stress and the disruption of mitochondrial proteostasis [ 16 , 17 ], and also serve as an inflammatory mediator through the Toll-like receptor 4 (TLR4)-myeloid differentiation factor 88 (Myd88)-nuclear factor-kappa B (NF-kB) signaling pathway [ 18 ]. Specifically, upon TLR4 activation, a complex of tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and NADPH oxidase 2 (NOX2) is formed to promote the production of ROS, thereby eliciting the activation in inositol-requiring enzyme 1 (IRE1) of the UPR [ 19 , 20 ]. In this regard, an antiaging-associated protein, Klotho, has been proposed as an intermediate of these aging-related cellular processes via the downregulation of the TLR4/NF-κB pathway [ 21 ] and attenuation of ER stress [ 22 ] or oxidative stress [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

Resistance Training Modulates Reticulum Endoplasmic Stress, Independent of Oxidative and Inflammatory Responses, in Elderly People

et al. 2022

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Aging is related to changes in the redox status, low-grade inflammation, and decreased endoplasmic reticulum unfolded protein response (UPR). Exercise has been shown to regulate the inflammatory response, balance redox homeostasis, and ameliorate the UPR. This work aimed to investigate the effects of resistance training on changes in the UPR, oxidative status, and inflammatory responses in peripheral blood mononuclear cells of elderly subjects. Thirty elderly subjects volunteered to participate in an 8-week resistance training program, and 11 youth subjects were included for basal assessments. Klotho, heat shock protein 60 (HSP60), oxidative marker expression (catalase, glutathione, lipid peroxidation, nuclear factor erythroid 2-related factor 2, protein carbonyls, reactive oxygen species, and superoxide dismutase 1 and 2), the IRE1 arm of UPR, and TLR4/TRAF6/pIRAK1 pathway activation were evaluated before and following training. No changes in the HSP60 and Klotho protein content, oxidative status markers, and TLR4/TRAF6/pIRAK1 pathway activation were found with exercise. However, an attenuation of the reduced pIRE1/IRE1 ratio was observed following training. Systems biology analysis showed that a low number of proteins (RPS27A, SYVN1, HSPA5, and XBP1) are associated with IRE1, where XBP1 and RPS27A are essential nodes according to the centrality analysis. Additionally, a gene ontology analysis confirms that endoplasmic reticulum stress is a key mechanism modulated by IRE1. These findings might partially support the modulatory effect of resistance training on the endoplasmic reticulum in the elderly.

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TLR4/TRAF6/NOX2 signaling pathway is involved in ventilation-induced lung injury via endoplasmic reticulum stress in murine model

Cited by 16 publications

References 27 publications

Inhibition of IP3R/Ca2+ Dysregulation Protects Mice From Ventilator-Induced Lung Injury via Endoplasmic Reticulum and Mitochondrial Pathways

Inhibition of IP3R/Ca2+ Dysregulation Protects Mice From Ventilator-Induced Lung Injury via Endoplasmic Reticulum and Mitochondrial Pathways

Mechanistic Understanding of Lung Inflammation: Recent Advances and Emerging Techniques

Resistance Training Modulates Reticulum Endoplasmic Stress, Independent of Oxidative and Inflammatory Responses, in Elderly People

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