Mechanisms of TLR4-Mediated Autophagy and Nitroxidative Stress

Zhang, Kunli; Huang, Qiuyan; Deng, Shoulong; Yang, Yecheng; Li, Jianhao; Wang, Sutian

doi:10.3389/fcimb.2021.766590

Cited by 26 publications

(29 citation statements)

References 142 publications

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“…TLR4-mediated generation of oxidants and free radicals, especially ROS, (Ikram et al 2019;Park et al 2004;Sasaki et al 2008;Zhang et al 2021) represents a key event leading to oxidative stress and subsequent cell injury/apoptosis. Excessive ROS levels beget oxidative stress via several mechanisms, including inactivation of antioxidant defenses (Nrf2and Nrf-2-dependent factors HO-1, SOD2, and Catalase) (Bhattacharya 2015).…”

Section: Discussionmentioning

confidence: 99%

FGF1 alleviates LPS-induced acute lung injury via suppression of inflammation and oxidative stress

Dhlamini

Wang

Feng

et al. 2022

Mol Med

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Background Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), are devastating clinical disorders with high mortality, and for which more effective therapies are urgently needed. FGF1, the prototype member of the FGF family, is shown to exert protective effects against injurious stimuli in multiple disease models. Here we aimed to evaluate whether FGF1 pretreatment is protective against LPS-induced ALI and elucidate the potential underlying mechanisms. Methods For drug-treated groups, C57B/6 mice received a single i.p. injection of FGF1 (1 mg/kg) 1 h before the LPS challenge or not. To induce the ALI model, the mice were treated by intratracheal instillation of LPS (5 mg/kg). Then, histopathological changes in lung tissues were assessed by hematoxylin and eosin staining and transmission electron microscopy. ELISA and qPCR assays were used to detect pro-inflammatory cytokine levels in BALF and lung tissues, respectively. The total number of inflammatory cells (neutrophils and macrophages) in BALF were counted using the Wright-Giemsa method. The expressions of reactive oxygen species (ROS) and malondialdehyde (MDA) were measured using their respective kits. Western blot and immunostaining were used to evaluate the expressions of antioxidants (Nrf-2, HO-1, SOD2, GPX4, and Catalase), as well as the inflammatory and/or apoptosis-related factors (TLR4, NF-κB, and Cleaved- caspase 3). Results FGF1 pretreatment significantly ameliorated the LPS-induced histopathological changes, reduced lung wet/dry ratios, ROS and MDA levels, total BALF protein, inflammatory cell infiltration, proinflammatory cytokine levels, and significantly increased the expression of antioxidant proteins (Nrf-2, HO-1, Catalase, and SOD2). In addition, FGF1 pretreatment significantly reduced the expression of TLR4 and cleaved- caspase 3, inhibited NF-κB activation, and reduced LPS-induced cell apoptosis. Conclusions Altogether, our results suggest that FGF1 pretreatment is protective against LPS-induced ALI through mediating anti-inflammatory and antioxidant effects, which may be attributed to the downregulation of TLR4 expression and inhibition of NF-κB activation, as well as promotion of antioxidant defenses. Therefore, FGF1 administration may prove beneficial in preventative strategies for ALI/ARDS.

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Section: Discussionmentioning

confidence: 99%

FGF1 alleviates LPS-induced acute lung injury via suppression of inflammation and oxidative stress

Dhlamini

Wang

Feng

et al. 2022

Mol Med

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“…Our study is the first to reveal that activation of TLR4 and NFκB in lung tissues after SAH could be induced by the massive release of HMGB-1 from neuronal cells [ 23 ]. TLR4 has been demonstrated to trigger the activation of autophagy via a number of downstream signaling pathways, including TNF receptor-associated factor (TRAF)6, Toll/IL-1 receptor domain-containing adaptor interferon-B (TRIF), phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, and the MyD88/NFκB pathway [ 24 ]. A previous in vitro study on macrophages identified TLR4 as a major trigger for LPS-induced proinflammatory cytokine release and autophagic activation [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Dexmedetomidine attenuates subarachnoid hemorrhage-induced acute lung injury through regulating autophagy and TLR/NF-kappaB signaling pathway

Han

Lim

et al. 2022

Korean J Anesthesiol

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Background: Acute lung injury (ALI) is the most serious complication of subarachnoid hemorrhage (SAH). We investigated role of autophagy and inflammatory signaling pathways in lung damage and therapeutic effects of dexmedetomidine (DEX).Methods: Fifty male Wistar rats were randomly divided into five groups: sham, SAH, SAH+ DEX5, SAH+DEX25, and SAH+DEX50. SAH was induced using endovascular perforation technique. All rats received mechanical ventilation for 60 minutes. At 2 and 24 h of SAH induction, SAH+DEX groups were treated with 5, 25, and 50 µg/kg of dexmedetomidine, respectively.Histological ALI score and pulmonary edema were assessed after 48 hours. Lung expression of LC3B, ATG3, p62, TLR4, TLR9, and NFκB was assessed using western blotting and quantitative PCR. Blood levels of IL-6, IL-1β, IFN-γ, and TNFα were also assessed.Results: SAH induced ALI and pulmonary edema, which were attenuated in SAH+DEX5 (P<0.001 for both) and SAH+DEX25 groups (P=0.001 and P<0.001 for ALI and edema, respectively). Lung expressions of LC3B and ATG3 were upregulated in SAH group, which was attenuated in SAH+DEX5 and SAH+DEX25 groups. Lung expressions of TLR4, TLR9, and NFκB were increased in SAH group, which was attenuated in SAH+DEX5 group. Blood IL-6 level was increased in SAH group and attenuated in SAH+DEX5 and SAH+DEX25 groups. Blood IFN-γ level was lower in SAH group than in sham group, and it was increased in SAH+DEX25 group.Conclusions: Low-dose DEX treatment after SAH may protect against ALI by disrupting pathological brain-lung crosstalk and alleviating autophagy flux and TLR-dependent inflammatory pathways.

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“…Another crucial role of TOLLIP is the promotion of autophagy, which it facilitates by bridging ubiquitinated protein aggregates with LC3 and inhibiting the phosphorylation of vacuolar protein sorting 34 (VPS34), an important protein involved in autophagy [30]. Impaired autophagy and excessive ROS generation contribute to IPF progression.…”

Section: Discussionmentioning

confidence: 99%

Toll interacting protein (TOLLIP) increases in fibrotic lung tissue of connective tissue disease-associated interstitial lung disease and is associated with clinical outcome

Cui

Lyu

et al. 2022

Preprint

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Objective There is a lack of Toll interacting protein (TOLLIP) histological data in the lung tissue of patients with connective tissue disease-associated interstitial lung disease (CTD-ILD). We aim to demonstrate the features of TOLLIP expression in the lung tissue of CTD-ILD patients and to associate TOLLIP expression with polymorphisms and clinical characteristics. Methods Sixteen patients diagnosed with CTD-ILD who underwent lung transbronchial cryobiopsy (TBCB) at our institution between 2015 and 2021 were recruited. TOLLIP was localized in lung TBCB specimens. Rs3750920 was genotyped. Clinical characteristics, CT and pathological scores, and follow-up data were recorded. Results TOLLIP expressed in both alveolar and bronchiolar epithelial cells in patients with CTD-ILD. TOLLIP expression significantly increased in fibrotic areas. The distribution of rs3750920 was C/C: 43.7%, C/T:56.3%, T/T: 0%. There was no significant difference in clinical characteristics between C/C and C/T groups. The average follow-up time was 39.61 ± 16.78 months. During the follow-up, the change in G-score of chest thin-section CT (HRCT) was moderately negatively correlated with TOLLIP expression level in alveolar epithelial cells (r=-0.596, P = 0.024) and strongly negatively correlated with TOLLIP expression level in bronchiolar epithelial cells (r=-0.739, P = 0.004). Conclusions TOLLIP might play an important role in the regulation of pulmonary fibrosis in CTD-ILD. Patients with higher TOLLIP expression show greater improvement of ground glass opacity on HRCT, which implies TOLLIP expression is associated with prognosis. Further research is warranted to reveal the pathophysiologic mechanisms of TOLLIP in CTD, and identify potential therapeutic strategies to mitigate these diseases.

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Mechanisms of TLR4-Mediated Autophagy and Nitroxidative Stress

Cited by 26 publications

References 142 publications

FGF1 alleviates LPS-induced acute lung injury via suppression of inflammation and oxidative stress

FGF1 alleviates LPS-induced acute lung injury via suppression of inflammation and oxidative stress

Dexmedetomidine attenuates subarachnoid hemorrhage-induced acute lung injury through regulating autophagy and TLR/NF-kappaB signaling pathway

Toll interacting protein (TOLLIP) increases in fibrotic lung tissue of connective tissue disease-associated interstitial lung disease and is associated with clinical outcome

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