The antioxidant N-acetylcysteine promotes immune response and inhibits epithelial-mesenchymal transition to alleviate pulmonary fibrosis in chronic obstructive pulmonary disease by suppressing the VWF/p38 MAPK axis

Zhu, Lihua Julie; Xu, Fei; Kang, Xiuhua; Zhou, Jing; Yao, Qinqin; Yang, Lefu; Zhang, Wei

doi:10.1186/s10020-021-00342-y

Cited by 25 publications

(18 citation statements)

References 42 publications

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“…A recent study has elaborated the relation between inflammation and OA pain and prognosis, and that new appealing therapies targeting inflammation might contribute to satisfactory pain relief [47]. A large body of evidence has verified that activation of inflammatory factors, including IL1β, TNF-α, and IL-6 [48], is implicated in the development and progression of and OA [49,50], while the blockage of these proinflammatory cytokines serves as an appealing treatment option for OA [51]. Moreover, elevation of IL-1β can be observed in synovial fluid, subchondral bone, and cartilage tissues from OA patients [52].…”

Section: Discussionmentioning

confidence: 99%

miR-3960 from Mesenchymal Stem Cell-Derived Extracellular Vesicles Inactivates SDC1/Wnt/β-Catenin Axis to Relieve Chondrocyte Injury in Osteoarthritis by Targeting PHLDA2

Wei

et al. 2022

Stem Cells International

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Osteoarthritis (OA) is a serious disease of the articular cartilage characterized by excessive inflammation. Lately, mesenchymal stem cell- (MSC-) derived extracellular vesicles (EVs) have been proposed as a novel strategy for the treatment of OA. We aimed to investigate the effects of EV-encapsulated miR-3960 derived from MSCs on chondrocyte injury in OA. The cartilage tissues from OA patients were collected to experimentally determine expression patterns of miR-3960, PHLDA2, SDC1, and β-catenin. Next, luciferase assay was implemented to testify the binding affinity among miR-3960 and PHLDA2. EVs were isolated from MSCs and cocultured with IL-1β-induced OA chondrocytes. Afterwards, cellular biological behaviors and levels of extracellular matrix- (ECM-) related protein anabolic markers (collagen II and aggrecan), catabolic markers (MMP13 and ADAMTS5), and inflammatory factors (IL-6 and TNF-α) in chondrocytes were assayed upon miR-3960 and/or PHLDA2 gain- or loss-of-function. Finally, the effects of miR-3960 contained in MSC-derived EVs in OA mouse models were also explored. MSCs-EVs could reduce IL-1β-induced inflammatory response and extracellular matrix (ECM) degradation in chondrocytes. miR-3960 expression was downregulated in cartilage tissues of OA patients but enriched in MSC-derived EVs. miR-3960 could target and inhibit PHLDA2, which was positively correlated with SDC1 and Wnt/β-catenin pathway activation. miR-3960 shuttled by MSC-derived EVs protected against apoptosis and ECM degradation in chondrocytes. In vivo experiment also confirmed that miR-3960 alleviated chondrocyte injury in OA. Collectively, MSC-derived EV-loaded miR-3960 downregulated PHLDA2 to inhibit chondrocyte injury via SDC1/Wnt/β-catenin.

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Section: Discussionmentioning

confidence: 99%

miR-3960 from Mesenchymal Stem Cell-Derived Extracellular Vesicles Inactivates SDC1/Wnt/β-Catenin Axis to Relieve Chondrocyte Injury in Osteoarthritis by Targeting PHLDA2

Wei

et al. 2022

Stem Cells International

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“…MAPK, an intracellular Ser/Thr protein kinase, is involved in a variety of signaling pathways and plays an important role in cell cycle regulation [ 137 ]. Studies have reported that NAC can improve COPD-related pulmonary fibrosis by activating immune response and suppressing the EMT process through VWF/P38 MAPK signaling pathway in vivo and in vitro experiments [ 15 ]. In addition, TACE/TGF-α/EGFR signaling pathway is found activated in CSE-exposed human airway epithelial cells, and blocking the TACE/TGF-α/EGFR signaling pathway can inhibit the CSE-induced EMT process [ 138 ].…”

Section: Signalling Pathways Involved In Emt Induced By Cigarette Smo...mentioning

confidence: 99%

“…This suggested antioxidant N -acetylcysteine may contribute to EMT inhibition, thereby alleviating COPD pulmonary fibrosis. NAC could ameliorate COPD-induced pulmonary fibrosis by promoting immune response and inhibiting the EMT process via the VWF/p38 MAPK axis [ 15 ].…”

Section: Potential Therapies For Emt In Copdmentioning

confidence: 99%

“…Moreover, EMT is increasingly being considered a possible core pathophysiological factor in COPD and lung cancer progression [ 10 – 14 ]. In smoking-related COPD, recent studies further highlight that EMT is associated with airway remodeling, airway fibrosis, and subsequent airflow obstruction and may be associated with a higher prevalence of lung cancer [ 15 – 18 ]. All of these findings suggest the importance of EMT in the development of smoking-related COPD.…”

Section: Introductionmentioning

confidence: 99%

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The effects of epithelial–mesenchymal transitions in COPD induced by cigarette smoke: an update

Zhu

Lin

et al. 2022

Respir Res

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Cigarette smoke is a complex aerosol containing a large number of compounds with a variety of toxicity and carcinogenicity. Long-term exposure to cigarette smoke significantly increases the risk of a variety of diseases, including chronic obstructive pulmonary disease (COPD) and lung cancer. Epithelial–mesenchymal transition (EMT) is a unique biological process, that refers to epithelial cells losing their polarity and transforming into mobile mesenchymal cells, playing a crucial role in organ development, fibrosis, and cancer progression. Numerous recent studies have shown that EMT is an important pathophysiological process involved in airway fibrosis, airway remodeling, and malignant transformation of COPD. In this review, we summarized the effects of cigarette smoke on the development and progression of COPD and focus on the specific changes and underlying mechanisms of EMT in COPD induced by cigarette smoke. We spotlighted the signaling pathways involved in EMT induced by cigarette smoke and summarize the current research and treatment approaches for EMT in COPD, aiming to provide ideas for potential new treatment and research directions.

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“…The antioxidant and anti-inflammatory actions of NAC in diverse respiratory diseases have been proved [ 9 ]. NAC is associated with alleviation in symptoms and delay in exacerbations of chronic obstructive pulmonary disease [ 10 ]. In addition, NAC has been found to inhibit COVID-19 replication and virus-induced apoptosis [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

N-Acetyl-L-Cysteine Protects Airway Epithelial Cells during Respiratory Syncytial Virus Infection against Mucin Synthesis, Oxidative Stress, and Inflammatory Response and Inhibits HSPA6 Expression

Chi¹,

Shan²,

Cui³

2022

Analytical Cellular Pathology

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Objective. Respiratory syncytial virus (RSV) infection is an important cause of hospitalization of children worldwide, leading to significant morbidity and mortality. RSV infection leads to increasing inflammatory and apoptosis events in the airway epithelium through mechanisms involving ROS generation. The antioxidant N-acetyl-L-cysteine (NAC) has been shown to inhibit influenza virus replication and to reduce the secretion of inflammatory and apoptotic mediators during virus infection. The study aims to investigate the effects of NAC on human bronchial epithelial cells BEAS-2B and HSPA6 expression during RSV infection. Methods. CCK-8 assays were performed to evaluate cell survival. The production of proinflammatory factors, TNF-α, IL-6, IL-1β, IL-18, and MUC5AC was examined by quantitative real-time PCR and ELISA. Oxidative stress was determined by reactive oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH)/glutathione disulfide (GSSG) ratio. Immunoblotting analysis of epidermal growth factor receptor (EGFR) and its phosphorylation was performed. The antiviral effect of NAC was assessed by determining viral titers using plaque assay. Results. RSV infection reduced cell survival, promoted the release of proinflammatory factors, increased the ROS production and MDA concentration, and diminished the SOD activity and GSH/GSSG ratio, all which were attenuated by NAC treatment. Accordingly, NAC treatment inhibited the activation of EGFR and MUC5AC in BEAS-2B cells with RSV infection. Furthermore, NAC administration resulted in a marked decrease in RSV-induced HSPA6 expression in BEAS-2B cells. Concomitantly, EPB treatment led to an evident inhibition of RSV fusion gene and viral replication in RSV-infected BEAS-2B cells. Conclusion. This work supports the use of NAC to exert antimucin synthesis, anti-inflammatory, antioxidant, and antiviral effects on airway epithelium during RSV infection.

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The antioxidant N-acetylcysteine promotes immune response and inhibits epithelial-mesenchymal transition to alleviate pulmonary fibrosis in chronic obstructive pulmonary disease by suppressing the VWF/p38 MAPK axis

Cited by 25 publications

References 42 publications

miR-3960 from Mesenchymal Stem Cell-Derived Extracellular Vesicles Inactivates SDC1/Wnt/β-Catenin Axis to Relieve Chondrocyte Injury in Osteoarthritis by Targeting PHLDA2

miR-3960 from Mesenchymal Stem Cell-Derived Extracellular Vesicles Inactivates SDC1/Wnt/β-Catenin Axis to Relieve Chondrocyte Injury in Osteoarthritis by Targeting PHLDA2

The effects of epithelial–mesenchymal transitions in COPD induced by cigarette smoke: an update

N-Acetyl-L-Cysteine Protects Airway Epithelial Cells during Respiratory Syncytial Virus Infection against Mucin Synthesis, Oxidative Stress, and Inflammatory Response and Inhibits HSPA6 Expression

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