Molecular pathogenesis in chronic obstructive pulmonary disease and therapeutic potential by targeting AMP‐activated protein kinase

Zhang, Zhihui; Cheng, Xiaoyu; Li, Yue; Cui, Wenhui; Zhou, Wencheng; Gao, Jian; Yao, Hongwei

doi:10.1002/jcp.25844

Cited by 25 publications

(24 citation statements)

References 85 publications

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“…According to the Global Disease Burden Research Project and the World Health Organization, COPD will become the third largest cause of death in the world and the fifth largest economic burden in the world by 2020 (2). COPD is a universally preventable and treatable disease characterized by persistent airflow limitation, and is usually associated with progressive development and an increase in the chronic inflammatory response in the respiratory tract, including the lung (3). Bronchoscopy reveals infiltration of neutrophils, lymphocytes and macrophages in the airways of affected patients (4).…”

Section: Introductionmentioning

confidence: 99%

Type 2 innate lymphoid cells participate in IL‑33‑stimulated Th2‑associated immune response in chronic obstructive pulmonary disease

et al. 2019

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The aim of the present study was to investigate the roles of type 2 innate lymphoid cells (ILC2s) and interleukin-33 (IL-33) in chronic obstructive pulmonary disease (COPD). Serum and peripheral blood mononuclear cells (PBMCs) were isolated from healthy controls and COPD patients. ILC2 cells from the peripheral blood of COPD patients were stimulated with IL-33 or neutralizing ST2 antibody+IL-33 in vitro. The cell viability was assessed using a Cell Counting Kit-8 assay. ELISA was used to detect serum IL-33 and the levels of IL-4, IL-5, IL-6, IL-13 and soluble ST2 (sST2) in the culture supernatant. The percentage of ILC2 cells was measured by flow cytometry. The mRNA expression levels of GATA binding protein 3 (GATA3), RAR-related orphan receptor (ROR)α, ST2 and prostaglandin D2 receptor 2 (CRTH2) were detected by reverse transcription-quantitative PCR. It was revealed that IL-33, IL-5, IL-6 and IL-13 were significantly elevated in peripheral blood of patients with COPD. The proportion of ILC2s in peripheral blood of COPD patients was significantly increased, and the expression of RORA and CRTH2 was increased. The proportion of ST2 + ILC2 cells was significantly increased. After 48 h of IL-33 stimulation in vitro, the ratio of linage-CD45 + CD127 + CRTH2 + cells reached a maximum. In addition, the viability of ILC2 cells, the expression levels of RORA, GATA3, ST2 and CRTH2 mRNA and the cytokines IL-4, IL-6, IL-5, IL-13 and sST2 were significantly increased. These effects were abrogated by treatment with anti-ST2. In conclusion, IL-33 is upregulated in the serum of patients with COPD and the proportion of ILC2s among the PBMCs is increased. IL-33 may promote the proliferation of ILC2 cells and secrete type 2 T-helper cell cytokines to participate in the immune response in COPD.

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Section: Introductionmentioning

confidence: 99%

Type 2 innate lymphoid cells participate in IL‑33‑stimulated Th2‑associated immune response in chronic obstructive pulmonary disease

et al. 2019

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“…To further explore the potential mechanism, as shown in Fig. 5C and D, we explored the effect of AMPK / mTOR and analyzed the role of Compound C, which was used as a AMPK inhibitor to confirm whether upstream pathway is activated in neferine-induced autophagy [34] . Decreased LC3II and p-AMPK expression and increased p-mTOR expression revealed that compound C significantly inhibited autophagy and lost the role of neferine to protect AEC-II from CSE.…”

Section: Statisticsmentioning

confidence: 99%

Neferine Enhances Autophagy to Alleviate Cytotoxicity and Apoptosis Induced by CSE in AEC-II through AMPK/mTOR Signaling Pathway

Wang¹,

Yu²,

Sun³

et al. 2020

Preprint

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COPD is a clinical common chronic respiratory disease, its incidence case fatality rate is higher, there is currently no cure drugs and methods. In this study, in order to make clear its role in the development of autophagy in COPD, COPD cell model is established.To further explore whether regulating autophagy could have a protective effect to fight against CSE-induced cytotoxicity and apoptosis, we choose neferine as an autophagy inducer. Neferine activated cell autophagy in an vitro CSE-induced COPD cell model and gradually attenuated CSE-induced cell apoptosis. Furthermore, this process happens largely through the AMPK/mTOR signaling pathway. As a autophagic flux inhibitor, chloroquine abolished the prosurvival autophagy effect, and AMPK inhibitor Compound C blocked neferine-mediated autophagy and then neferine failed to protect COPD cell model from CSE-induced apoptosis. Overall,our findings suggested that neferine possibly has a potentially protective effect in cell damage mechanisms caused by CSE. It hints that neferine has the prospect of turning into a potential therapeutics to cure CSE-induced cytotoxicity and apoptosis and even COPD patients.

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“…Thus, CS-mediated stress triggers adaptive changes that allow increased mitochondrial efficiency and activation of alternative pathways to preserve energy and antioxidant levels, and thus cell survival. AMPK activation may facilitate these processes (89). Indeed, AMPK activation has been reported in human bronchial epithelial cells and macrophages, and mouse lungs after CS exposure, in a ROS-dependent manner (90,91).…”

Section: Metabolic Reprogrammingmentioning

confidence: 99%

“…Sirt1 (97,98) and FoxO3 (90,99,100) are reduced in the lungs of patients with COPD as a result of chronic exposure to CS, suggesting an impairment of the AMPK-Sirt1-FoxO axis, with potentially detrimental effects on the ability of the cells to reprogram their metabolism and respond to stress. A number of studies have demonstrated a protective role for these pathways against the development of emphysema and inflammation in mouse models of COPD (76,89,(97)(98)(99); however, their role in metabolic function in the lungs is still elusive. Conversely, prolonged activation of adaptive mechanisms could also drive pathogenic processes.…”

Section: Metabolic Reprogrammingmentioning

confidence: 99%

“…CS-induced up-regulation of FAO, via a family with sequence similarity 13 member A (FAM13A)/Sirt1-dependent pathway, was shown to promote lung epithelial cell apoptosis through increased ROS production (101). AMPK has been shown to promote inflammation through NF-kB activation in CS-exposed mice and human macrophages (89)(90)(91), and to induce cell senescence (102,103).…”

Section: Metabolic Reprogrammingmentioning

confidence: 99%

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Dealing with Stress: Defective Metabolic Adaptation in Chronic Obstructive Pulmonary Disease Pathogenesis

et al. 2017

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The mitochondrion is the main site of energy production and a hub of key signaling pathways. It is also central in stress-adaptive response due to its dynamic morphology and ability to interact with other organelles. In response to stress, mitochondria fuse into networks to increase bioenergetic efficiency and protect against oxidative damage. Mitochondrial damage triggers segregation of damaged mitochondria from the mitochondrial network through fission and their proteolytic degradation by mitophagy. Post-translational modifications of the mitochondrial proteome and nuclear cross-talk lead to reprogramming of metabolic gene expression to maintain energy production and redox balance. Chronic obstructive pulmonary disease (COPD) is caused by chronic exposure to oxidative stress arising from inhaled irritants, such as cigarette smoke. Impaired mitochondrial structure and function, due to oxidative stress-induced damage, may play a key role in causing COPD. Deregulated metabolic adaptation may contribute to the development and persistence of mitochondrial dysfunction in COPD. We discuss the evidence for deregulated metabolic adaptation and highlight important areas for investigation that will allow the identification of molecular targets for protecting the COPD lung from the effects of dysfunctional mitochondria.

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Molecular pathogenesis in chronic obstructive pulmonary disease and therapeutic potential by targeting AMP‐activated protein kinase

Cited by 25 publications

References 85 publications

Type 2 innate lymphoid cells participate in IL‑33‑stimulated Th2‑associated immune response in chronic obstructive pulmonary disease

Type 2 innate lymphoid cells participate in IL‑33‑stimulated Th2‑associated immune response in chronic obstructive pulmonary disease

Neferine Enhances Autophagy to Alleviate Cytotoxicity and Apoptosis Induced by CSE in AEC-II through AMPK/mTOR Signaling Pathway

Dealing with Stress: Defective Metabolic Adaptation in Chronic Obstructive Pulmonary Disease Pathogenesis

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