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      Necroptosis Mediates Cigarette Smoke-Induced Inflammatory Responses in Macrophages

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          Cigarette smoke (CS)-induced inflammation in macrophages is involved in the pathological process of chronic obstructive pulmonary disease (COPD). Necroptosis, which is a form of programmed necrosis, has a close relationship with robust inflammation, while its roles in COPD are unclear.

          Materials and Methods

          Necroptosis markers were measured in mouse alveolar macrophages and cultured bone marrow-derived macrophages (BMDMs). Necroptosis inhibitors were used to block necroptosis in BMDMs, and inflammatory cytokines were detected. We further explored the related signaling pathways.


          In this study, we demonstrated the way in which necroptosis, in addition to its upstream and downstream signals, regulates CS-induced inflammatory responses in macrophages. We observed that CS exposure caused a significant increase in the levels of necroptosis markers (receptor interacting kinases [RIPK] 1 and 3) in mouse alveolar macrophages and BMDMs. Pharmacological inhibition of RIPK1 or 3 caused a significant suppression in CS extract (CSE)-induced inflammatory cytokines, chemokine ligands (CXCL) 1 and 2, and interleukin (IL)-6 in BMDMs. CSE-induced necroptosis was regulated by mitochondrial reactive oxygen species (mitoROS), which also promoted inflammation in BMDMs. Furthermore, necroptosis regulated CSE-induced inflammatory responses in BMDMs, most likely through activation of the nuclear factor-κB pathway.


          Taken together, our results demonstrate that mitoROS-dependent necroptosis is essential for CS-induced inflammation in BMDMs and suggest that inhibition of necroptosis in macrophages may represent effective therapeutic approaches for COPD patients.

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          Most cited references 25

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          Chronic obstructive pulmonary disease

          Summary Chronic obstructive pulmonary disease (COPD) is characterised by progressive airflow obstruction that is only partly reversible, inflammation in the airways, and systemic effects or comorbities. The main cause is smoking tobacco, but other factors have been identified. Several pathobiological processes interact on a complex background of genetic determinants, lung growth, and environmental stimuli. The disease is further aggravated by exacerbations, particularly in patients with severe disease, up to 78% of which are due to bacterial infections, viral infections, or both. Comorbidities include ischaemic heart disease, diabetes, and lung cancer. Bronchodilators constitute the mainstay of treatment: β2 agonists and long-acting anticholinergic agents are frequently used (the former often with inhaled corticosteroids). Besides improving symptoms, these treatments are also thought to lead to some degree of disease modification. Future research should be directed towards the development of agents that notably affect the course of disease.
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            Egr-1 Regulates Autophagy in Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease

            Background Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by abnormal cellular responses to cigarette smoke, resulting in tissue destruction and airflow limitation. Autophagy is a degradative process involving lysosomal turnover of cellular components, though its role in human diseases remains unclear. Methodology and Principal Findings Increased autophagy was observed in lung tissue from COPD patients, as indicated by electron microscopic analysis, as well as by increased activation of autophagic proteins (microtubule-associated protein-1 light chain-3B, LC3B, Atg4, Atg5/12, Atg7). Cigarette smoke extract (CSE) is an established model for studying the effects of cigarette smoke exposure in vitro. In human pulmonary epithelial cells, exposure to CSE or histone deacetylase (HDAC) inhibitor rapidly induced autophagy. CSE decreased HDAC activity, resulting in increased binding of early growth response-1 (Egr-1) and E2F factors to the autophagy gene LC3B promoter, and increased LC3B expression. Knockdown of E2F-4 or Egr-1 inhibited CSE-induced LC3B expression. Knockdown of Egr-1 also inhibited the expression of Atg4B, a critical factor for LC3B conversion. Inhibition of autophagy by LC3B-knockdown protected epithelial cells from CSE-induced apoptosis. Egr-1 −/− mice, which displayed basal airspace enlargement, resisted cigarette-smoke induced autophagy, apoptosis, and emphysema. Conclusions We demonstrate a critical role for Egr-1 in promoting autophagy and apoptosis in response to cigarette smoke exposure in vitro and in vivo. The induction of autophagy at early stages of COPD progression suggests novel therapeutic targets for the treatment of cigarette smoke induced lung injury.
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              Cytotoxic activity of tumor necrosis factor is mediated by early damage of mitochondrial functions. Evidence for the involvement of mitochondrial radical generation.

              Structural mitochondrial damage accompanies the cytotoxic effects of several drugs including tumor necrosis factor (TNF). Using various inhibitors of mitochondrial electron transport we have investigated the mechanism of TNF-mediated cytotoxicity in L929 and WEHI 164 clone 13 mouse fibrosarcoma cells. Inhibitors with different sites of action modulated TNF cytotoxicity, however, with contrasting effects on final cell viability. Inhibition of mitochondrial electron transport at complex III (cytochrome c reductase) by antimycin A resulted in a marked potentiation of TNF-mediated injury. In contrast, when the electron flow to ubiquinone was blocked, either at complex I (NADH-ubiquinone oxidoreductase) with amytal or at complex II (succinate-ubiquinone reductase) with thenoyltrifluoroacetone, cells were markedly protected against TNF cytotoxicity. Neither uncouplers nor inhibitors of oxidative phosphorylation nor complex IV (cytochrome c oxidase) inhibitors significantly interfered with TNF-mediated effects, ruling out the involvement of energy-coupled phenomena. In addition, the toxic effects of TNF were counteracted by the addition of antioxidants and iron chelators. Furthermore, we analyzed the direct effect of TNF on mitochondrial morphology and functions. Treatment of L929 cells with TNF led to an early degeneration of the mitochondrial ultrastructure without any pronounced damage of other cellular organelles. Analysis of the mitochondrial electron flow revealed that TNF treatment led to a rapid inhibition of the mitochondria to oxidize succinate and NADH-linked substrates. The inhibition of electron transport was dose-dependent and became readily detectable 60 min after the start of TNF treatment, thus preceding the onset of cell death by at least 3-6 h. In contrast, only minor effects were observed on complex IV activity. The different effects observed with the mitochondrial respiratory chain inhibitors provide suggestive evidence that mitochondrial production of oxygen radicals mainly generated at the ubisemiquinone site is a causal mechanism of TNF cytotoxicity. This conclusion is further supported by the protective effect of antioxidants as well as the selective pattern of damage of mitochondrial chain components and characteristic alterations of the mitochondrial ultrastructure.

                Author and article information

                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                International Journal of Chronic Obstructive Pulmonary Disease
                18 May 2020
                : 15
                : 1093-1101
                [1 ]Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Anhui Medical University , Hefei 230022, People’s Republic of China
                Author notes
                Correspondence: Ai-Hui Xu Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Anhui Medical University , 218 Jixi Road, Hefei230022, People’s Republic of China Email
                © 2020 Wang et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (

                Page count
                Figures: 5, References: 39, Pages: 9
                Original Research

                Respiratory medicine

                cigarette smoke, macrophage, necroptosis, inflammatory response, nf-κb pathway


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