Cigarette smoke extract promotes proliferation of airway smooth muscle cells through suppressing C/EBP-α expression

Guan, Peng; Cai, Wentao; Yu, Hui; Wu, Zhiyong; Li, Wei; Wu, Jie; Chen, Juan; Gu, Feng

doi:10.3892/etm.2017.4126

Cited by 14 publications

(10 citation statements)

References 28 publications

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“…Our results proved that direct CSE exposure of adventitia fibroblasts and media smooth muscle cells contributed to vascular remodeling through various mechanisms, such as induction of a cell senescent phenotype. Conversely, previous reports demonstrate that in human airway structural cells, cigarette smoke exposure promotes a pro-proliferative effect [12,41,42]. In agreement with our results, other studies indicate that interstitial lung fibroblasts from COPD patients have a reduced proliferation rate [53].…”

Section: Discussionsupporting

confidence: 93%

“…Studies in animal models and human cells demonstrate a wide variability of results with respect to the effects of CSE in cellular proliferation. In human airway structural cells a proproliferative effect has been observed [12,41,42], but opposite results were observed in human pulmonary artery endothelial cells [17]. However, the direct effects of CSE on…”

Section: Cse Exposure Diminishes Hpafib and Hpasmc Proliferative Capamentioning

confidence: 99%

“…Additionally, they point out that cigarette smoke plays an important role in pulmonary vascular remodeling. In this respect, results from animal models and human cells have shown that cigarette smoke induces proliferation in rat pulmonary artery smooth muscle cells, fibroblasts and endothelial cells and in human airway and aortic smooth muscle cells [12][13][14]. Conversely, other studies demonstrate that exposure to cigarette smoke inhibits proliferation of lung fibroblasts [15] and human pulmonary artery endothelial cells (hPAEC) [16], while inducing their senescence, which leads to improved smooth muscle cell (hPASMC) proliferation and migration [17].…”

Section: Introductionmentioning

confidence: 99%

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Direct Effects of Cigarette Smoke in Pulmonary Arterial Cells alter Vascular Tone through Arterial Remodeling and Kv7.4 Channel Dysregulation

Sevilla-Montero¹,

Labrousse-Arias²,

Fernández-Pérez³

et al. 2019

Preprint

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Chronic obstructive pulmonary disease (COPD) is a widespread disease, with no curative therapies nowadays. Exposure to cigarette smoking is considered the chief leading cause of COPD. Current drugs therapies improve patient quality of life, however they do not revert the progression of the disease. Therefore, a deeper study of the cellular and molecular mechanisms that underlie this pathology is required to be able to carry out targeted and effective treatments. Although the effects of cigarette smoke in the progressive deterioration of the airway have been extensively studied in COPD patients, its effects on pulmonary vasculature have been unexplored, due to the classic conception that vascular damage is a consequence of alveolar hypoxia and loss of capillary bed. In this paper, we aimed to study the effects of cigarette smoke extract (CSE) in regulating pulmonary arterial cells phenotypic modulation, in particular the effects in fibroblasts (hPAFib) and smooth muscle cells (hPASMC), and in murine pulmonary arteries. Our results demonstrated that CSE exposure had direct effects on hPAFib and hPASMC, promoting a senescent phenotype that in turn contributed, through the secretion of inflammatory molecules, to increase the proliferative potential of non-exposed cells. CSE also increased total ROS levels in hPAFib and hPASMC, and upregulated NADPH oxidase subunits NOX1 and p22 phox . Most importantly, CSE affected cell contractility and dysregulated the expression and activity of voltage-gated K + channel Kv7.4. This contributed to limit vascular responses impairing vasoconstriction and endotheliumdependent and independent relaxation.

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Section: Discussionsupporting

confidence: 93%

Section: Cse Exposure Diminishes Hpafib and Hpasmc Proliferative Capamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Direct Effects of Cigarette Smoke in Pulmonary Arterial Cells alter Vascular Tone through Arterial Remodeling and Kv7.4 Channel Dysregulation

Sevilla-Montero¹,

Labrousse-Arias²,

Fernández-Pérez³

et al. 2019

Preprint

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“…Recently, increasingly data suggests that imbalanced proliferation and apoptosis of different lung cells might contribute to the pathogenesis of COPD (Calabrese et al, 2005; Demedts et al, 2006; Yu and Guo, 2007; Sohal, 2017; Guan et al, 2017), causing damage in airway-vessel and lung tissue structure, and subsequent development of airway-vessel remodeling and emphysema (Demedts et al, 2006; Henson et al, 2006; Yamada et al, 2016). The intrinsic, extrinsic and ERS-associated apoptotic pathway were implicated in apoptosis in COPD (Lin et al, 2015; Lin et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Ursolic Acid Protected Lung of Rats From Damage Induced by Cigarette Smoke Extract

Hou

Han

et al. 2019

Front. Pharmacol.

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Background: We found previously that ursolic acid (UA) administration could alleviate cigarette smoke-induced emphysema in rats partly through the unfolded protein response (UPR) PERK-CHOP and Nrf2 pathways, thus alleviating endoplasmic reticulum stress (ERS)-associated oxidative stress and cell apoptosis. We hypothesized that other UPR pathways may play similar roles in cigarette smoke extract (CSE)-induced emphysema. So, we sought to investigate the dynamic changes and effects of UPR and the downstream apoptotic pathways. Further, we investigated whether UA could alleviate CSE-induced emphysema and airway remodelling in rats, whether and when it exerts its effects through UPR pathways as well as Smads pathways. Methods: One hundred eight Sprague Dawley (SD) rats were randomly divided into three groups: Sham group, CSE group, and UA group, and each group was further divided into three subgroups, administered CSE (vehicle) for 2, 3, or 4 weeks; each subgroup had 12 rats. We examined pathological changes, analyzed the three UPR signaling pathways and subsequent ERS, intrinsic and extrinsic apoptotic pathway indicators, as well as activation of Smad2,3 molecules in rat lungs. Results: Exposure to CSE for 3 or 4 weeks could apparently induce emphysema and airway remodeling in rats, including gross and microscopic changes, alteration of mean alveolar number (MAN), mean linear intercept (MLI), and mean airway thickness in lung tissue sections. UA intervention could significantly alleviate CSE-induced emphysema and airway remodeling in rats. UA exerted its effects through ameliorating apoptosis by down regulating UPR signalling pathways and subsequent apoptosis pathways, as well as, downregulating p-Smad2 and p-Smad3 molecules. Conclusions: UA attenuated CSE-induced emphysema and airway remodeling, exerting its effects partly through regulation of three UPR pathways, amelioration downstream apoptotic pathways, and alleviating activation of Smad2 and Smad3.

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“…lactate, glutamine, fatty acids, and amino acids, increased biosynthesis and redox imbalance in ASM of patients with COPD, and supported ASM proliferation and survival [ 10 ]. The cigarette smoke extract (CSE) is the most dangerous environmental factor that promotes the proliferation of ASM in COPD, and it happens in connection with up-regulated expression of calreticulin and down-regulated expression of C/EBPα [ 39 ]. Moreover, CSE enhances proliferation of ASM by up-regulation of PCNA and Cyclin E [ 40 ].…”

Section: Change Of Asm Remodelingmentioning

confidence: 99%

Roles of airway smooth muscle dysfunction in chronic obstructive pulmonary disease

et al. 2018

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The airway smooth muscle (ASM) plays an indispensable role in airway structure and function. Dysfunction in ASM plays a central role in the pathogenesis of chronic obstructive pulmonary disease (COPD) and contributes to alterations of contractility, inflammatory response, immunoreaction, phenotype, quantity, and size of airways. ASM makes a key contribution in COPD by various mechanisms including altered contractility and relaxation induce by [Ca2+]i, cell proliferation and hypertrophy, production and modulation of extracellular cytokines, and release of pro-and-anti-inflammatory mediators. Multiple dysfunctions of ASM contribute to modulating airway responses to stimuli, remodeling, and fibrosis, as well as influence the compliance of lungs. The present review highlights regulatory roles of multiple factors in the development of ASM dysfunction in COPD, aims to understand the regulatory mechanism by which ASM dysfunctions are initiated, and explores the clinical significance of ASM on alterations of airway structure and function in COPD and development of novel therapeutic strategies for COPD.

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Cigarette smoke extract promotes proliferation of airway smooth muscle cells through suppressing C/EBP-α expression

Cited by 14 publications

References 28 publications

Direct Effects of Cigarette Smoke in Pulmonary Arterial Cells alter Vascular Tone through Arterial Remodeling and Kv7.4 Channel Dysregulation

Direct Effects of Cigarette Smoke in Pulmonary Arterial Cells alter Vascular Tone through Arterial Remodeling and Kv7.4 Channel Dysregulation

Ursolic Acid Protected Lung of Rats From Damage Induced by Cigarette Smoke Extract

Roles of airway smooth muscle dysfunction in chronic obstructive pulmonary disease

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