scholarly journals Autophagy plays an essential role in cigarette smoke-induced expression of MUC5AC in airway epithelium

2016 ◽  
Vol 310 (11) ◽  
pp. L1042-L1052 ◽  
Author(s):  
Jie-Sen Zhou ◽  
Yun Zhao ◽  
Hong-Bin Zhou ◽  
Yong Wang ◽  
Yin-Fang Wu ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cigarette Smoke ◽  
Critical Role ◽  
Airway Epithelial Cells ◽  
Lung Epithelial Cells ◽  
Cigarette Smoke Exposure ◽  
Pathological Feature ◽  
Mucus Production ◽  
Mucin Expression ◽  
Chronic Airway

Mucus hypersecretion is a common pathological feature of chronic airway inflammatory diseases including chronic obstructive pulmonary disease (COPD). However, the molecular basis for this condition remains incompletely understood. We have previously demonstrated a critical role of autophagy in COPD pathogenesis through mediating apoptosis of lung epithelial cells. In this study, we aimed to investigate the function of autophagy as well as its upstream and downstream signals in cigarette smoke-induced mucus production in human bronchial epithelial (HBE) cells and in mouse airways. Cigarette smoke extract (CSE), as well as the classical autophagy inducers starvation or Torin-1, significantly triggered MUC5AC expression, and inhibition of autophagy markedly attenuated CSE-induced mucus production. The CSE-induced autophagy was mediated by mitochondrial reactive oxygen species (mitoROS), which regulated mucin expression through the JNK and activator protein-1 pathway. Epidermal growth factor receptor (EGFR) was also required for CSE-induced MUC5AC in HBE cells, but it exerted inconsiderable effects on the autophagy-JNK signaling cascade. Airways of mice with dysfunctional autophagy-related genes displayed a markedly reduced number of goblet cells and attenuated levels of Muc5ac in response to cigarette smoke exposure. These results altogether suggest that mitoROS-dependent autophagy is essential for cigarette smoke-induced mucus hyperproduction in airway epithelial cells, and reemphasize autophagy inhibition as a novel therapeutic strategy for chronic airway diseases.

scholarly journals The impact of cigarette smoke exposure, and COPD or asthma status on ABC transporter gene expression in human airway epithelial cells

2018 ◽  
Author(s):  
Jennifer A. Aguiar ◽  
Andrea Tamminga ◽  
Briallen Lobb ◽  
Ryan D. Huff ◽  
Jenny Nguyen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Epithelial Cells ◽  
Cigarette Smoke ◽  
Abc Transporters ◽  
Airway Epithelial Cells ◽  
Cigarette Smoke Exposure ◽  
Airway Epithelial ◽  
Respiratory Mucosa

AbstractRationaleThe respiratory mucosa coordinates responses to infections, allergens, and exposures to air pollution. A relatively unexplored aspect of the respiratory mucosa are the expression and function of ATP Binding Cassette (ABC) transporters. ABC transporters are conserved in prokaryotes and eukaryotes, with humans expressing 48 transporters divided into 7 classes (ABCA, ABCB, ABCC, ABCD, ABDE, ABCF, and ABCG). Throughout the human body, ABC transporters regulate cAMP levels, chloride secretion, lipid transport, and anti-oxidant responses. A deeper exploration of the expression patterns of ABC transporters in the respiratory mucosa is warranted to determine their relevance in lung health and disease.MethodsWe used a bioinformatic approach complemented with in vitro experimental methods for validation of candidate ABC transporters. We analyzed the expression profiles of all 48 human ABC transporters in the respiratory mucosa using bronchial epithelial cell gene expression datasets available in NCBI GEO from well-characterized patient populations of healthy subjects and individuals that smoke cigarettes, or have been diagnosed with COPD or asthma. The Calu-3 airway epithelial cell line was used to interrogate selected results using a cigarette smoke extract exposure model.ResultsUsing 9 distinct gene-expression datasets of primary human airway epithelial cells, we completed a focused analysis on 48 ABC transporters in samples from healthy subjects and individuals that smoke cigarettes, or have been diagnosed with COPD or asthma. In situ gene expression data demonstrate that ABC transporters are i) variably expressed in epithelial cells from different airway generations (top three expression levels - ABCA5, ABCA13, and ABCC5), ii) regulated by cigarette smoke exposure (ABCA13, ABCB6, ABCC1, and ABCC3), and iii) differentially expressed in individuals with COPD and asthma (ABCA13, ABCC1, ABCC2, ABCC9). An in vitro cell culture model of cigarette smoke exposure was able to recapitulate the in situ changes observed in cigarette smokers for ABCA13 and ABCC1.ConclusionsOur in situ human gene expression data analysis reveals that ABC transporters are expressed throughout the airway generations in airway epithelial cells and can be modulated by environmental exposures important in chronic respiratory disease (e.g. cigarette smoking) and in individuals with chronic lung diseases (e.g. COPD or asthma). Our work highlights select ABC transporter candidates of interest and a relevant in vitro model that will enable a deeper understanding of the contribution of ABC transporters in the respiratory mucosa in lung health and disease.

scholarly journals Targeted epigenetic editing of SPDEF reduces mucus production in lung epithelial cells

2017 ◽  
Vol 312 (3) ◽  
pp. L334-L347 ◽  
Author(s):  
Juan Song ◽  
David Cano-Rodriquez ◽  
Melanie Winkle ◽  
Rutger A. F. Gjaltema ◽  
Désirée Goubert ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Critical Role ◽  
Dna Methyltransferases ◽  
Lung Epithelial Cells ◽  
The Novel ◽  
Mucus Production ◽  
Lung Epithelial ◽  
Mrna And Protein Expression ◽  
Novel Strategy ◽  
Epigenetic Editing

Airway mucus hypersecretion contributes to the morbidity and mortality in patients with chronic inflammatory lung diseases. Reducing mucus production is crucial for improving patients’ quality of life. The transcription factor SAM-pointed domain–containing Ets-like factor ( SPDEF) plays a critical role in the regulation of mucus production and, therefore, represents a potential therapeutic target. This study aims to reduce lung epithelial mucus production by targeted silencing SPDEF using the novel strategy, epigenetic editing. Zinc fingers and CRISPR/dCas platforms were engineered to target repressors (KRAB, DNA methyltransferases, histone methyltransferases) to the SPDEF promoter. All constructs were able to effectively suppress both SPDEF mRNA and protein expression, which was accompanied by inhibition of downstream mucus-related genes [anterior gradient 2 ( AGR2), mucin 5AC ( MUC5AC)]. For the histone methyltransferase G9A, and not its mutant or other effectors, the obtained silencing was mitotically stable. These results indicate efficient SPDEF silencing and downregulation of mucus-related gene expression by epigenetic editing, in human lung epithelial cells. This opens avenues for epigenetic editing as a novel therapeutic strategy to induce long-lasting mucus inhibition.

scholarly journals Cigarette smoke dampens antiviral signaling in small airway epithelial cells by disrupting TLR3 cleavage

2018 ◽  
Vol 314 (3) ◽  
pp. L505-L513 ◽  
Author(s):  
Parker F. Duffney ◽  
Claire E. McCarthy ◽  
Aitor Nogales ◽  
Thomas H. Thatcher ◽  
Luis Martinez-Sobrido ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cigarette Smoke ◽  
Airway Epithelial Cells ◽  
Smoke Exposure ◽  
Small Airway ◽  
Poly I:C ◽  
Cigarette Smoke Exposure ◽  
Airway Epithelial ◽  
Antiviral Responses ◽  
Small Airway Epithelial Cells

Cigarette smokers and people exposed to second-hand smoke are at an increased risk for pulmonary viral infections, and yet the mechanism responsible for this heightened susceptibility is not understood. To understand the effect of cigarette smoke on susceptibility to viral infection, we used an air-liquid interface culture system and exposed primary human small airway epithelial cells (SAEC) to whole cigarette smoke, followed by treatment with the viral mimetic polyinosinic polycytidylic acid (poly I:C) or influenza A virus (IAV). We found that prior smoke exposure strongly inhibited production of proinflammatory (interleukin-6 and interleukin-8) and antiviral [interferon-γ-induced protein 10 (IP-10) and interferons] mediators in SAECs in response to poly I:C and IAV infection. Impaired antiviral responses corresponded to increased infection with IAV. This was associated with a decrease in phosphorylation of the key antiviral transcription factor interferon response factor 3 (IRF3). Here, we found that cigarette smoke exposure inhibited activation of Toll-like receptor 3 (TLR3) by impairing TLR3 cleavage, which was required for downstream phosphorylation of IRF3 and production of IP-10. These results identify a novel mechanism by which cigarette smoke exposure impairs antiviral responses in lung epithelial cells, which may contribute to increased susceptibility to respiratory infections.

scholarly journals Identification of the SARS-CoV-2 Entry Receptor ACE2 as a Direct Target for Transcriptional Repression by Miz1

2021 ◽  
Vol 12 ◽  
Author(s):  
Jing Yang ◽  
Edith A. Perez ◽  
Changchun Hou ◽  
Pin Zhang ◽  
Michelle Van Scoyk ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Angiotensin Converting Enzyme ◽  
Cigarette Smoke ◽  
Lung Epithelial Cells ◽  
Cigarette Smoke Exposure ◽  
Chronic Obstructive ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Copd Patients ◽  
Lung Epithelial

Multiple lines of evidence have demonstrated that cigarette smoke or Chronic Obstructive Pulmonary Disease upregulates angiotensin-converting enzyme 2, the cellular receptor for the entry of the severe acute respiratory syndrome coronavirus 2, which predisposes individuals to develop severe Coronavirus disease 2019. The reason for this observation is unknown. We recently reported that the loss of function of Miz1 in the lung epithelium in mice leads to a spontaneous COPD-like phenotype, associated with upregulation of angiotensin-converting enzyme 2. We also reported that cigarette smoke exposure downregulates Miz1 in lung epithelial cells and in mice, and Miz1 is also downregulated in the lungs of COPD patients. Here, we provide further evidence that Miz1 directly binds to and represses the promoter of angiotensin-converting enzyme 2 in mouse and human lung epithelial cells. Our data provide a potential molecular mechanism for the upregulation of angiotensin-converting enzyme 2 observed in smokers and COPD patients, with implication in severe Coronavirus disease 2019.

scholarly journals Prolonged cigarette smoke exposure alters mitochondrial structure and function in airway epithelial cells

2013 ◽  
Vol 14 (1) ◽  
pp. 97 ◽  
Author(s):  
Roland F Hoffmann ◽  
Sina Zarrintan ◽  
Simone M Brandenburg ◽  
Arjan Kol ◽  
Harold G de Bruin ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cigarette Smoke ◽  
Airway Epithelial Cells ◽  
Structure And Function ◽  
Smoke Exposure ◽  
Cigarette Smoke Exposure ◽  
Airway Epithelial ◽  
Mitochondrial Structure ◽  
And Function

Disease modelling following organoid-based expansion of airway epithelial cells

2021 ◽  
Author(s):  
Evelien Eenjes ◽  
Sander van Riet ◽  
Andre A. Kroon ◽  
Annelies M. Slats ◽  
P. Padmini. S.J. Khedoe ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cigarette Smoke ◽  
Airway Epithelial Cells ◽  
Smoke Exposure ◽  
Clinical Samples ◽  
Cigarette Smoke Exposure ◽  
Airway Epithelial ◽  
Cell Numbers ◽  
The Impact ◽  
Preterm Newborns

Air-liquid interface (ALI) cultures are frequently used in lung research but require substantial cell numbers that cannot readily be obtained from patients. We explored whether organoid expansion (3D) can be used to establish ALI cultures from clinical samples with low epithelial cell numbers. Airway epithelial cells were obtained from tracheal aspirates (TA) from preterm newborns, and from bronchoalveolar lavage (BAL) or bronchial tissue (BT) from adults. TA and BAL cells were 3D-expanded, whereas cells from BT were expanded in 3D and 2D. Following expansion, cells were cultured at ALI to induce differentiation. The impact of cell origin and 2D or 3D expansion was assessed with respect to (i) cellular composition; (ii) response to cigarette smoke exposure; (iii) effect of Notch inhibition or IL-13 stimulation on cellular differentiation. We established well-differentiated ALI cultures from all samples. Cellular compositions (basal, ciliated and goblet cells) were comparable. All 3D-expanded cultures showed a similar stress response following cigarette smoke exposure but differed from the 2D-expanded cultures. Higher peak levels of antioxidant genes HMOX1 and NQO1 and a more rapid return to baseline, and a lower unfolded protein response was observed after cigarette smoke exposure in 3D-derived cultures compared to 2D-derived cultures. Additionally, TA- and BAL-derived cultures were less sensitive to modulation by DAPT or IL-13 than BT-derived cultures. Organoid-based expansion of clinical samples with low cell numbers, such as TA from preterm newborns is a valid method and tool to establish ALI cultures.

scholarly journals p66Shc Mediates Mitochondrial Dysfunction Dependent on PKC Activation in Airway Epithelial Cells Induced by Cigarette Smoke

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Ming Zhang ◽  
Jingjing Tang ◽  
Hu Shan ◽  
Qiuhong Zhang ◽  
Xia Yang ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Mitochondrial Dysfunction ◽  
Cigarette Smoke ◽  
Cell Injury ◽  
Critical Role ◽  
Adaptor Protein ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Mitochondrial Injury ◽  
Mitochondrial Translocation

Airway epithelial mitochondrial injury plays a critical role in the pathogenesis of chronic obstructive pulmonary disease (COPD). The p66Shc adaptor protein is a newly recognized mediator of mitochondrial dysfunction. However, little is known about the effect of p66Shc on airway epithelial damage in the development of COPD. The aim of the present study is to investigate the roles of p66Shc and its upstream regulators in the mitochondrial injury of airway epithelial cells (Beas-2b) induced by cigarette smoke extract (CSE). Our present study revealed that CSE increased p66Shc expression and its mitochondrial translocation in concentration and time-dependent manners in airway epithelial cells. And p66Shc siRNA significantly attenuated mitochondrial dysfunction and cell injury when airway epithelial cells were stimulated with 7.5% CSE. The total and phosphorylated expression of PKCβ and PKCδ was significantly increased associated with mitochondrial dysfunction and cell injury when airway epithelial cells were exposed to 7.5% CSE. The pretreatments with pharmacological inhibitors of PKCβ and PKCδ could notably suppress p66Shc phosphorylation and its mitochondrial translocation and protect the mitochondria and cells against oxidative damage when airway epithelial cells were incubated with 7.5% CSE. These data suggest that a novel PKCβ/δ-p66Shc signaling pathway may be involved in the pathogenesis of COPD and other oxidative stress-associated pulmonary diseases and provide a potential therapeutic target for these diseases.

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