Aberrant airway epithelial differentiation resulting from cigarette smoke exposure leads to loss of constitutive antimicrobial peptide and protein (AMP) expression

2016 ◽  
Author(s):  
Pieter S. Hiemstra ◽  
Gimano D. Amatngalim ◽  
Jasmijn A. Schrumpf ◽  
Fernanda Dishchekenian ◽  
Tinne C.J. Mertens ◽  
...  
Keyword(s):  
Antimicrobial Peptide ◽  
Cigarette Smoke ◽  
Epithelial Differentiation ◽  
Smoke Exposure ◽  
Cigarette Smoke Exposure ◽  
Airway Epithelial

scholarly journals Impact of acute exposure to cigarette smoke on airway gene expression

2018 ◽  
Vol 50 (9) ◽  
pp. 705-713 ◽  
Author(s):  
E. Billatos ◽  
A. Faiz ◽  
Y. Gesthalter ◽  
A. LeClerc ◽  
Y. O. Alekseyev ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Lung Cancer ◽  
Cigarette Smoke ◽  
Smoke Exposure ◽  
Acute Exposure ◽  
Cigarette Smoke Exposure ◽  
Airway Epithelial ◽  
Long Term Effects ◽  
Chronic Smoking

Background: Understanding effects of acute smoke exposure (ASE) on airway epithelial gene expression and their relationship with the effects of chronic smoke exposure may provide biological insights into the development of smoking-related respiratory diseases. Methods: Bronchial airway epithelial cell brushings were collected from 63 individuals without recent cigarette smoke exposure and before and 24 h after smoking three cigarettes. RNA from these samples was profiled on Affymetrix Human Gene 1.0 ST microarrays. Results: We identified 91 genes differentially expressed 24 h after ASE (false discovery rate < 0.25). ASE induced genes involved in xenobiotic metabolism, oxidative stress, and inflammation and repressed genes related to cilium morphogenesis and cell cycle. While many genes altered by ASE are altered similarly in chronic smokers, metallothionein genes are induced by ASE and suppressed in chronic smokers. Metallothioneins are also suppressed in current and former smokers with lung cancer relative to those without lung cancer. Conclusions: Acute exposure to as little as three cigarettes and chronic smoking induce largely concordant changes in airway epithelial gene expression. Differences in short-term and long-term effects of smoking on metallothionein expression and their relationship to lung cancer requires further study given these enzymes’ role in the oxidative stress response.

scholarly journals Direct exposure to SARS-CoV-2 and cigarette smoke increases infection severity and alters the stem cell-derived airway repair response

2020 ◽  
Author(s):  
Arunima Purkayastha ◽  
Chandani Sen ◽  
Gustavo Garcia ◽  
Justin Langerman ◽  
Preethi Vijayaraj ◽  
...  
Keyword(s):  
Viral Infection ◽  
Cigarette Smoke ◽  
Smoke Exposure ◽  
Disease Spread ◽  
Interferon Response ◽  
Cigarette Smoke Exposure ◽  
Airway Epithelial ◽  
Airway Injury ◽  
Increased Risk ◽  
Airway Cells

SUMMARYMost demographic studies are now associating current smoking status with increased risk of severe COVID-19 and mortality from the disease but there remain many questions about how direct cigarette smoke exposure affects SARS-CoV-2 airway cell infection. We directly exposed mucociliary air-liquid interface (ALI) cultures derived from primary human nonsmoker airway basal stem cells (ABSCs) to short term cigarette smoke and infected them with live SARS-CoV-2. We found an increase in the number of infected airway cells after cigarette smoke exposure as well as an increased number of apoptotic cells. Cigarette smoke exposure alone caused airway injury that resulted in an increased number of ABSCs, which proliferate to repair the airway. But we found that acute SARS-CoV-2 infection or the combination of exposure to cigarette smoke and SARS-CoV-2 did not induce ABSC proliferation. We set out to examine the underlying mechanism governing the increased susceptibility of cigarette smoke exposed ALI to SARS-CoV-2 infection. Single cell profiling of the cultures showed that infected airway cells displayed a global reduction in gene expression across all airway cell types. Interestingly, interferon response genes were induced in SARS-CoV-2 infected airway epithelial cells in the ALI cultures but smoking exposure together with SARS-CoV-2 infection reduced the interferon response. Treatment of cigarette smoke-exposed ALI cultures with Interferon β-1 abrogated the viral infection, suggesting that the lack of interferon response in the cigarette smoke-exposed ALI cultures allows for more severe viral infection and cell death. In summary, our data show that acute smoke exposure allows for more severe proximal airway epithelial disease from SARS-CoV-2 by reducing the mucosal innate immune response and ABSC proliferation and has implications for disease spread and severity in people exposed to cigarette smoke.

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 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

scholarly journals Cigarette Smoke Specifically Affects Small Airway Epithelial Cell Populations and Triggers the Expansion of Inflammatory and Squamous Differentiation Associated Basal Cells

2021 ◽  
Vol 22 (14) ◽  
pp. 7646
Author(s):  
Christian T. Wohnhaas ◽  
Julia A. Gindele ◽  
Tobias Kiechle ◽  
Yang Shen ◽  
Germán G. Leparc ◽  
...  
Keyword(s):  
Cigarette Smoke ◽  
Basal Cell ◽  
Secretory Cell ◽  
Inflammatory Responses ◽  
Airway Epithelial Cells ◽  
Smoke Exposure ◽  
Small Airway ◽  
Cigarette Smoke Exposure ◽  
Small Airways ◽  
Airway Epithelial

Smoking is a major risk factor for chronic obstructive pulmonary disease (COPD) and causes remodeling of the small airways. However, the exact smoke-induced effects on the different types of small airway epithelial cells (SAECs) are poorly understood. Here, using air–liquid interface (ALI) cultures, single-cell RNA-sequencing reveals previously unrecognized transcriptional heterogeneity within the small airway epithelium and cell type-specific effects upon acute and chronic cigarette smoke exposure. Smoke triggers detoxification and inflammatory responses and aberrantly activates and alters basal cell differentiation. This results in an increase of inflammatory basal-to-secretory cell intermediates and, particularly after chronic smoke exposure, a massive expansion of a rare inflammatory and squamous metaplasia associated KRT6A+ basal cell state and an altered secretory cell landscape. ALI cultures originating from healthy non-smokers and COPD smokers show similar responses to cigarette smoke exposure, although an increased pro-inflammatory profile is conserved in the latter. Taken together, the in vitro models provide high-resolution insights into the smoke-induced remodeling of the small airways resembling the pathological processes in COPD airways. The data may also help to better understand other lung diseases including COVID-19, as the data reflect the smoke-dependent variable induction of SARS-CoV-2 entry factors across SAEC populations.

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.

Evaluation of a novel CFTR potentiator in copd ferrets with acquired cftr dysfunction

2021 ◽  
pp. 2101581
Author(s):  
Niroop Kaza ◽  
Vivian Y. Lin ◽  
Denise Stanford ◽  
Shah S. Hussain ◽  
Emily Falk Libby ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Chronic Bronchitis ◽  
Cigarette Smoke ◽  
Smoke Exposure ◽  
Cigarette Smoke Exposure ◽  
Wall Thickening ◽  
Lung Pathology ◽  
Airway Epithelial ◽  
Tomography Imaging ◽  
Pathologic Features

Rationale.The majority of chronic obstructive pulmonary disease (COPD) patients have chronic bronchitis, for which specific therapies are unavailable. Acquired cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction is observed in chronic bronchitis, but has not been proven in a controlled animal model with airway disease. Furthermore, the potential of CFTR as a therapeutic target has not been tested in vivo, given limitations to rodent models of COPD. Ferrets exhibit cystic fibrosis-related lung pathology when CFTR is absent and COPD with bronchitis following cigarette smoke exposure.Objectives.To evaluate CFTR dysfunction induced by smoking and test its pharmacologic reversal by a novel CFTR potentiator, GLPG2196, in a ferret model of COPD with chronic bronchitis.Methods.Ferrets were exposed for six months to cigarette smoke to induce COPD and chronic bronchitis and then treated with eneral GLPG2196 once daily for one month. Electrophysiologic measurements of ion transport and CFTR function, assessment of mucociliary function by one-micron optical coherence tomography imaging and particle tracking microrhelogy, microcomputed tomography imaging, histopathological analysis, and quantification of CFTR protein and mRNA expression were used to evaluate mechanistic and pathophysiological changes.Measurements and Main Results.Following cigarette smoke exposure, ferrets exhibited CFTR dysfunction, increased mucus viscosity, delayed mucociliary clearance, airway wall thickening, and airway epithelial hypertrophy. In COPD ferrets, GLPG2196 treatment reversed CFTR dysfunction, increased mucus transport by decreasing mucus viscosity, and reduced brochial wall thickening and airway epithelial hypertrophy.Conclusions.The pharmacologic reversal of acquired CFTR dysfunction is beneficial against pathologic features of chronic bronchitis in a COPD ferret model.

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