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.

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

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 DNA damage response at telomeres contributes to lung aging and chronic obstructive pulmonary disease

2015 ◽  
Vol 309 (10) ◽  
pp. L1124-L1137 ◽  
Author(s):  
Jodie Birch ◽  
Rhys K. Anderson ◽  
Clara Correia-Melo ◽  
Diana Jurk ◽  
Graeme Hewitt ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cigarette Smoke ◽  
Airway Epithelial Cells ◽  
Small Airway ◽  
Cigarette Smoke Exposure ◽  
Telomere Dysfunction ◽  
Airway Epithelial ◽  
Murine Lung ◽  
Small Airway Epithelial Cells ◽  
Lung Aging

Cellular senescence has been associated with the structural and functional decline observed during physiological lung aging and in chronic obstructive pulmonary disease (COPD). Airway epithelial cells are the first line of defense in the lungs and are important to COPD pathogenesis. However, the mechanisms underlying airway epithelial cell senescence, and particularly the role of telomere dysfunction in this process, are poorly understood. We aimed to investigate telomere dysfunction in airway epithelial cells from patients with COPD, in the aging murine lung and following cigarette smoke exposure. We evaluated colocalization of γ-histone protein 2A.X and telomeres and telomere length in small airway epithelial cells from patients with COPD, during murine lung aging, and following cigarette smoke exposure in vivo and in vitro. We found that telomere-associated DNA damage foci increase in small airway epithelial cells from patients with COPD, without significant telomere shortening detected. With age, telomere-associated foci increase in small airway epithelial cells of the murine lung, which is accelerated by cigarette smoke exposure. Moreover, telomere-associated foci predict age-dependent emphysema, and late-generation Terc null mice, which harbor dysfunctional telomeres, show early-onset emphysema. We found that cigarette smoke accelerates telomere dysfunction via reactive oxygen species in vitro and may be associated with ataxia telangiectasia mutated-dependent secretion of inflammatory cytokines interleukin-6 and -8. We propose that telomeres are highly sensitive to cigarette smoke-induced damage, and telomere dysfunction may underlie decline of lung function observed during aging and in COPD.

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