scholarly journals Increased expression of ACE2, the SARS-CoV-2 entry receptor, in alveolar and bronchial epithelium of smokers and COPD subjects

2020 ◽  
Author(s):  
Merel Jacobs ◽  
Hannelore P Van Eeckhoutte ◽  
Sara RA Wijnant ◽  
Wim Janssens ◽  
Guy F Joos ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Cigarette Smoke ◽  
Lung Tissue ◽  
Bronchial Epithelium ◽  
Chronic Obstructive ◽  
Protein Levels ◽  
Populations At Risk ◽  
Increased Risk ◽  
Entry Receptor ◽  
Severe Copd

ABSTRACTRationaleSmokers and patients with chronic obstructive pulmonary disease (COPD) are at increased risk for severe Coronavirus Disease 2019 (COVID-19).ObjectivesWe investigated the expression of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry receptor ACE2 and the protease TMPRSS2 in lung tissue from never smokers and smokers with and without COPD.MethodsIn a cross-sectional, observational study we measured mRNA expression of ACE2 and TMPRSS2 by RT-PCR in lung tissue samples from 120 well phenotyped subjects. Next, protein levels of ACE2 were visualized by immunohistochemistry on paraffin sections from 87 subjects and quantified in alveolar and bronchial epithelium. Finally, primary human bronchial epithelial cells (HBECs) were cultured at air liquid interface and exposed to air or cigarette smoke.ResultsACE2 mRNA expression was significantly higher in lung tissue from current smokers and subjects with moderate to very severe COPD and correlated with physiological parameters of airway obstruction and emphysema. Pulmonary expression levels of TMPRSS2 were significantly higher in patients with (very) severe COPD and correlated significantly with ACE2 expression. Importantly, protein levels of ACE2 were elevated in both alveolar and bronchial epithelium of current smokers and subjects with moderate to very severe COPD. Finally, TMPRSS2 mRNA expression increased in in vitro cultured HBECs upon acute exposure to cigarette smoke.ConclusionsWe demonstrate increased expression of ACE2 in lungs of smokers and COPD subjects, which might facilitate host cell entry of SARS-CoV-2. These findings help identifying populations at risk for severe COVID-19.

scholarly journals Increased IgA production by B-cells in COPDvialung epithelial interleukin-6 and TACI pathways

2014 ◽  
Vol 45 (4) ◽  
pp. 980-993 ◽  
Author(s):  
Maha Zohra Ladjemi ◽  
Marylène Lecocq ◽  
Birgit Weynand ◽  
Holly Bowen ◽  
Hannah J. Gould ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cigarette Smoke ◽  
Lung Tissue ◽  
Plasma Cells ◽  
Bronchial Epithelium ◽  
Chronic Obstructive ◽  
Promoting Effect ◽  
Obstructive Pulmonary Disease

Despite their relevance to mucosal defense, production of IgA and the function of lung B-cells remain unknown in chronic obstructive pulmonary disease (COPD).We assessed IgA synthesis in the lungs of COPD (n=28) and control (n=21) patients, and regulation of B-cells co-cultured within vitro-reconstituted airway epithelium.In COPD lung tissue, synthesis of IgA1 was increased, which led to its accumulation in subepithelial areas.In vitro, the COPD bronchial epithelium imprinted normal human B-cells for increased production of IgA (mainly IgA1) and maturation into CD38+plasma cells. These effects were associated with upregulation of TACI (transmembrane activator and CAML interactor) and were observed under resting conditions, while being partly inhibited upon stimulation with cigarette smoke extract. Interleukin (IL)-6 and BAFF (B-cell activating factor)/APRIL (a proliferation-inducing ligand) were upregulated in the COPD epithelium and lung tissue, respectively; the IgA-promoting effect of the COPD bronchial epithelium was inhibited by targeting IL-6 and, to a lower extent, by blocking TACI.These data show that in COPD, the bronchial epithelium imprints B-cells with signals promoting maturation into IgA-producing plasma cells through the action of two epithelial/B-cell axes, namely the IL-6/IL-6 receptor and BAFF-APRIL/TACI pathways, while cigarette smoke partly counteracts this IgA-promoting effect.

scholarly journals Expression of ACE2, the SARS-CoV-2 receptor, in lung tissue of patients with type 2 diabetes

2020 ◽  
Author(s):  
Ada Admin ◽  
Sara RA Wijnant ◽  
Merel Jacobs ◽  
Hannelore P Van Eeckhoutte ◽  
Bruno Lapauw ◽  
...  
Keyword(s):  
Protein Expression ◽  
Mrna Expression ◽  
Lung Tissue ◽  
Bronchial Epithelium ◽  
Rt Pcr ◽  
Tissue Samples ◽  
Protein Levels ◽  
Patients With Diabetes ◽  
Alveolar Tissue ◽  
Control Samples

Increased expression of pulmonary ACE2, the SARS-CoV-2 receptor, could contribute to increased infectivity of COVID-19 in subjects with diabetes, but ACE2 expression has not been studied in lung tissue of subjects with diabetes. We therefore studied ACE2 mRNA and protein expression in lung tissue samples of patients with and without diabetes that were collected between 2002 and 2020 from patients undergoing lobectomy for lung tumors. For RT-PCR analyses, samples from 15 subjects with diabetes were compared to 91 randomly chosen control samples. For immunohistochemical staining, samples from 26 subjects with diabetes were compared to 66 randomly chosen control samples. mRNA expression of ACE2 was measured by quantitative RT-PCR. Protein levels of ACE2 were visualized by immunohistochemistry on paraffin-embedded lung tissue samples and quantified in alveolar and bronchial epithelium. Pulmonary ACE2 mRNA expression was not different between subjects with or without diabetes. In contrast, protein levels of ACE2 were significantly increased in both alveolar tissue and bronchial epithelium of patients with diabetes as compared with control subjects, independent of smoking, COPD, BMI, RAAS-inhibitor use and other potential confounders. To conclude, we show increased bronchial and alveolar ACE2 protein expression in patients with diabetes. Further research is needed to elucidate whether up-regulation of ACE2 expression in airways and lungs has consequences on infectivity and clinical outcomes of COVID-19.

scholarly journals Expression of ACE2, the SARS-CoV-2 receptor, in lung tissue of patients with type 2 diabetes

2020 ◽  
Author(s):  
Ada Admin ◽  
Sara RA Wijnant ◽  
Merel Jacobs ◽  
Hannelore P Van Eeckhoutte ◽  
Bruno Lapauw ◽  
...  
Keyword(s):  
Protein Expression ◽  
Mrna Expression ◽  
Lung Tissue ◽  
Bronchial Epithelium ◽  
Rt Pcr ◽  
Tissue Samples ◽  
Protein Levels ◽  
Patients With Diabetes ◽  
Alveolar Tissue ◽  
Control Samples

Increased expression of pulmonary ACE2, the SARS-CoV-2 receptor, could contribute to increased infectivity of COVID-19 in subjects with diabetes, but ACE2 expression has not been studied in lung tissue of subjects with diabetes. We therefore studied ACE2 mRNA and protein expression in lung tissue samples of patients with and without diabetes that were collected between 2002 and 2020 from patients undergoing lobectomy for lung tumors. For RT-PCR analyses, samples from 15 subjects with diabetes were compared to 91 randomly chosen control samples. For immunohistochemical staining, samples from 26 subjects with diabetes were compared to 66 randomly chosen control samples. mRNA expression of ACE2 was measured by quantitative RT-PCR. Protein levels of ACE2 were visualized by immunohistochemistry on paraffin-embedded lung tissue samples and quantified in alveolar and bronchial epithelium. Pulmonary ACE2 mRNA expression was not different between subjects with or without diabetes. In contrast, protein levels of ACE2 were significantly increased in both alveolar tissue and bronchial epithelium of patients with diabetes as compared with control subjects, independent of smoking, COPD, BMI, RAAS-inhibitor use and other potential confounders. To conclude, we show increased bronchial and alveolar ACE2 protein expression in patients with diabetes. Further research is needed to elucidate whether up-regulation of ACE2 expression in airways and lungs has consequences on infectivity and clinical outcomes of COVID-19.

scholarly journals Cigarette smoke-induced epithelial expression of WNT-5B: implications for COPD

2016 ◽  
Vol 48 (2) ◽  
pp. 504-515 ◽  
Author(s):  
Irene H. Heijink ◽  
Harold G. de Bruin ◽  
Robin Dennebos ◽  
Marnix R. Jonker ◽  
Jacobien A. Noordhoek ◽  
...  
Keyword(s):  
Cigarette Smoke ◽  
Lung Tissue ◽  
Transforming Growth Factor ◽  
Bronchial Epithelium ◽  
Smoke Exposure ◽  
Cigarette Smoke Exposure ◽  
Chronic Obstructive ◽  
Airway Remodelling ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients

Wingless/integrase-1 (WNT) signalling is associated with lung inflammation and repair, but its role in chronic obstructive pulmonary disease (COPD) pathogenesis is unclear. We investigated whether cigarette smoke-induced dysregulation of WNT-5B contributes to airway remodelling in COPD.We analysed WNT-5B protein expression in the lung tissue of COPD patients and (non)smoking controls, and investigated the effects of cigarette smoke exposure on WNT-5B expression in COPD and control-derived primary bronchial epithelial cells (PBECs). Additionally, we studied downstream effects of WNT-5B on remodelling related genes fibronectin, matrix metalloproteinase (MMP)-2, MMP-9 and SnaiI in BEAS-2B and air–liquid interface (ALI)-cultured PBECs.We observed that airway epithelial WNT-5B expression is significantly higher in lung tissue from COPD patients than controls. Cigarette smoke extract significantly increased mRNA expression of WNT-5B in COPD, but not control-derived PBECs. Exogenously added WNT-5B augmented the expression of remodelling related genes in BEAS-2B cells, which was mediated by transforming growth factor (TGF)-β/Smad3 signalling. In addition, WNT-5B upregulated the expression of these genes in ALI-cultured PBECs, particularly PBECs from COPD patients.Together, our results provide evidence that exaggerated WNT-5B expression upon cigarette smoke exposure in the bronchial epithelium of COPD patients leads to TGF-β/Smad3-dependent expression of genes related to airway remodelling.

Postnatal glucocorticoids induce α-ENaC formation and regulate glucocorticoid receptors in the preterm rabbit lung

2004 ◽  
Vol 286 (1) ◽  
pp. L73-L80 ◽  
Author(s):  
Shamimunisa B. Mustafa ◽  
Robert J. DiGeronimo ◽  
Jean A. Petershack ◽  
Joseph L. Alcorn ◽  
Steven R. Seidner
Keyword(s):  
Mrna Expression ◽  
Lung Tissue ◽  
Glucocorticoid Receptors ◽  
Fold Increase ◽  
Lung Epithelial Cells ◽  
Lung Water ◽  
Protein Levels ◽  
Tissue Weight ◽  
Postnatal Treatment ◽  
Distal Lung

At birth, lung fluid clearance is coupled to Na+ transport through epithelial Na+ channels (ENaC) in the distal lung epithelium. We evaluated the effect of postnatal glucocorticoids (GC) on lung α-ENaC expression in preterm 29-day gestational age (GA) fetal rabbits. Postnatal treatment of 29-day GA fetuses with 0.5 mg/kg of dexamethasone (Dex) iv resulted in a 2- and 22-fold increase in lung α-ENaC mRNA expression compared with saline-treated fetuses after 8 and 16 h, respectively. Lung α-ENaC protein levels in Dex-treated fetuses were also elevated compared with saline-treated counterparts. The extravascular lung water (EVLW)/dry lung tissue weight ratios of 29-day GA fetuses treated with either saline or Dex decreased over 24 h compared with that observed at birth; however, at 24 h, the EVLW/dry lung tissue weight ratios of saline- and Dex-treated fetuses were similar. Dex-induced α-ENaC mRNA and protein levels were attenuated by glucocorticoid receptor (GCR) antagonist RU-486 in fetal distal lung epithelial cells isolated from 29-day GA fetuses, indicating that GC-dependent augmentation of lung α-ENaC requires the presence of functional GCR. Lung GCR mRNA expression and protein levels were elevated in 29-day GA fetuses compared with fetuses at earlier GA. Exposure of 29-day GA fetuses to Dex for 16 h caused a 2.1-fold increase in lung GCR mRNA expression, but GCR protein levels were decreased in Dex-treated fetuses after 24 h. We conclude that postnatal treatment of preterm 29-day GA fetal rabbits with GC results in an elevation of lung α-ENaC accompanied by an autoregulation of pulmonary GCR.

Adenoviral E1A primes alveolar epithelial cells to PM10-induced transcription of interleukin-8

2001 ◽  
Vol 281 (3) ◽  
pp. L598-L606 ◽  
Author(s):  
Peter S. Gilmour ◽  
Irfan Rahman ◽  
Shizu Hayashi ◽  
James C. Hogg ◽  
Kenneth Donaldson ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Epithelial Cells ◽  
Mrna Expression ◽  
Protein Release ◽  
Alveolar Epithelial Cells ◽  
Chronic Obstructive ◽  
Alveolar Epithelial ◽  
Nuclear Binding ◽  
Increased Risk ◽  
Proinflammatory Responses

The presence of the adenoviral early region 1A (E1A) protein in human lungs has been associated with an increased risk of chronic obstructive pulmonary disease (COPD), possibly by a mechanism involving amplification of proinflammatory responses. We hypothesize that enhanced inflammation results from increased transcription factor activation in E1A-carrying cells, which may afford susceptibility to environmental particulate matter < 10 μm (PM10)-mediated oxidative stress. We measured interleukin (IL)-8 mRNA expression and protein release in human alveolar epithelial cells (A549) transfected with the E1A gene (E1A+ve). Both E1A+ve and −ve cells released IL-8 after incubation with TNF-α, but only E1A+ve cells were sensitive to LPS stimulation in IL-8 mRNA expression and protein release. E1A+ve cells showed an enhanced IL-8 mRNA and protein response after treatment with H2O2and PM10. E1A-enhanced induction of IL-8 was accompanied by increases in activator protein-1 and nuclear factor-κB nuclear binding in E1A+ve cells, which also showed higher basal nuclear binding of these transcription factors. These data suggest that the presence of E1A primes the cell transcriptional machinery for oxidative stress signaling and therefore facilitates amplification of proinflammatory responses. By this mechanism, susceptibility to exacerbation of COPD in response to particulate air pollution may occur in individuals harboring E1A.

Cigarette smoke-induced disruption of pulmonary barrier and bacterial translocation drive tumor-associated inflammation and growth

2015 ◽  
Vol 309 (6) ◽  
pp. L605-L613 ◽  
Author(s):  
C. Jungnickel ◽  
B. Wonnenberg ◽  
O. Karabiber ◽  
A. Wolf ◽  
M. Voss ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cigarette Smoke ◽  
Tumor Tissue ◽  
Human Cancer ◽  
Bacterial Pathogens ◽  
Microbial Colonization ◽  
Chronic Obstructive ◽  
Tumor Proliferation ◽  
Increased Risk ◽  
Metastatic Growth

Microorganisms have an important role in tumorgenesis by the induction of inflammation and by a direct impact on tumor cells. Chronic obstructive pulmonary disease (COPD) is associated with an increased risk for lung cancer and microbial colonization. We asked whether bacterial pathogens act as tumor promoters during CS-induced pulmonary inflammation. In a metastatic lung cancer (LC) model, Lewis lung carcinoma (LLC) cells were injected in mice to initiate the growth of tumors in the lung. Exposure to the combination of cigarette smoke (CS) and nontypeable Haemophilus influenzae (NTHi) synergistically increased metastatic growth. Lung levels of albumin and LDH, translocation of bacterial factors into tumor tissue, tumor inflammation, and tumor proliferation were significantly increased in mice exposed to CS in combination with NTHi. Bacterial pathogens increased the proliferation of cultured LLC cells and human cancer cell lines. Metastatic growth induced by the exposure to CS in combination with NTHi was reduced in mice deficient for IL-17. Our data provide evidence that CS-induced loss of pulmonary barrier integrity allows bacterial factors to translocate into tumor tissue and to regulate tumor-associated inflammation and tumor proliferation. Translocation of bacterial factors in tumor tissue links CS-induced inflammation with tumor proliferation.

scholarly journals Omacor Protects Normotensive and Hypertensive Rats Exposed to Continuous Light from Increased Risk to Malignant Cardiac Arrhythmias

Marine Drugs ◽  
2021 ◽  
Vol 19 (12) ◽  
pp. 659
Author(s):  
Tamara Egan Benova ◽  
Csilla Viczenczova ◽  
Barbara Szeiffova Bacova ◽  
Jitka Zurmanova ◽  
Vladimir Knezl ◽  
...  
Keyword(s):  
Connexin 43 ◽  
Electrical Coupling ◽  
Continuous Light ◽  
Male Rat ◽  
Human Populations ◽  
Omega 3 ◽  
Spontaneously Hypertensive ◽  
Protein Levels ◽  
Populations At Risk ◽  
Increased Risk

Light pollution disturbs circadian rhythm, and this can also be deleterious to the heart by increased susceptibility to arrhythmias. Herein, we investigated if rats exposed to continuous light had altered myocardial gene transcripts and/or protein expression which affects arrhythmogenesis. We then assessed if Omacor® supplementation benefitted affected rats. Male and female spontaneously hypertensive (SHR) and normotensive Wistar rats (WR) were housed under standard 12 h/12 h light/dark cycles or exposed to 6-weeks continuous 300 lux light for 24 h. Half the rats were then treated with 200 mg/100 g b.w. Omacor®. Continuous light resulted in higher male rat vulnerability to malignant ventricular fibrillation (VF). This was linked with myocardial connexin-43 (Cx43) down-regulation and deteriorated intercellular electrical coupling, due in part to increased pro-inflammatory NF-κB and iNOS transcripts and decreased sarcoplasmic reticulum Ca2+ATPase transcripts. Omacor® treatment increased the electrical threshold to induce the VF linked with amelioration of myocardial Cx43 mRNA and Cx43 protein levels and the suppression of NF-κB and iNOS. This indicates that rat exposure to continuous light results in deleterious cardiac alterations jeopardizing intercellular Cx43 channel-mediated electrical communication, thereby increasing the risk of malignant arrhythmias. The adverse effects were attenuated by treatment with Omacor®, thus supporting its potential benefit and the relevance of monitoring omega-3 index in human populations at risk.

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