In well-differentiated primary human bronchial epithelial cells, TGF-<b>β</b>1 and TGF-<b>β</b>2 induce expression of furin

O’Sullivan, Michael J.; Mitchel, Joseph F.; Mwase, C.; McGill, Maureen; Kanki, Phyllis; Park, Jin‐Ah

doi:10.1152/ajplung.00423.2020

Cited by 19 publications

(20 citation statements)

References 47 publications

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“…results from NHBECs studies because these experiments were performed with basal cells in submerged culture and not with differentiated cells in air-liquid interface culture. The receptors of IAV and SARS-CoV-2 are expressed in differentiated epithelial cells, including goblet and ciliated cells [71][72][73]. Thus, the air-liquid interface culture system is a better model for studying pathologic processes during viral infection 71.…”

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confidence: 99%

Tissue factor expression, extracellular vesicles, and thrombosis after infection with the respiratory viruses influenza A virus and coronavirus

Mackman

Grover

Antoniak

2021

Journal of Thrombosis and Haemostasis

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Tissue factor (TF) is induced in a variety of cell types during viral infection, which likely contributes to disseminated intravascular coagulation and thrombosis. TFexpressing cells also release TF-positive extracellular vesicles (EVs) into the circulation that can be measured using an EVTF activity assay. This review summarizes studies that analyze TF expression, TF-positive EVs, activation of coagulation, and thrombosis after infection with influenza A virus (IAV) and coronaviruses (CoVs), including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), SARS-CoV, and Middle East respiratory syndrome CoV (MERS-CoV). The current pandemic of coronavirus disease 2019 (COVID-19) is caused by infection with SARS-CoV-2. Infection of mice with IAV increased TF expression in lung epithelial cells as well as increased EVTF activity and activation of coagulation in the bronchoalveolar lavage fluid (BALF). Infection of mice with MERS-CoV, SARS-CoV, and SARS-CoV-2 also increased lung TF expression. Single-cell RNA sequencing analysis on the BALF from severe COVID-19 patients revealed increased TF mRNA expression in epithelial cells. TF expression was observed in peripheral blood mononuclear cells infected with SARS-CoV. TF was also expressed by peripheral blood mononuclear cells, monocytes in platelet-monocyte aggregates, and neutrophils isolated from COVID-19 patients. Elevated circulating EVTF activity was observed in severe IAV and COVID-19 patients. Importantly, EVTF activity was associated with mortality in severe IAV patients and with plasma D-dimer, severity, thrombosis, and mortality in COVID-19 patients. These studies strongly suggest that increased TF expression in patients infected with IAV and pathogenic CoVs contributes to thrombosis.

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confidence: 99%

Tissue factor expression, extracellular vesicles, and thrombosis after infection with the respiratory viruses influenza A virus and coronavirus

Mackman

Grover

Antoniak

2021

Journal of Thrombosis and Haemostasis

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“…A recent study indicated that osthole suppressed TGF-β1-induced epithelial-mesenchymal transition (EMT) in lung cancer A549 cells [32]. Because TGF-β1 activates furin expression in several cell lines [33,34], and Ethanol extracts of crude drugs (20 µg/mL) were pre-incubated with cell lysates and added to fluorogenic substrates (pyr-RTKR-MCA).…”

Section: Resultsmentioning

confidence: 99%

Screening for inhibitory effects of crude drugs on furin-like enzymatic activities

Kiba

Misawa

et al. 2021

J Nat Med

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The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contains a cleavage motif R-X-X-R for furin-like enzymes at the boundary of the S1/S2 subunits. The cleavage of the site by cellular proteases is essential for S protein activation and virus entry. We screened the inhibitory effects of crude drugs on in vitro furin-like enzymatic activities using a fluorogenic substrate with whole-cell lysates. Of the 124 crude drugs listed in the Japanese Pharmacopeia, aqueous ethanolic extract of Cnidii Monnieris Fructus, which is the dried fruit of Cnidium monnieri Cussion, significantly inhibited the furin-like enzymatic activities. We further fractionated the plant extract and isolated the two active compounds with the inhibitory activity, namely, imperatorin and osthole, whose IC 50 values were 1.45 mM and 9.45 µM, respectively. Our results indicated that Cnidii Monnieris Fructus might exert inhibitory effects on furin-like enzymatic activities, and that imperatorin and osthole of the crude drug could be potential inhibitors of the motif cleavage.

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“…ACE2 expression was predominantly observed in ciliated epithelial cells consistent with single-cell transcriptomics data showing higher expression of ACE2 in ciliated cells compared with goblet cells, and with immunohistochemical staining in bronchial tissues ( Hikmet et al, 2020 ; Lee et al, 2020 ; Gerayeli et al, 2021 ). TMPRSS2 and furin, like ACE2, are localized to ciliated cells ( O'Sullivan et al, 2021 ). Thus, the higher the proportion of secretory cells, the lower the level of ACE2.…”

Section: Discussionmentioning

confidence: 99%

ACE2 Expression in Organotypic Human Airway Epithelial Cultures and Airway Biopsies

Chen

Langenbach

et al. 2022

Front. Pharmacol.

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Coronavirus disease 2019 (COVID-19) caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an acute respiratory disease with systemic complications. Therapeutic strategies for COVID-19, including repurposing (partially) developed drugs are urgently needed, regardless of the increasingly successful vaccination outcomes. We characterized two-dimensional (2D) and three-dimensional models (3D) to establish a physiologically relevant airway epithelial model with potential for investigating SARS-CoV-2 therapeutics. Human airway basal epithelial cells maintained in submerged 2D culture were used at low passage to retain the capacity to differentiate into ciliated, club, and goblet cells in both air-liquid interface culture (ALI) and airway organoid cultures, which were then analyzed for cell phenotype makers. Airway biopsies from non-asthmatic and asthmatic donors enabled comparative evaluation of the level and distribution of immunoreactive angiotensin-converting enzyme 2 (ACE2). ACE2 and transmembrane serine proteinase 2 (TMPRSS2) mRNA were expressed in ALI and airway organoids at levels similar to those of native (i.e., non-cultured) human bronchial epithelial cells, whereas furin expression was more faithfully represented in ALI. ACE2 was mainly localized to ciliated and basal epithelial cells in human airway biopsies, ALI, and airway organoids. Cystic fibrosis appeared to have no influence on ACE2 gene expression. Neither asthma nor smoking status had consistent marked influence on the expression or distribution of ACE2 in airway biopsies. SARS-CoV-2 infection of ALI cultures did not increase the levels of selected cytokines. Organotypic, and particularly ALI airway cultures are useful and practical tools for investigation of SARS-CoV-2 infection and evaluating the clinical potential of therapeutics for COVID-19.

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In well-differentiated primary human bronchial epithelial cells, TGF-β1 and TGF-β2 induce expression of furin

Cited by 19 publications

References 47 publications

Tissue factor expression, extracellular vesicles, and thrombosis after infection with the respiratory viruses influenza A virus and coronavirus

Tissue factor expression, extracellular vesicles, and thrombosis after infection with the respiratory viruses influenza A virus and coronavirus

Screening for inhibitory effects of crude drugs on furin-like enzymatic activities

ACE2 Expression in Organotypic Human Airway Epithelial Cultures and Airway Biopsies

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