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Article ; Online: The airway epithelium in asthma.

Bonser, Luke R / Erle, David J

2019 Volume 142, Page(s) 1–34

Abstract: Asthma is a genetically and phenotypically complex disease that has a major impact on global health. Signs and symptoms of asthma are caused by the obstruction of airflow through the airways. The epithelium that lines the airways plays a major role in ... ...

Abstract	Asthma is a genetically and phenotypically complex disease that has a major impact on global health. Signs and symptoms of asthma are caused by the obstruction of airflow through the airways. The epithelium that lines the airways plays a major role in maintaining airway patency and in host defense. The epithelium initiates responses to inhaled or aspirated substances, including allergens, viruses, and bacteria, and epithelial-derived cytokines are important in the recruitment and activation of immune cells in the airway. Changes in the structure and function of the airway epithelium are a prominent feature of asthma. Approximately half of individuals with asthma have evidence of active type 2 immune responses in the airway. In these individuals, epithelial cytokines promote type 2 responses, and responses to type 2 cytokines result in increased epithelial mucus production and other effects that cause airway obstruction. Recent work also implicates other epithelial responses, including interleukin-17, interferon and ER stress responses, that may contribute to asthma pathogenesis and provide new targets for therapy.
MeSH term(s)	Alarmins/metabolism ; Allergens/immunology ; Animals ; Asthma/etiology ; Asthma/immunology ; Asthma/metabolism ; Endoplasmic Reticulum/immunology ; Endoplasmic Reticulum/metabolism ; Humans ; Interferons/metabolism ; Interleukin-13/metabolism ; Interleukin-17/metabolism ; Lung/immunology ; Lung/metabolism ; Respiratory Mucosa/cytology ; Respiratory Mucosa/immunology
Chemical Substances	Alarmins ; Allergens ; Interleukin-13 ; Interleukin-17 ; Interferons (9008-11-1)
Language	English
Publishing date	2019-07-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	80226-8
ISSN	1557-8445 ; 0065-2776
ISSN (online)	1557-8445
ISSN	0065-2776
DOI	10.1016/bs.ai.2019.05.001
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Article ; Online: Putting Mucins on the Map.

Bonser, Luke R / Erle, David J

American journal of respiratory and critical care medicine

2018 Volume 199, Issue 6, Page(s) 681–682

MeSH term(s)	Humans ; Mucin 5AC ; Mucin-5B ; Mucins ; Respiratory System
Chemical Substances	MUC5AC protein, human ; MUC5B protein, human ; Mucin 5AC ; Mucin-5B ; Mucins
Language	English
Publishing date	2018-10-29
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	1180953-x
ISSN	1535-4970 ; 0003-0805 ; 1073-449X
ISSN (online)	1535-4970
ISSN	0003-0805 ; 1073-449X
DOI	10.1164/rccm.201809-1818ED
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Article: Airway Mucus and Asthma: The Role of MUC5AC and MUC5B.

Bonser, Luke R / Erle, David J

Journal of clinical medicine

2017 Volume 6, Issue 12

Abstract: Asthma is characterized by mucus abnormalities. Airway epithelial hyperplasia and metaplasia result in changes in stored and secreted mucin and the production of a pathologic mucus gel. Mucus transport is impaired, culminating in mucus plugging and ... ...

Abstract	Asthma is characterized by mucus abnormalities. Airway epithelial hyperplasia and metaplasia result in changes in stored and secreted mucin and the production of a pathologic mucus gel. Mucus transport is impaired, culminating in mucus plugging and airway obstruction-a major cause of morbidity in asthma. The polymeric mucins MUC5AC and MUC5B are integral components of airway mucus.
Language	English
Publishing date	2017-11-29
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2662592-1
ISSN	2077-0383
ISSN	2077-0383
DOI	10.3390/jcm6120112
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Article ; Online: Genomic characterization and therapeutic utilization of IL-13-responsive sequences in asthma.

Koh, Kyung Duk / Bonser, Luke R / Eckalbar, Walter L / Yizhar-Barnea, Ofer / Shen, Jiangshan / Zeng, Xiaoning / Hargett, Kirsten L / Sun, Dingyuan I / Zlock, Lorna T / Finkbeiner, Walter E / Ahituv, Nadav / Erle, David J

Cell genomics

2022 Volume 3, Issue 1, Page(s) 100229

Abstract: Epithelial responses to the cytokine interleukin-13 (IL-13) cause airway obstruction in asthma. Here we utilized multiple genomic techniques to identify IL-13-responsive regulatory elements in bronchial epithelial cells and used these data to develop a ... ...

Abstract	Epithelial responses to the cytokine interleukin-13 (IL-13) cause airway obstruction in asthma. Here we utilized multiple genomic techniques to identify IL-13-responsive regulatory elements in bronchial epithelial cells and used these data to develop a CRISPR interference (CRISPRi)-based therapeutic approach to downregulate airway obstruction-inducing genes in a cell type- and IL-13-specific manner. Using single-cell RNA sequencing (scRNA-seq) and acetylated lysine 27 on histone 3 (H3K27ac) chromatin immunoprecipitation sequencing (ChIP-seq) in primary human bronchial epithelial cells, we identified IL-13-responsive genes and regulatory elements. These sequences were functionally validated and optimized via massively parallel reporter assays (MPRAs) for IL-13-inducible activity. The top secretory cell-selective sequence from the MPRA, a novel, distal enhancer of the sterile alpha motif pointed domain containing E-26 transformation-specific transcription factor (
Language	English
Publishing date	2022-12-07
Publishing country	United States
Document type	Journal Article
ISSN	2666-979X
ISSN (online)	2666-979X
DOI	10.1016/j.xgen.2022.100229
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Article ; Online: Airway Mucus and Asthma

Luke R. Bonser / David J. Erle

Journal of Clinical Medicine, Vol 6, Iss 12, p

The Role of MUC5AC and MUC5B

2017 Volume 112

Abstract	Asthma is characterized by mucus abnormalities. Airway epithelial hyperplasia and metaplasia result in changes in stored and secreted mucin and the production of a pathologic mucus gel. Mucus transport is impaired, culminating in mucus plugging and airway obstruction—a major cause of morbidity in asthma. The polymeric mucins MUC5AC and MUC5B are integral components of airway mucus. MUC5AC and MUC5B gene expression is altered in asthma, and recent work sheds light on their contribution to asthma pathogenesis. Herein, we review our current understanding of the role of MUC5AC and MUC5B in mucus dysfunction in asthma.
Keywords	MUC5AC ; MUC5B ; asthma ; Medicine ; R
Language	English
Publishing date	2017-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The Type 2 Asthma Mediator IL-13 Inhibits Severe Acute Respiratory Syndrome Coronavirus 2 Infection of Bronchial Epithelium.

Bonser, Luke R / Eckalbar, Walter L / Rodriguez, Lauren / Shen, Jiangshan / Koh, Kyung Duk / Ghias, Khadija / Zlock, Lorna T / Christenson, Stephanie / Woodruff, Prescott G / Finkbeiner, Walter E / Erle, David J

American journal of respiratory cell and molecular biology

2022 Volume 66, Issue 4, Page(s) 391–401

Abstract: Asthma is associated with chronic changes in the airway epithelium, a key target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Many epithelial changes, including goblet cell metaplasia, are driven by the type 2 cytokine IL-13, but the ... ...

Abstract	Asthma is associated with chronic changes in the airway epithelium, a key target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Many epithelial changes, including goblet cell metaplasia, are driven by the type 2 cytokine IL-13, but the effects of IL-13 on SARS-CoV-2 infection are unknown. We found that IL-13 stimulation of differentiated human bronchial epithelial cells (HBECs) cultured at air-liquid interface reduced viral RNA recovered from SARS-CoV-2-infected cells and decreased double-stranded RNA, a marker of viral replication, to below the limit of detection in our assay. An intact mucus gel reduced SARS-CoV-2 infection of unstimulated cells, but neither a mucus gel nor SPDEF, which is required for goblet cell metaplasia, were required for the antiviral effects of IL-13. Bulk RNA sequencing revealed that IL-13 regulated 41 of 332 (12%) mRNAs encoding SARS-CoV-2-associated proteins that were detected in HBECs (>1.5-fold change; false discovery rate < 0.05). Although both IL-13 and IFN-α each inhibit SARS-CoV-2 infection, their transcriptional effects differed markedly. Single-cell RNA sequencing revealed cell type-specific differences in SARS-CoV-2-associated gene expression and IL-13 responses. Many IL-13-induced gene expression changes were seen in airway epithelium from individuals with type 2 asthma and chronic obstructive pulmonary disease. IL-13 effects on airway epithelial cells may protect individuals with type 2 asthma from COVID-19 and could lead to identification of novel strategies for reducing SARS-CoV-2 infection.
MeSH term(s)	Asthma ; COVID-19 ; Cells, Cultured ; Epithelial Cells ; Epithelium ; Humans ; Interleukin-13/pharmacology ; SARS-CoV-2
Chemical Substances	Interleukin-13
Language	English
Publishing date	2022-01-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1025960-0
ISSN	1535-4989 ; 1044-1549
ISSN (online)	1535-4989
ISSN	1044-1549
DOI	10.1165/rcmb.2021-0364OC
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Article ; Online: Genomic characterization and therapeutic utilization of IL-13-responsive sequences in asthma

Kyung Duk Koh / Luke R. Bonser / Walter L. Eckalbar / Ofer Yizhar-Barnea / Jiangshan Shen / Xiaoning Zeng / Kirsten L. Hargett / Dingyuan I. Sun / Lorna T. Zlock / Walter E. Finkbeiner / Nadav Ahituv / David J. Erle

Cell Genomics, Vol 3, Iss 1, Pp 100229- (2023)

2023

Abstract: Summary: Epithelial responses to the cytokine interleukin-13 (IL-13) cause airway obstruction in asthma. Here we utilized multiple genomic techniques to identify IL-13-responsive regulatory elements in bronchial epithelial cells and used these data to ... ...

Abstract	Summary: Epithelial responses to the cytokine interleukin-13 (IL-13) cause airway obstruction in asthma. Here we utilized multiple genomic techniques to identify IL-13-responsive regulatory elements in bronchial epithelial cells and used these data to develop a CRISPR interference (CRISPRi)-based therapeutic approach to downregulate airway obstruction-inducing genes in a cell type- and IL-13-specific manner. Using single-cell RNA sequencing (scRNA-seq) and acetylated lysine 27 on histone 3 (H3K27ac) chromatin immunoprecipitation sequencing (ChIP-seq) in primary human bronchial epithelial cells, we identified IL-13-responsive genes and regulatory elements. These sequences were functionally validated and optimized via massively parallel reporter assays (MPRAs) for IL-13-inducible activity. The top secretory cell-selective sequence from the MPRA, a novel, distal enhancer of the sterile alpha motif pointed domain containing E-26 transformation-specific transcription factor (SPDEF) gene, was utilized to drive CRISPRi and knock down SPDEF or mucin 5AC (MUC5AC), both involved in pathologic mucus production in asthma. Our work provides a catalog of cell type-specific genes and regulatory elements involved in IL-13 bronchial epithelial response and showcases their use for therapeutic purposes.
Keywords	enhancer ; IL-13 ; cell-specific ; CRISPRi ; HBEC ; SPDEF ; Genetics ; QH426-470 ; Internal medicine ; RC31-1245
Subject code	572
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Fluorogenic reporter enables identification of compounds that inhibit SARS-CoV-2.

Nature microbiology

2023 Volume 8, Issue 1, Page(s) 121–134

Abstract: The coronavirus SARS-CoV-2 causes the severe disease COVID-19. SARS-CoV-2 infection is initiated by interaction of the viral spike protein and host receptor angiotensin-converting enzyme 2 (ACE2). We report an improved bright and reversible fluorogenic ... ...

Abstract	The coronavirus SARS-CoV-2 causes the severe disease COVID-19. SARS-CoV-2 infection is initiated by interaction of the viral spike protein and host receptor angiotensin-converting enzyme 2 (ACE2). We report an improved bright and reversible fluorogenic reporter, named SURF (split UnaG-based reversible and fluorogenic protein-protein interaction reporter), that we apply to monitor real-time interactions between spike and ACE2 in living cells. SURF has a large dynamic range with a dark-to-bright fluorescence signal that requires no exogenous cofactors. Utilizing this reporter, we carried out a high-throughput screening of small-molecule libraries. We identified three natural compounds that block replication of SARS-CoV-2 in both Vero cells and human primary nasal and bronchial epithelial cells. Cell biological and biochemical experiments validated all three compounds and showed that they block the early stages of viral infection. Two of the inhibitors, bruceine A and gamabufotalin, were also found to block replication of the Delta and Omicron variants of SARS-CoV-2. Both bruceine A and gamabufotalin exhibited potent antiviral activity in K18-hACE2 and wild-type C57BL6/J mice, as evidenced by reduced viral titres in the lung and brain, and protection from alveolar and peribronchial inflammation in the lung, thereby limiting disease progression. We propose that our fluorescent assay can be applied to identify antiviral compounds with potential as therapeutic treatment for COVID-19 and other respiratory diseases.
MeSH term(s)	Chlorocebus aethiops ; Mice ; Humans ; Animals ; SARS-CoV-2/metabolism ; COVID-19 ; Vero Cells ; Angiotensin-Converting Enzyme 2 ; Peptidyl-Dipeptidase A/metabolism ; Antiviral Agents/pharmacology
Chemical Substances	bruceine A (25514-31-2) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Peptidyl-Dipeptidase A (EC 3.4.15.1) ; Antiviral Agents
Language	English
Publishing date	2023-01-05
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	2058-5276
ISSN (online)	2058-5276
DOI	10.1038/s41564-022-01288-5
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Article ; Online: Epithelial tethering of MUC5AC-rich mucus impairs mucociliary transport in asthma.

Bonser, Luke R / Zlock, Lorna / Finkbeiner, Walter / Erle, David J

The Journal of clinical investigation

2016 Volume 126, Issue 6, Page(s) 2367–2371

Abstract: The development of pathologic mucus, which is not readily cleared from the airways, is an important contributor to the morbidity and mortality associated with asthma. It is not clear how the major airway mucins MUC5AC and MUC5B are organized within the ... ...

Abstract	The development of pathologic mucus, which is not readily cleared from the airways, is an important contributor to the morbidity and mortality associated with asthma. It is not clear how the major airway mucins MUC5AC and MUC5B are organized within the mucus gel or how this gel contributes to airway obstruction in asthma. Here, we demonstrated that mucus plugs from individuals with fatal asthma are heterogeneous gels with distinct MUC5AC- and MUC5B-containing domains. Stimulation of cultured human bronchial epithelial cells with IL-13, a key mediator in asthma, induced the formation of heterogeneous mucus gels and dramatically impaired mucociliary transport. Impaired transport was not associated with defects in ciliary function but instead was related to tethering of MUC5AC-containing mucus gel domains to mucus-producing cells in the epithelium. Replacement of tethered mucus with untethered mucus restored mucociliary transport. Together, our results indicate that tethering of MUC5AC-containing domains to the epithelium causes mucostasis and likely represents a major cause of mucus plugging in asthma.
MeSH term(s)	Airway Obstruction/etiology ; Airway Obstruction/physiopathology ; Asthma/complications ; Asthma/physiopathology ; Case-Control Studies ; Gels ; Humans ; Mucin 5AC/metabolism ; Mucin-5B/metabolism ; Mucociliary Clearance/physiology ; Mucus/metabolism ; Respiratory Mucosa/physiopathology
Chemical Substances	Gels ; MUC5AC protein, human ; MUC5B protein, human ; Mucin 5AC ; Mucin-5B
Language	English
Publishing date	2016--01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI84910
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Article: The type 2 asthma mediator IL-13 inhibits SARS-CoV-2 infection of bronchial epithelium.

Bonser, Luke R / Eckalbar, Walter L / Rodriguez, Lauren / Shen, Jiangshan / Koh, Kyung Duk / Zlock, Lorna T / Christenson, Stephanie / Woodruff, Prescott G / Finkbeiner, Walter E / Erle, David J

bioRxiv : the preprint server for biology

2021

Abstract: Rationale: Asthma is associated with chronic changes in the airway epithelium, a key target of SARS-CoV-2. Many epithelial changes are driven by the type 2 cytokine IL-13, but the effects of IL-13 on SARS-CoV-2 infection are unknown.: Objectives: We ... ...

Abstract	Rationale: Asthma is associated with chronic changes in the airway epithelium, a key target of SARS-CoV-2. Many epithelial changes are driven by the type 2 cytokine IL-13, but the effects of IL-13 on SARS-CoV-2 infection are unknown. Objectives: We sought to discover how IL-13 and other cytokines affect expression of genes encoding SARS-CoV-2-associated host proteins in human bronchial epithelial cells (HBECs) and determine whether IL-13 stimulation alters susceptibility to SARS-CoV-2 infection. Methods: We used bulk and single cell RNA-seq to identify cytokine-induced changes in SARS-CoV-2-associated gene expression in HBECs. We related these to gene expression changes in airway epithelium from individuals with mild-moderate asthma and chronic obstructive pulmonary disease (COPD). We analyzed effects of IL-13 on SARS-CoV-2 infection of HBECs. Measurements and main results: Transcripts encoding 332 of 342 (97%) SARS-CoV-2-associated proteins were detected in HBECs (≥1 RPM in 50% samples). 41 (12%) of these mRNAs were regulated by IL-13 (>1.5-fold change, FDR < 0.05). Many IL-13-regulated SARS-CoV-2-associated genes were also altered in type 2 high asthma and COPD. IL-13 pretreatment reduced viral RNA recovered from SARS-CoV-2 infected cells and decreased dsRNA, a marker of viral replication, to below the limit of detection in our assay. Mucus also inhibited viral infection. Conclusions: IL-13 markedly reduces susceptibility of HBECs to SARS-CoV-2 infection through mechanisms that likely differ from those activated by type I interferons. Our findings may help explain reports of relatively low prevalence of asthma in patients diagnosed with COVID-19 and could lead to new strategies for reducing SARS-CoV-2 infection.
Language	English
Publishing date	2021-02-25
Publishing country	United States
Document type	Preprint
DOI	10.1101/2021.02.25.432762
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