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Article ; Online: The Impact of Hypoxia on Neutrophil Degranulation and Consequences for the Host.

Lodge, Katharine M / Cowburn, Andrew S / Li, Wei / Condliffe, Alison M

International journal of molecular sciences

2020 Volume 21, Issue 4

Abstract: Neutrophils are key effector cells of innate immunity, rapidly recruited to defend the host against invading pathogens. Neutrophils may kill pathogens intracellularly, following phagocytosis, or extracellularly, by degranulation and the release of ... ...

Abstract	Neutrophils are key effector cells of innate immunity, rapidly recruited to defend the host against invading pathogens. Neutrophils may kill pathogens intracellularly, following phagocytosis, or extracellularly, by degranulation and the release of neutrophil extracellular traps; all of these microbicidal strategies require the deployment of cytotoxic proteins and proteases, packaged during neutrophil development within cytoplasmic granules. Neutrophils operate in infected and inflamed tissues, which can be profoundly hypoxic. Neutrophilic infiltration of hypoxic tissues characterises a myriad of acute and chronic infectious and inflammatory diseases, and as well as potentially protecting the host from pathogens, neutrophil granule products have been implicated in causing collateral tissue damage in these scenarios. This review discusses the evidence for the enhanced secretion of destructive neutrophil granule contents observed in hypoxic environments and the potential mechanisms for this heightened granule exocytosis, highlighting implications for the host. Understanding the dichotomy of the beneficial and detrimental consequences of neutrophil degranulation in hypoxic environments is crucial to inform potential neutrophil-directed therapeutics in order to limit persistent, excessive, or inappropriate inflammation.
MeSH term(s)	Animals ; Cell Degranulation ; Cell Hypoxia ; Extracellular Traps/immunology ; Humans ; Hypoxia/immunology ; Immunity, Innate ; Infections/immunology ; Inflammation/immunology ; Neutrophil Activation ; Neutrophils/cytology ; Neutrophils/immunology ; Neutrophils/physiology ; Secretory Vesicles/immunology
Language	English
Publishing date	2020-02-11
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms21041183
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Endothelial cell regulation of systemic haemodynamics and metabolism acts through the HIF transcription factors.

Lambden, Simon / Cowburn, Andrew S / Macias, David / Garrud, Tessa A C / Krause, Bernardo J / Giussani, Dino A / Summers, Charlotte / Johnson, Randall S

Intensive care medicine experimental

2021 Volume 9, Issue 1, Page(s) 28

Abstract: Background: The vascular endothelium has important endocrine and paracrine roles, particularly in the regulation of vascular tone and immune function, and it has been implicated in the pathophysiology of a range of cardiovascular and inflammatory ... ...

Abstract	Background: The vascular endothelium has important endocrine and paracrine roles, particularly in the regulation of vascular tone and immune function, and it has been implicated in the pathophysiology of a range of cardiovascular and inflammatory conditions. This study uses a series of transgenic murine models to explore for the first time the role of the hypoxia-inducible factors, HIF-1α and HIF-2α in the pulmonary and systemic circulations as potential regulators of systemic vascular function in normoxic or hypoxic conditions and in response to inflammatory stress. We developed a series of transgenic mouse models, the HIF-1α Tie2Cre, deficient in HIF1-α in the systemic and pulmonary vascular endothelium and the L1Cre, a pulmonary endothelium specific knockout of HIF-1α or HIF-2α. In vivo, arterial blood pressure and metabolic activity were monitored continuously in normal atmospheric conditions and following an acute stimulus with hypoxia (10%) or lipopolysaccharide (LPS). Ex vivo, femoral artery reactivity was assessed using wire myography. Results: Under normoxia, the HIF-1α Tie2Cre mouse had increased systolic and diastolic arterial pressure compared to litter mate controls over the day-night cycle under normal environmental conditions. VO Conclusions: These data show that deficiency of HIF-1α in the systemic or pulmonary endothelium is associated with increased systemic blood pressure and metabolic rate, a pattern that persists in both normoxic conditions and in response to acute stress with potential implications for our understanding of the pathophysiology of vascular dysfunction in acute and chronic disease.
Language	English
Publishing date	2021-06-11
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2740385-3
ISSN	2197-425X
ISSN	2197-425X
DOI	10.1186/s40635-021-00390-y
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Article ; Online: The Impact of Hypoxia on Neutrophil Degranulation and Consequences for the Host

Katharine M. Lodge / Andrew S. Cowburn / Wei Li / Alison M. Condliffe

International Journal of Molecular Sciences, Vol 21, Iss 4, p

2020 Volume 1183

Abstract	Neutrophils are key effector cells of innate immunity, rapidly recruited to defend the host against invading pathogens. Neutrophils may kill pathogens intracellularly, following phagocytosis, or extracellularly, by degranulation and the release of neutrophil extracellular traps; all of these microbicidal strategies require the deployment of cytotoxic proteins and proteases, packaged during neutrophil development within cytoplasmic granules. Neutrophils operate in infected and inflamed tissues, which can be profoundly hypoxic. Neutrophilic infiltration of hypoxic tissues characterises a myriad of acute and chronic infectious and inflammatory diseases, and as well as potentially protecting the host from pathogens, neutrophil granule products have been implicated in causing collateral tissue damage in these scenarios. This review discusses the evidence for the enhanced secretion of destructive neutrophil granule contents observed in hypoxic environments and the potential mechanisms for this heightened granule exocytosis, highlighting implications for the host. Understanding the dichotomy of the beneficial and detrimental consequences of neutrophil degranulation in hypoxic environments is crucial to inform potential neutrophil-directed therapeutics in order to limit persistent, excessive, or inappropriate inflammation.
Keywords	neutrophils ; hypoxia ; degranulation ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Language	English
Publishing date	2020-02-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Lithographically defined encoded magnetic heterostructures for the targeted screening of kidney cancer.

Leulmi Pichot, Selma / Vemulkar, Tarun / Verheyen, Jeroen / Wallis, Lauren / Jones, James O / Stewart, Andrew P / Welsh, Sarah J / Stewart, Grant D / Cowburn, Russell P

Nanoscale advances

2023 Volume 6, Issue 1, Page(s) 276–286

Abstract: Renal cell carcinoma (RCC) is the 7th commonest cancer in the UK and the most lethal urological malignancy; 50% of all RCC patients will die from the condition. However, if identified early enough, small RCCs are usually cured by surgery or percutaneous ... ...

Abstract	Renal cell carcinoma (RCC) is the 7th commonest cancer in the UK and the most lethal urological malignancy; 50% of all RCC patients will die from the condition. However, if identified early enough, small RCCs are usually cured by surgery or percutaneous procedures, with 95% 10 year survival. This study describes a newly developed non-invasive urine-based assay for the early detection of RCC. Our approach uses encoded magnetically controllable heterostructures as a substrate for immunoassays. These heterostructures have molecular recognition abilities and embedded patterned codes for a rapid identification of RCC biomarkers. The magnetic heterostructures developed for this study have a magnetic configuration designed for a remote multi axial control of their orientation by external magnetic fields, this control facilitates the code readout when the heterostructures are in liquid. Furthermore, the optical encoding of each set of heterostructures provides a multiplexed analyte capture platform, as different sets of heterostructures, specific to different biomarkers can be mixed together in a patient sample. Our results show a precise magnetic control of the heterostructures with an efficient code readout during liquid immunoassays. The use of functionalised magnetic heterostructures as a substrate for immunoassay is validated for urine specimen spiked with recombinant RCC biomarkers. Initial results of the newly proposed screening method on urine samples from RCC patients, and controls with no renal disorders are presented in this study. Comprehensive optimisation cycles are in progress to validate the robustness of this technology as a novel, non-invasive screening method for RCC.
Language	English
Publishing date	2023-12-11
Publishing country	England
Document type	Journal Article
ISSN	2516-0230
ISSN (online)	2516-0230
DOI	10.1039/d3na00701d
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Article ; Online: Targeting HIF2α-ARNT hetero-dimerisation as a novel therapeutic strategy for pulmonary arterial hypertension.

Macias, David / Moore, Stephen / Crosby, Alexi / Southwood, Mark / Du, Xinlin / Tan, Huiling / Xie, Shanhai / Vassallo, Arlette / Wood, Alexander J T / Wallace, Eli M / Cowburn, Andrew S

The European respiratory journal

2021 Volume 57, Issue 3

Abstract: Pulmonary arterial hypertension (PAH) is a destructive disease of the pulmonary vasculature often leading to right heart failure and death. Current therapeutic intervention strategies only slow disease progression. The role of aberrant hypoxia-inducible ... ...

Abstract	Pulmonary arterial hypertension (PAH) is a destructive disease of the pulmonary vasculature often leading to right heart failure and death. Current therapeutic intervention strategies only slow disease progression. The role of aberrant hypoxia-inducible factor (HIF)2α stability and function in the initiation and development of pulmonary hypertension (PH) has been an area of intense interest for nearly two decades.Here we determine the effect of a novel HIF2α inhibitor (PT2567) on PH disease initiation and progression, using two pre-clinical models of PH. Haemodynamic measurements were performed, followed by collection of heart, lung and blood for pathological, gene expression and biochemical analysis. Blood outgrowth endothelial cells from idiopathic PAH patients were used to determine the impact of HIF2α-inhibition on endothelial function.Global inhibition of HIF2a reduced pulmonary vascular haemodynamics and pulmonary vascular remodelling in both su5416/hypoxia prevention and intervention models. PT2567 intervention reduced the expression of PH-associated target genes in both lung and cardiac tissues and restored plasma nitrite concentration. Treatment of monocrotaline-exposed rodents with PT2567 reduced the impact on cardiovascular haemodynamics and promoted a survival advantage.
MeSH term(s)	Animals ; Basic Helix-Loop-Helix Transcription Factors/antagonists & inhibitors ; Cells, Cultured ; Endothelial Cells ; Humans ; Hypertension, Pulmonary/drug therapy ; Pulmonary Arterial Hypertension ; Pulmonary Artery
Chemical Substances	Basic Helix-Loop-Helix Transcription Factors ; endothelial PAS domain-containing protein 1 (1B37H0967P)
Language	English
Publishing date	2021-03-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639359-7
ISSN	1399-3003 ; 0903-1936
ISSN (online)	1399-3003
ISSN	0903-1936
DOI	10.1183/13993003.02061-2019
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Zs.A 2322: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 292: Show issues

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Article ; Online: Cardiovascular adaptation to hypoxia and the role of peripheral resistance.

Cowburn, Andrew S / Macias, David / Summers, Charlotte / Chilvers, Edwin R / Johnson, Randall S

eLife

2017 Volume 6

Abstract: Systemic vascular pressure in vertebrates is regulated by a range of factors: one key element of control is peripheral resistance in tissue capillary beds. Many aspects of the relationship between central control of vascular flow and peripheral ... ...

Abstract	Systemic vascular pressure in vertebrates is regulated by a range of factors: one key element of control is peripheral resistance in tissue capillary beds. Many aspects of the relationship between central control of vascular flow and peripheral resistance are unclear. An important example of this is the relationship between hypoxic response in individual tissues, and the effect that response has on systemic cardiovascular adaptation to oxygen deprivation. We show here how hypoxic response via the HIF transcription factors in one large vascular bed, that underlying the skin, influences cardiovascular response to hypoxia in mice. We show that the response of the skin to hypoxia feeds back on a wide range of cardiovascular parameters, including heart rate, arterial pressures, and body temperature. These data represent the first demonstration of a dynamic role for oxygen sensing in a peripheral tissue directly modifying cardiovascular response to the challenge of hypoxia.
MeSH term(s)	Adaptation, Physiological ; Animals ; Blood Pressure ; Heart Rate ; Hypoxia/physiopathology ; Mice ; Skin Physiological Phenomena ; Temperature ; Vascular Resistance
Language	English
Publishing date	2017-10-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.28755
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Article ; Online: Syk Activation in Circulating and Tissue Innate Immune Cells in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

Prendecki, Maria / Gulati, Kavita / Pisacano, Noelle / Pinheiro, Damilola / Bhatt, Tejal / Mawhin, Marie-Anne / Toulza, Frederic / Masuda, Esteban S / Cowburn, Andrew / Lodge, Katharine M / Tam, Frederick W K / Roufosse, Candice / Pusey, Charles D / McAdoo, Stephen P

Arthritis & rheumatology (Hoboken, N.J.)

2022 Volume 75, Issue 1, Page(s) 84–97

Abstract: Objective: Syk is a cytoplasmic protein tyrosine kinase that plays a role in signaling via B cell and Fc receptors (FcR). FcR engagement and signaling via Syk is thought to be important in antineutrophil cytoplasm antibody (ANCA) IgG-mediated neutrophil ...

Abstract	Objective: Syk is a cytoplasmic protein tyrosine kinase that plays a role in signaling via B cell and Fc receptors (FcR). FcR engagement and signaling via Syk is thought to be important in antineutrophil cytoplasm antibody (ANCA) IgG-mediated neutrophil activation. This study was undertaken to investigate the role of Syk in ANCA-induced myeloid cell activation and vasculitis pathogenesis. Methods: Phosphorylation of Syk in myeloid cells from healthy controls and ANCA-associated vasculitis (AAV) patients was analyzed using flow cytometry. The effect of Syk inhibition on myeloperoxidase (MPO)-ANCA IgG activation of cells was investigated using functional assays (interleukin-8 and reactive oxygen species production) and targeted gene analysis with NanoString. Total and phosphorylated Syk at sites of tissue inflammation in patients with AAV was assessed using immunohistochemistry and RNAscope in situ hybridization. Results: We identified increased phosphorylated Syk at critical activatory tyrosine residues in blood neutrophils and monocytes from patients with active AAV compared to patients with disease in remission or healthy controls. Syk was phosphorylated in vitro following MPO-ANCA IgG stimulation, and Syk inhibition was able to prevent ANCA-mediated cellular responses. Using targeted gene expression analysis, we identified up-regulation of FcR- and Syk-dependent signaling pathways following MPO-ANCA IgG stimulation. Finally, we showed that Syk is expressed and phosphorylated in tissue leukocytes at sites of organ inflammation in AAV. Conclusion: These findings indicate that Syk plays a critical role in MPO-ANCA IgG-induced myeloid cell responses and that Syk is activated in circulating immune cells and tissue immune cells in AAV; therefore, Syk inhibition may be a potential therapeutic option.
MeSH term(s)	Humans ; Antibodies, Antineutrophil Cytoplasmic ; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis ; Inflammation ; Receptors, Fc ; Immunoglobulin G ; Immunity, Innate ; Peroxidase ; Syk Kinase
Chemical Substances	Antibodies, Antineutrophil Cytoplasmic ; Receptors, Fc ; Immunoglobulin G ; Peroxidase (EC 1.11.1.7) ; SYK protein, human (EC 2.7.10.2) ; Syk Kinase (EC 2.7.10.2)
Language	English
Publishing date	2022-11-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2756371-6
ISSN	2326-5205 ; 2326-5191
ISSN (online)	2326-5205
ISSN	2326-5191
DOI	10.1002/art.42321
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Article ; Online: Correction: HIF-2α is essential for carotid body development and function.

Macias, David / Cowburn, Andrew S / Torres-Torrelo, Hortensia / Ortega-Sáenz, Patricia / López-Barneo, José / Johnson, Randall

eLife

2018 Volume 7

Language	English
Publishing date	2018-06-04
Publishing country	England
Document type	Journal Article ; Published Erratum
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.38781
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Article ; Online: Role of social deprivation on asthma care quality among a cohort of children in US community health centres.

Lucas, Jennifer A / Marino, Miguel / Fankhauser, Katie / Bazemore, Andrew / Giebultowicz, Sophia / Cowburn, Stuart / Kaufmann, Jorge / Ezekiel-Herrera, David / Heintzman, John

BMJ open

2021 Volume 11, Issue 6, Page(s) e045131

Abstract: Objective: Social deprivation is associated with worse asthma outcomes. The Social Deprivation Index is a composite measure of social determinants of health used to identify neighbourhood-level disadvantage in healthcare. Our objective was to determine ... ...

Abstract	Objective: Social deprivation is associated with worse asthma outcomes. The Social Deprivation Index is a composite measure of social determinants of health used to identify neighbourhood-level disadvantage in healthcare. Our objective was to determine if higher neighbourhood-level social deprivation is associated with documented asthma care quality measures among children treated at community health centres (CHCs). Methods setting, participants, outcome measures: We used data from CHCs in 15 states in the Accelerating Data Value Across a National Community Health Center Network (ADVANCE). The sample included 34 266 children with asthma from 2008 to 2017, aged 3-17 living in neighbourhoods with differing levels of social deprivation measured using quartiles of the Social Deprivation Index score. We conducted logistic regression to examine the odds of problem list documentation of asthma and asthma severity, and negative binomial regression for rates of albuterol, inhaled steroid and oral steroid prescription adjusted for patient-level covariates. Results: Children from the most deprived neighbourhoods had increased rates of albuterol (rate ratio (RR)=1.22, 95% CI 1.13 to 1.32) compared with those in the least deprived neighbourhoods, while the point estimate for inhaled steroids was higher, but fell just short of significance at the alpha=0.05 level (RR=1.16, 95% CI 0.99 to 1.34). We did not observe community-level differences in problem list documentation of asthma or asthma severity. Conclusions: Higher neighbourhood-level social deprivation was associated with more albuterol and inhaled steroid prescriptions among children with asthma, while problem list documentation of asthma and asthma severity varied little across neighbourhoods with differing deprivation scores. While the homogeneity of the CHC safety net setting studied may mitigate variation in diagnosis and documentation of asthma, enhanced clinician awareness of differences in community risk could help target paediatric patients at risk of lower quality asthma care.
MeSH term(s)	Albuterol ; Asthma/drug therapy ; Asthma/epidemiology ; Child ; Cohort Studies ; Community Health Centers ; Humans ; Residence Characteristics
Chemical Substances	Albuterol (QF8SVZ843E)
Language	English
Publishing date	2021-06-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2599832-8
ISSN	2044-6055 ; 2044-6055
ISSN (online)	2044-6055
ISSN	2044-6055
DOI	10.1136/bmjopen-2020-045131
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Article ; Online: Hypoxia Increases the Potential for Neutrophil-mediated Endothelial Damage in Chronic Obstructive Pulmonary Disease.

Lodge, Katharine M / Vassallo, Arlette / Liu, Bin / Long, Merete / Tong, Zhen / Newby, Paul R / Agha-Jaffar, Danya / Paschalaki, Koralia / Green, Clara E / Belchamber, Kylie B R / Ridger, Victoria C / Stockley, Robert A / Sapey, Elizabeth / Summers, Charlotte / Cowburn, Andrew S / Chilvers, Edwin R / Li, Wei / Condliffe, Alison M

American journal of respiratory and critical care medicine

2022 Volume 205, Issue 8, Page(s) 903–916

Abstract: Rationale: ...

Abstract	Rationale:
MeSH term(s)	Endothelial Cells/metabolism ; Humans ; Hypoxia/metabolism ; Leukocyte Elastase/metabolism ; Neutrophils/metabolism ; Pulmonary Disease, Chronic Obstructive/metabolism ; Vascular System Injuries/metabolism
Chemical Substances	Leukocyte Elastase (EC 3.4.21.37)
Language	English
Publishing date	2022-02-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1180953-x
ISSN	1535-4970 ; 0003-0805 ; 1073-449X
ISSN (online)	1535-4970
ISSN	0003-0805 ; 1073-449X
DOI	10.1164/rccm.202006-2467OC
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