NO donors don??t inhibit neutrophil function ex vivo

1993 ◽  
Vol &NA; (874) ◽  
pp. 10
Author(s):  
&NA;
Keyword(s):  
Ex Vivo ◽  
Neutrophil Function ◽  
No Donors

scholarly journals Neuraminidase inhibitors rewire neutrophil function in vivo in murine sepsis and ex vivo in COVID-19

2020 ◽  
Author(s):  
Rodrigo O. Formiga ◽  
Flávia C. Amaral ◽  
Camila F. Souza ◽  
Daniel A. G. B. Mendes ◽  
Carlos W. S. Wanderley ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Ex Vivo ◽  
Neutrophil Function ◽  
Human Neutrophils ◽  
Data Sets ◽  
Neuraminidase Inhibitors ◽  
Severe Infections ◽  
Whole Blood Cells ◽  
Neutrophil Dysfunction

ABSTRACTNeutrophil overstimulation plays a crucial role in tissue damage during severe infections. Neuraminidase (NEU)-mediated cleavage of surface sialic acid has been demonstrated to regulate leukocyte responses. Here, we report that antiviral NEU inhibitors constrain host NEU activity, surface sialic acid release, ROS production, and NETs released by microbial-activated human neutrophils. In vivo, treatment with Oseltamivir results in infection control and host survival in peritonitis and pneumonia models of sepsis. Single-cell RNA sequencing re-analysis of publicly data sets of respiratory tract samples from critical COVID-19 patients revealed an overexpression of NEU1 in infiltrated neutrophils. Moreover, Oseltamivir or Zanamivir treatment of whole blood cells from severe COVID-19 patients reduces host NEU-mediated shedding of cell surface sialic acid and neutrophil overactivation. These findings suggest that neuraminidase inhibitors can serve as host-directed interventions to dampen neutrophil dysfunction in severe infections.

scholarly journals Autophagy Induced by Palmitic Acid: a Brake in NAFLD Neutrophils

2021 ◽  
Author(s):  
Zhicheng Peng ◽  
Heyuan Wang ◽  
Alan Y. Hsu ◽  
Xiliang Du ◽  
Yuchen Yang ◽  
...  
Keyword(s):  
Palmitic Acid ◽  
Metabolic Diseases ◽  
Ex Vivo ◽  
Neutrophil Function ◽  
List Type ◽  
Nonalcoholic Fatty Liver ◽  
Blood Constituents ◽  
Key Points ◽  
Ethanol Toxicity

AbstractInnate immune suppression and high blood fatty acid levels are the pathological basis of multiple metabolic diseases. Neutrophil vacuolation is an indicator of the immune status of patients, which is associated with autophagy-dependent granule degradation. Vacuolated neutrophils are observed in ethanol toxicity and septicemia patients due to the changes in their blood constituents, but how about the neutrophils in nonalcoholic fatty liver disease (NAFLD) patient is unknown. Here, we confirmed that an adhesion deficiency and an increased autophagy level existed in NAFLD neutrophils, and the three neutrophil granule subunits, namely, the azurophil granules, specific granules and gelatinase granules, could be engulfed by autophagosomes for degradation, and these autophagy-triggered granule degradation events were associated with vacuolation in palmitic acid (PA)-treated and NAFLD neutrophils. Concordantly, the adhesion-associated molecules CD11a, CD11b, CD18 and Rap1 on the three granule subunits were degraded during PA induced autophagy. Moreover, the cytosolic CD11a, CD11b, CD18 and Rap1 were targeted by Hsc70 and then delivered to lysosomal-like granules for degradation. Notably, in vitro and ex vivo, PA induced autophagy by inhibiting the p-PKCα/PKD2 pathway. Overall, we showed that high blood PA level inhibited the p-PKCα/PKD2 pathway to induce NAFLD neutrophil autophagy, which promoted the degradation of CD11a, CD11b, CD18 and Rap1 and further decreased the adhesion of neutrophils, thereby impairing the neutrophil function of NAFLD patients. This theory provides a new therapeutic strategy to improve the immune deficiency in NAFLD patients.Visual AbstractKey PointsVacuolation and adhesion deficiency of NAFLD neutrophils are associated with autophagy-dependent granule degradationPA inhibits p-PKCα/PKD2 to induce autophagy, which induces the degradation of CD11a, CD11b, CD18 and Rap1 and decreases neutrophil adhesion

scholarly journals A Multi-Modal Toolkit for Studying Neutrophils in Cancer and Beyond

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5331
Author(s):  
Diana Changirwa ◽  
Jared Schlechte ◽  
Braedon McDonald
Keyword(s):  
Single Cell Analysis ◽  
Ex Vivo ◽  
Neutrophil Function ◽  
Model Systems ◽  
Cellular Heterogeneity ◽  
High Dimensional ◽  
Integrated Analysis ◽  
Functional Plasticity ◽  
Ex Vivo Model

As key effector cells of the innate immune response, neutrophils are rapidly deployed to sites of inflammation where they deliver a payload of potent effector mechanisms that are essential for host defense against pathogens as well as tissue homeostasis. In addition, neutrophils are central contributors to the pathogenesis of a vast spectrum of inflammatory, degenerative, and neoplastic diseases. As our understanding of neutrophils in health and disease continually expands, so too does our appreciation of their complex and dynamic nature in vivo; from development, maturation, and trafficking to cellular heterogeneity and functional plasticity. Therefore, contemporary neutrophil research relies on multiple complementary methodologies to perform integrated analysis of neutrophil phenotypic heterogeneity, organ- and stimulus-specific trafficking mechanisms, as well as tailored effector functions in vivo. This review discusses established and emerging technologies used to study neutrophils, with a focus on in vivo imaging in animal models, as well as next-generation ex vivo model systems to study mechanisms of neutrophil function. Furthermore, we discuss how high-dimensional single-cell analysis technologies are driving a renaissance in neutrophil biology by redefining our understanding of neutrophil development, heterogeneity, and functional plasticity. Finally, we discuss innovative applications and emerging opportunities to integrate these high-dimensional, multi-modal techniques to deepen our understanding of neutrophils in cancer research and beyond.

Ex vivo neutrophil function in response to three different doses of glycosylated rHuG‐CSF (Lenograstim)

1997 ◽  
Vol 96 (1) ◽  
pp. 46-54 ◽  
Author(s):  
J. Turzanski ◽  
S. P. M. Crouch ◽  
J. Fletcher ◽  
A. Hunter
Keyword(s):  
Ex Vivo ◽  
Neutrophil Function ◽  
Different Doses

Evidence against oxidative stress as mechanism of endothelial dysfunction in methionine loading model

2001 ◽  
Vol 280 (3) ◽  
pp. H1334-H1339 ◽  
Author(s):  
Angus K. Nightingale ◽  
Philip P. James ◽  
Jayne Morris-Thurgood ◽  
Fraser Harrold ◽  
Richard Tong ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Smooth Muscle ◽  
Endothelial Dysfunction ◽  
Healthy Subjects ◽  
Ex Vivo ◽  
Venous Blood ◽  
No Donors ◽  
Flow Mediated Dilatation ◽  
Markers Of Oxidative Stress ◽  
No Bioavailability

Endothelial dysfunction reflects reduced nitric oxide (NO) bioavailability due to either reduced production, inactivation of NO, or reduced smooth muscle responsiveness. Oral methionine loading causes acute endothelial dysfunction in healthy subjects and provides a model in which to study mechanisms. Endothelial function was assessed using flow-mediated dilatation (FMD) of the brachial artery in humans. Three markers of oxidative stress were measured ex vivo in venous blood. NO responsiveness was assessed in vascular smooth muscle and platelets. Oral methionine loading induced endothelial dysfunction (FMD decreased from 2.8 ± 0.8 to 0.3 ± 0.3% with methionine and from 2.8 ± 0.8 to 1.3 ± 0.3% with placebo; P < 0.05). No significant changes in measures of plasma oxidative stress or in vascular or platelet sensitivity to submaximal doses of NO donors were detected. These data suggest that oxidative stress is not the mechanism of endothelial dysfunction after oral methionine loading. Furthermore, the preservation of vascular and platelet NO sensitivity makes a signal transduction abnormality unlikely.

scholarly journals Optimization of nitric oxide donors for investigating biofilm dispersal response in Pseudomonas aeruginosa clinical isolates

2020 ◽  
Vol 104 (20) ◽  
pp. 8859-8869
Author(s):  
Yu-ming Cai ◽  
Jeremy S. Webb
Keyword(s):  
Nitric Oxide ◽  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Clinical Trials ◽  
Ex Vivo ◽  
Light Exposure ◽  
Clinical Isolates ◽  
No Donor ◽  
No Donors ◽  
Short Period

Abstract Pseudomonas aeruginosa biofilms contribute heavily to chronic lung infection in cystic fibrosis patients, leading to morbidity and mortality. Nitric oxide (NO) has been shown to disperse P. aeruginosa biofilms in vitro, ex vivo and in clinical trials as a promising anti-biofilm agent. Traditional NO donors such as sodium nitroprusside (SNP) have been extensively employed in different studies. However, the dosage of SNP in different studies was not consistent, ranging from 500 nM to 500 μM. SNP is light sensitive and produces cyanide, which may lead to data misinterpretation and inaccurate predictions of dispersal responses in clinical settings. New NO donors and NO delivery methods have therefore been explored. Here we assessed 7 NO donors using P. aeruginosa PAO1 and determined that SNP and Spermine NONOate (S150) successfully reduced > 60% biomass within 24 and 2 h, respectively. While neither dosage posed toxicity towards bacterial cells, chemiluminescence assays showed that SNP only released NO upon light exposure in M9 media and S150 delivered much higher performance spontaneously. S150 was then tested on 13 different cystic fibrosis P. aeruginosa (CF-PA) isolates; most CF-PA biofilms were significantly dispersed by 250 μM S150. Our work therefore discovered a commercially available NO donor S150, which disperses CF-PA biofilms efficiently within a short period of time and without releasing cyanide, as an alternative of SNP in clinical trials in the future. Key points • S150 performs the best in dispersing P. aeruginosa biofilms among 7 NO donors. • SNP only releases NO in the presence of light, while S150 releases NO spontaneously. • S150 successfully disperses biofilms formed by P. aeruginosa cystic fibrosis clinical isolates.

[209] EX VIVO ENDOTOXIN REMOVAL FROM PLASMA RESTORES NEUTROPHIL FUNCTION

2007 ◽  
Vol 46 ◽  
pp. S87 ◽  
Author(s):  
V. Stadlbauer ◽  
R.P. Mookerjee ◽  
S. Lidder ◽  
S.J. Hodges ◽  
N.A. Davies ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Neutrophil Function

Differences in MSU-induced Superoxide Responses by Neutrophils from Gout Subjects Compared to Healthy Controls and a Role for Environmental Inflammatory Cytokines and Hyperuricemia in Neutrophil Function and Survival

2010 ◽  
Vol 37 (6) ◽  
pp. 1228-1235 ◽  
Author(s):  
WILLIAM JOHN MARTIN ◽  
REBECCA GRAINGER ◽  
ANDREW HARRISON ◽  
JACQUIE L. HARPER
Keyword(s):  
Neutralizing Antibodies ◽  
Ex Vivo ◽  
Elevated Serum ◽  
Neutrophil Function ◽  
Superoxide Production ◽  
Healthy Controls ◽  
Serum Samples ◽  
Tnf Α ◽  
Neutrophil Superoxide ◽  
Factor Α

Objective.To determine whether monosodium urate (MSU) crystal-induced superoxide production is greater for neutrophils from patients with gout compared to asymptomatic hyperuricemic and healthy controls, and whether neutrophil functions are altered by an MSU crystal-induced inflammatory environment.Methods.Neutrophils were purified from the whole blood of study participants, restimulated with 500 mg MSU crystalsex vivo, and superoxide production measured using the colorimetric dye WST-1. Purified neutrophils were exposed to conditioned media from MSU crystal-activated blood monocyte cultures with and without neutralizing antibodies for interleukin 1ß (IL-1ß), IL-8 (CXCL8), IL-6, and tumor necrosis factor-α (TNF-α). Neutrophil superoxide production was measured and neutrophil apoptosis and IL-8 production were determined by flow cytometry. Serum samples were collected from participants and analyzed by Lincoplex bead array for IL-1ß, IL-8, IL-6, and TNF-α.Results.Neutrophils from gout and asymptomatic hyperuricemic subjects produced higher levels of MSU crystal-induced superoxide, and a weak trend toward elevated serum cytokines was observed compared to healthy controls. A correlation between serum uric acid and elevated neutrophil superoxide production was also observed. Neutrophils exposed to media from MSU crystal-activated monocytes exhibited enhanced superoxide production to MSU-crystal stimulation, increased IL-8 production, and extended cell survival that was predominantly dependent on IL-8, TNF-α and IL-6, respectively.Conclusion.Neutrophils from gout and asymptomatic hyperuricemic individuals are primed for enhanced MSU crystal-induced superoxide production that may be driven by a subclinical inflammatory cytokine environment combined with hyperuricemia. This inflammatory environment likely contributes to elevated neutrophil IL-8 production and survival in the absence of direct crystal stimulation. Asymptomatic hyperuricemia is not associated with suppressed neutrophil function.

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