scholarly journals Metoprolol exerts a non-class effect against ischaemia–reperfusion injury by abrogating exacerbated inflammation

2020 ◽  
Vol 41 (46) ◽  
pp. 4425-4440 ◽  
Author(s):  
Agustín Clemente-Moragón ◽  
Mónica Gómez ◽  
Rocío Villena-Gutiérrez ◽  
Doménica V Lalama ◽  
Jaime García-Prieto ◽  
...  
Keyword(s):  
Conformational Changes ◽  
In Silico ◽  
Adrenergic Receptor ◽  
Neutrophil Migration ◽  
Neutrophil Infiltration ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion ◽  
Β Blockers

Abstract Aims Clinical guidelines recommend early intravenous β-blockers during ongoing myocardial infarction; however, it is unknown whether all β-blockers exert a similar cardioprotective effect. We experimentally compared three clinically approved intravenous β-blockers. Methods and results Mice undergoing 45 min/24 h ischaemia–reperfusion (I/R) received vehicle, metoprolol, atenolol, or propranolol at min 35. The effect on neutrophil infiltration was tested in three models of exacerbated inflammation. Neutrophil migration was evaluated in vitro and in vivo by intravital microscopy. The effect of β-blockers on the conformation of the β1 adrenergic receptor was studied in silico. Of the tested β-blockers, only metoprolol ameliorated I/R injury [infarct size (IS) = 18.0% ± 0.03% for metoprolol vs. 35.9% ± 0.03% for vehicle; P < 0.01]. Atenolol and propranolol had no effect on IS. In the three exacerbated inflammation models, neutrophil infiltration was significantly attenuated only in the presence of metoprolol (60%, 50%, and 70% reductions vs. vehicle in myocardial I/R injury, thioglycolate-induced peritonitis, and lipopolysaccharide-induced acute lung injury, respectively). Migration studies confirmed the particular ability of metoprolol to disrupt neutrophil dynamics. In silico analysis indicated different intracellular β1 adrenergic receptor conformational changes when bound to metoprolol than to the other two β-blockers. Conclusions Metoprolol exerts a disruptive action on neutrophil dynamics during exacerbated inflammation, resulting in an infarct-limiting effect not observed with atenolol or propranolol. The differential effect of β-blockers may be related to distinct conformational changes in the β1 adrenergic receptor upon metoprolol binding. If these data are confirmed in a clinical trial, metoprolol should become the intravenous β-blocker of choice for patients with ongoing infarction.

scholarly journals Proof-of-concept clinical trial of etokimab shows a key role for IL-33 in atopic dermatitis pathogenesis

2019 ◽  
Vol 11 (515) ◽  
pp. eaax2945 ◽  
Author(s):  
Yi-Ling Chen ◽  
Danuta Gutowska-Owsiak ◽  
Clare S. Hardman ◽  
Melanie Westmoreland ◽  
Teena MacKenzie ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Therapeutic Potential ◽  
Neutrophil Migration ◽  
Neutrophil Infiltration ◽  
Severity Index ◽  
Fundamental Biology ◽  
Targeted Inhibition

Targeted inhibition of cytokine pathways provides opportunities to understand fundamental biology in vivo in humans. The IL-33 pathway has been implicated in the pathogenesis of atopy through genetic and functional associations. We investigated the role of IL-33 inhibition in a first-in-class phase 2a study of etokimab (ANB020), an IgG1 anti–IL-33 monoclonal antibody, in patients with atopic dermatitis (AD). Twelve adult patients with moderate to severe AD received a single systemic administration of etokimab. Rapid and sustained clinical benefit was observed, with 83% achieving Eczema Area and Severity Index 50 (EASI50), and 33% EASI75, with reduction in peripheral eosinophils at day 29 after administration. We noted significant reduction in skin neutrophil infiltration after etokimab compared with placebo upon skin challenge with house dust mite, reactivity to which has been implicated in the pathogenesis of AD. We showed that etokimab also inhibited neutrophil migration to skin interstitial fluid in vitro. Besides direct effects on neutrophil migration, etokimab revealed additional unexpected CXCR1-dependent effects on IL-8–induced neutrophil migration. These human in vivo findings confirm an IL-33 upstream role in modulating skin inflammatory cascades and define the therapeutic potential for IL-33 inhibition in human diseases, including AD.

scholarly journals Effects of human neutrophil elastase (HNE) on neutrophil function in vitro and in inflamed microvessels

Blood ◽  
1993 ◽  
Vol 82 (7) ◽  
pp. 2188-2195 ◽  
Author(s):  
RC Woodman ◽  
PH Reinhardt ◽  
S Kanwar ◽  
FL Johnston ◽  
P Kubes
Keyword(s):  
Neutrophil Elastase ◽  
Human Neutrophil ◽  
Neutrophil Migration ◽  
Specific Inhibitor ◽  
Neutrophil Infiltration ◽  
Cathepsin G ◽  
Neutrophil Adhesion ◽  
Human Neutrophil Elastase

Abstract The primary objective of this study was to test the hypothesis that human neutrophil elastase (HNE) affects neutrophil infiltration (adhesion and emigration) into inflamed vessels. To determine whether HNE contributes to neutrophil adhesion in vivo, intravital microscopy was used to study neutrophil-endothelial cell interactions in single inflamed postcapillary venules. Superfusion of platelet-activating factor (PAF) (100 nmol/L) onto the mesentery caused an increase in neutrophil-neutrophil interactions, neutrophil adhesion to postcapillary venules, and cellular emigration out of the vasculature. Both L658 758 (an elastase-specific inhibitor), and Eglin C (an elastase and cathepsin G inhibitor) significantly attenuated all of these parameters in vivo. To further characterize the mechanism(s) involved, various in vitro parameters were assessed. HNE, but not trypsin, caused a dose-dependent (0.01 to 1.0 microgram/mL) increase in the expression of the beta subunit (CD18) of the CD11/CD18 adhesive glycoprotein complex on neutrophils. An HNE-dependent increase in CD11b expression was also observed; however, HNE did not affect the expression of other neutrophil adhesion molecules (L-selectin), superoxide production, or degranulation. PAF-enhanced CD18 expression on neutrophils and neutrophil migration were both abolished by L658 758 but PAF-induced neutrophil adhesion to endothelial monolayers was not affected by the antiproteinase. The in vitro data suggest that the antiproteinases do not directly prevent neutrophil adhesion in vivo but may be important in other CD18-dependent events such as neutrophil- neutrophil interaction or neutrophil infiltration (chemotaxis). These results translate into an important, rate-limiting role for elastase in the process of leukocyte infiltration and accumulation in inflamed microvessels.

The effect of relaxin on myocardial ischaemia-reperfusion injury and histamine release in vitro and in vivo

1996 ◽  
Vol 45 (S1) ◽  
pp. S27-S28 ◽  
Author(s):  
E. Masini ◽  
D. Salvemini ◽  
L. Mugnai ◽  
M. G. Bello ◽  
D. Bani ◽  
...  
Keyword(s):  
Histamine Release ◽  
Reperfusion Injury ◽  
Myocardial Ischaemia ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion ◽  
Release In Vitro

scholarly journals IL-4 Alleviates Ischaemia-Reperfusion Injury by Inducing Kupffer Cells M2 Polarization via STAT6-JMJD3 Pathway after Rat Liver Transplantation

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Minghua Deng ◽  
Jingyuan Wang ◽  
Hao Wu ◽  
Menghao Wang ◽  
Ding Cao ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Reperfusion Injury ◽  
Kupffer Cells ◽  
Interleukin 4 ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion ◽  
M2 Polarization ◽  
Hepatocellular Apoptosis

Background. Liver ischaemia-reperfusion injury (IRI) remains a problem in liver transplantation. Interleukin-4 (IL-4) has been found to reduce liver IRI, but the exact mechanism remains unclear. Methods. Donor livers were infused with recombinant IL-4 or normal saline during cold storage, and the hepatocellular apoptosis and the inflammatory response were detected. The effect of IL-4 treatment on Kupffer cells (KCs) polarization and expression of the STAT6-JMJD3 pathway was evaluated in vivo and in vitro. KCs in donor livers were depleted by clodronate liposome treatment or JMJD3 was inhibited by GSK-J4 before liver transplantation to determine whether the protective effect of IL-4 treatment was dependent on KCs. Results. IL-4 treatment decreased sALT and sAST levels and alleviated hepatocellular apoptosis and inflammation at 6 h after liver transplantation. IL-4 treatment induced KCs alternatively activated (M2) polarization in vitro and in vivo, and the expression of STAT6 and JMJD3 was increased. JMJD3 knockdown abolished KCs M2 polarization and reduced the antiapoptotic and anti-inflammatory effects induced by IL-4 treatment in vitro. In addition, the protection of IL-4 treatment against IRI induced by liver transplantation was significantly reduced after the depletion of KCs or the inhibition of JMJD3 in donor livers. Conclusions. IL-4 treatment-induced KCs M2 polarization was dependent on the STAT6-JMJD3 pathway and protected liver grafts from IRI after liver transplantation.

scholarly journals Effects of human neutrophil elastase (HNE) on neutrophil function in vitro and in inflamed microvessels

Blood ◽  
1993 ◽  
Vol 82 (7) ◽  
pp. 2188-2195
Author(s):  
RC Woodman ◽  
PH Reinhardt ◽  
S Kanwar ◽  
FL Johnston ◽  
P Kubes
Keyword(s):  
Neutrophil Elastase ◽  
Human Neutrophil ◽  
Neutrophil Migration ◽  
Specific Inhibitor ◽  
Neutrophil Infiltration ◽  
Cathepsin G ◽  
Neutrophil Adhesion ◽  
Human Neutrophil Elastase

The primary objective of this study was to test the hypothesis that human neutrophil elastase (HNE) affects neutrophil infiltration (adhesion and emigration) into inflamed vessels. To determine whether HNE contributes to neutrophil adhesion in vivo, intravital microscopy was used to study neutrophil-endothelial cell interactions in single inflamed postcapillary venules. Superfusion of platelet-activating factor (PAF) (100 nmol/L) onto the mesentery caused an increase in neutrophil-neutrophil interactions, neutrophil adhesion to postcapillary venules, and cellular emigration out of the vasculature. Both L658 758 (an elastase-specific inhibitor), and Eglin C (an elastase and cathepsin G inhibitor) significantly attenuated all of these parameters in vivo. To further characterize the mechanism(s) involved, various in vitro parameters were assessed. HNE, but not trypsin, caused a dose-dependent (0.01 to 1.0 microgram/mL) increase in the expression of the beta subunit (CD18) of the CD11/CD18 adhesive glycoprotein complex on neutrophils. An HNE-dependent increase in CD11b expression was also observed; however, HNE did not affect the expression of other neutrophil adhesion molecules (L-selectin), superoxide production, or degranulation. PAF-enhanced CD18 expression on neutrophils and neutrophil migration were both abolished by L658 758 but PAF-induced neutrophil adhesion to endothelial monolayers was not affected by the antiproteinase. The in vitro data suggest that the antiproteinases do not directly prevent neutrophil adhesion in vivo but may be important in other CD18-dependent events such as neutrophil- neutrophil interaction or neutrophil infiltration (chemotaxis). These results translate into an important, rate-limiting role for elastase in the process of leukocyte infiltration and accumulation in inflamed microvessels.

scholarly journals Transporters MRP1 and MRP2 Regulate Opposing Inflammatory Signals To Control Transepithelial Neutrophil Migration duringStreptococcus pneumoniaeLung Infection

mSphere ◽  
2018 ◽  
Vol 3 (4) ◽  
Author(s):  
Andrew Zukauskas ◽  
Randall J. Mrsny ◽  
Paula Cortés Barrantes ◽  
Jerrold R. Turner ◽  
John M. Leong ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Neutrophil Migration ◽  
Neutrophil Infiltration ◽  
Mortality Rates ◽  
Positive Bacterium ◽  
Immunomodulatory Agents ◽  
Content Type ◽  
Mouse Lungs

ABSTRACTStreptococcus pneumoniaeremains a source of morbidity and mortality in both developed and underdeveloped nations of the world. Disease can manifest as pneumonia, bacteremia, and meningitis, depending on the localization of infection. Interestingly, there is a correlation in experimental murine infections between the development of bacteremia and influx of neutrophils into the pulmonary lumen. Reduction of this neutrophil influx has been shown to improve survivability during infection. In this study, we usein vitrobiotinylation and neutrophil transmigration andin vivomurine infection to identify a system in which two epithelium-localized ATP-binding cassette transporters, MRP1 and MRP2, have inverse activities dictating neutrophil transmigration into the lumen of infected mouse lungs. MRP1 effluxes an anti-inflammatory molecule that maintains homeostasis in uninfected contexts, thus reducing neutrophil infiltration. During inflammatory events, however, MRP1 decreases and MRP2 both increases and effluxes the proinflammatory eicosanoid hepoxilin A3. If we then decrease MRP2 activity during experimental murine infection withS. pneumoniae, we reduce both neutrophil infiltration and bacteremia, showing that MRP2 coordinates this activity in the lung. We conclude that MRP1 assists in depression of polymorphonuclear cell (PMN) migration by effluxing a molecule that inhibits the proinflammatory effects of MRP2 activity.IMPORTANCEStreptococcus pneumoniaeis a Gram-positive bacterium that normally inhabits the human nasopharynx asymptomatically. However, it is also a major cause of pneumonia, bacteremia, and meningitis. The transition from pneumonia to bacteremia is critical, as patients that develop septicemia have ~20% mortality rates. Previous studies have shown that while neutrophils, a major bacterium-induced leukocyte, aid inS. pneumoniaeelimination, they also contribute to pathology and may mediate the lung-to-blood passage of the bacteria. Herein, we show that epithelium-derived MRP1 and MRP2 efflux immunomodulatory agents that assist in controlling passage of neutrophils during infection and that limiting neutrophil infiltration produced less bacteremia and better survival during murine infection. The importance of our work is twofold: ours is the first to identify an MRP1/MRP2 axis of neutrophil control in the lung. The second is to provide possible therapeutic targets to reduce excess inflammation, thus reducing the chances of developing bacteremia during pneumococcal pneumonia.

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