Mitigation of sepsis-induced inflammatory responses and organ injury through targeting Wnt/β-catenin signaling

AbstractCytokine release syndrome (CRS) is a major cause of the multi-organ injury and fatal outcome induced by SARS-CoV-2 infection in severe COVID-19 patients. Metabolism can modulate the immune responses against infectious diseases, yet our understanding remains limited on how host metabolism correlates with inflammatory responses and affects cytokine release in COVID-19 patients. Here we perform both metabolomics and cytokine/chemokine profiling on serum samples from healthy controls, mild and severe COVID-19 patients, and delineate their global metabolic and immune response landscape. Correlation analyses show tight associations between metabolites and proinflammatory cytokines/chemokines, such as IL-6, M-CSF, IL-1α, IL-1β, and imply a potential regulatory crosstalk between arginine, tryptophan, purine metabolism and hyperinflammation. Importantly, we also demonstrate that targeting metabolism markedly modulates the proinflammatory cytokines release by peripheral blood mononuclear cells isolated from SARS-CoV-2-infected rhesus macaques ex vivo, hinting that exploiting metabolic alterations may be a potential strategy for treating fatal CRS in COVID-19.

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Non-Alcoholic Steatohepatitis: Clinical and Translational Research

Journal of Pharmacy & Pharmaceutical Sciences ◽

10.18433/j3f61f ◽

2016 ◽

Vol 19 (1) ◽

pp. 8 ◽

Cited By ~ 2

Author(s):

Manuela G Neuman ◽

Mihai Voiculescu ◽

Radu M Nanau ◽

Yaakov Maor ◽

Ehud Melzer ◽

...

Keyword(s):

Fatty Liver ◽

Liver Damage ◽

Immune Modulation ◽

Inflammatory Responses ◽

Cell Types ◽

Organ Injury ◽

Alcoholic Fatty Liver ◽

Neuropsychological Disorders ◽

Alcoholic Steatohepatitis

The present review includes translational and clinical research that characterize non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Clinical and experimental evidence led to the recognition of the key toxic role played by lipotoxicity in the pathogenesis of NAFLD. The current understanding of lipotoxicity suggests that organ injury is initiated by the generation of oxidative metabolites and the translocation of gut-derived endotoxin. These processes lead to cellular injury and stimulation of the inflammatory responses mediated through a variety of molecules. The injury progresses through impairment of tissue regeneration and extracellular matrix turnover, leading to fibrogenesis and cirrhosis. Several cell types are involved in this process, predominantly stellate cells, macrophages and parenchymal cells. In response to inflammation, cytokines activate many signaling cascades that regulate fibrogenesis. This examination brings together research focusing on the underlying mechanisms of injury. It highlights the various processes and molecules that are likely involved in inflammation, immune modulation, and fibrogenesis in the liver. We searched electronic databases (Medline, Embase) for this review. This integrative work investigates different aspects of liver damage and possible repair. We aim to (1) determine the immuno-pathology of liver damage due to steatosis, (2) suggest diagnostic markers of NASH, (3) examine the role of behaviour in the development of NASH, and (4) develop common tools to study steatosis-induced effects in clinical studies. Special accent is put on co-morbidities with renal and neuropsychological disorders. Moreover, we review the evidence in literature on the role of moderate alcohol consumption in individuals that present NAFLD/NASH.Key Words: behavior, diet, imaging, non-alcoholic fatty liver, nonalcoholic steatohepatitis, laboratory markers.This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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Lithothamnion muelleri Controls Inflammatory Responses, Target Organ Injury and Lethality Associated with Graft-versus-Host Disease in Mice

Marine Drugs ◽

10.3390/md11072595 ◽

2013 ◽

Vol 11 (7) ◽

pp. 2595-2615 ◽

Cited By ~ 9

Author(s):

Barbara Rezende ◽

Priscila Bernardes ◽

Carolina Resende ◽

Rosa Arantes ◽

Danielle Souza ◽

...

Keyword(s):

Graft Versus Host Disease ◽

Inflammatory Responses ◽

Target Organ ◽

Organ Injury ◽

Host Disease ◽

Graft Versus Host

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Organ Injury and Cytokine Release Caused by Peptidoglycan Are Dependent on the Structural Integrity of the Glycan Chain

Infection and Immunity ◽

10.1128/iai.72.3.1311-1317.2004 ◽

2004 ◽

Vol 72 (3) ◽

pp. 1311-1317 ◽

Cited By ~ 19

Author(s):

Anders E. Myhre ◽

Jon Fredrik Stuestøl ◽

Maria K. Dahle ◽

Gunhild Øverland ◽

Christoph Thiemermann ◽

...

Keyword(s):

Structural Integrity ◽

Inflammatory Responses ◽

Ex Vivo ◽

Organ Injury ◽

Enzyme Linked Immunosorbent Assay ◽

Cytokine Release ◽

Ex Vivo Model ◽

Glycan Chain ◽

Tnf Α ◽

Glutamyl Transferase

ABSTRACT Several studies have implicated a role of peptidoglycan (PepG) as a pathogenicity factor in sepsis and organ injury, in part by initiating the release of inflammatory mediators. We wanted to elucidate the structural requirements of PepG to trigger inflammatory responses and organ injury. Injection of native PepG into anesthetized rats caused moderate but significant increases in the levels of alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transferase, and bilirubin (markers of hepatic injury and/or dysfunction) and creatinine and urea (markers of renal dysfunction) in serum, whereas PepG pretreated with muramidase to digest the glycan backbone failed to do this. In an ex vivo model of human blood, PepG containing different amino acids induced similar levels of the cytokines tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), IL-8, and IL-10, as determined by plasma analyses (enzyme-linked immunosorbent assay). Hydrolysis of the Staphylococcus aureus cross-bridge with lysostaphin resulted in moderately reduced release of TNF-α, IL-6, IL-8, and IL-10, whereas muramidase digestion nearly abolished the ability to induce cytokine release and IL-6 mRNA accumulation in CD14+ monocytes compared to intact PepG. However, additional experiments showed that muramidase-treated PepG synergized with lipopolysaccharide to induce TNF-α and IL-10 release in whole blood, despite its lack of inflammatory activity when administered alone. Based on these studies, we hypothesize that the structural integrity of the glycan chain of the PepG molecule is very important for the pathogenic effects of PepG. The amino acid composition of PepG, however, does not seem to be essential for the inflammatory properties of the molecule.

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(R)-Ketamine ameliorates lethal inflammatory responses and multi-organ injury in mice induced by cecum ligation and puncture

Life Sciences ◽

10.1016/j.lfs.2021.119882 ◽

2021 ◽

pp. 119882

Author(s):

Jiancheng Zhang ◽

Li Ma ◽

Yaeko Hashimoto ◽

Xiayun Wan ◽

Jiajing Shan ◽

...

Keyword(s):

Inflammatory Responses ◽

Organ Injury ◽

Cecum Ligation

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The role of adenosine 1a receptor signaling on GFR early after the induction of sepsis

AJP Renal Physiology ◽

10.1152/ajprenal.00051.2017 ◽

2018 ◽

Vol 314 (5) ◽

pp. F788-F797

Author(s):

Jonathan M. Street ◽

Erik H. Koritzinsky ◽

Tiffany R. Bellomo ◽

Xuzhen Hu ◽

Peter S. T. Yuen ◽

...

Keyword(s):

Knockout Mice ◽

Inflammatory Responses ◽

Cecal Ligation ◽

Kidney Injury ◽

Cumulative Effect ◽

Organ Damage ◽

Tubuloglomerular Feedback ◽

Organ Injury ◽

Sodium Reabsorption ◽

Wild Type

Sepsis and acute kidney injury (AKI) synergistically increase morbidity and mortality in the ICU. How sepsis reduces glomerular filtration rate (GFR) and causes AKI is poorly understood; one proposed mechanism includes tubuloglomerular feedback (TGF). When sodium reabsorption by the proximal tubules is reduced in normal animals, the macula densa senses increased luminal sodium chloride, and then adenosine-1a receptor (A1aR) signaling triggers tubuloglomerular feedback, reducing GFR through afferent arteriole vasoconstriction. We measured GFR and systemic hemodynamics early during cecal ligation and puncture-induced sepsis in wild-type and A1aR-knockout mice. A miniaturized fluorometer was attached to the back of each mouse and recorded the clearance of FITC-sinistrin via transcutaneous fluorescence to monitor GFR. Clinical organ injury markers and cytokines were measured and hemodynamics monitored using implantable transducer telemetry devices. In wild-type mice, GFR was stable within 1 h after surgery, declined by 43% in the next hour, and then fell to less than 10% of baseline after 2 h and 45 min. In contrast, in A1aR-knockout mice GFR was 37% below baseline immediately after surgery and then gradually declined over 4 h. A1aR-knockout mice had similar organ injury and inflammatory responses, albeit with lower heart rate. We conclude that transcutaneous fluorescence can accurately monitor GFR and detect changes rapidly during sepsis. Tubuloglomerular feedback plays a complex role in sepsis; initially, TGF helps maintain GFR in the 1st hour, and over the subsequent 3 h, TGF causes GFR to plummet. By 18 h, TGF has no cumulative effect on renal or extrarenal organ damage.

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Cutting Edge: Divergent Cell-Specific Functions of MyD88 for Inflammatory Responses and Organ Injury in Septic Peritonitis

The Journal of Immunology ◽

10.4049/jimmunol.1200038 ◽

2012 ◽

Vol 188 (12) ◽

pp. 5833-5837 ◽

Cited By ~ 25

Author(s):

Petra Gais ◽

Daniel Reim ◽

Gabriela Jusek ◽

Tanja Rossmann-Bloeck ◽

Heike Weighardt ◽

...

Keyword(s):

Inflammatory Responses ◽

Cutting Edge ◽

Organ Injury ◽

Septic Peritonitis

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Role of the Immune System in Hypertension

Physiological Reviews ◽

10.1152/physrev.00031.2016 ◽

2017 ◽

Vol 97 (3) ◽

pp. 1127-1164 ◽

Cited By ~ 109

Author(s):

Bernardo Rodriguez-Iturbe ◽

Hector Pons ◽

Richard J. Johnson

Keyword(s):

Blood Pressure ◽

Immune System ◽

High Blood Pressure ◽

Inflammatory Responses ◽

Immunosuppressive Drugs ◽

Organ Injury ◽

Mouse Strains ◽

Experimental Hypertension ◽

Immune Reactivity

High blood pressure is present in more than one billion adults worldwide and is the most important modifiable risk factor of death resulting from cardiovascular disease. While many factors contribute to the pathogenesis of hypertension, a role of the immune system has been firmly established by a large number of investigations from many laboratories around the world. Immunosuppressive drugs and inhibition of individual cytokines prevent or ameliorate experimental hypertension, and studies in genetically-modified mouse strains have demonstrated that lymphocytes are necessary participants in the development of hypertension and in hypertensive organ injury. Furthermore, immune reactivity may be the driving force of hypertension in autoimmune diseases. Infiltration of immune cells, oxidative stress, and stimulation of the intrarenal angiotensin system are induced by activation of the innate and adaptive immunity. High blood pressure results from the combined effects of inflammation-induced impairment in the pressure natriuresis relationship, dysfunctional vascular relaxation, and overactivity of the sympathetic nervous system. Imbalances between proinflammatory effector responses and anti-inflammatory responses of regulatory T cells to a large extent determine the severity of inflammation. Experimental and human studies have uncovered autoantigens (isoketal-modified proteins and heat shock protein 70) of potential clinical relevance. Further investigations on the immune reactivity in hypertension may result in the identification of new strategies for the treatment of the disease.

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Self-Control of Inflammation during Tail Regeneration of Lizards

Journal of Developmental Biology ◽

10.3390/jdb9040048 ◽

2021 ◽

Vol 9 (4) ◽

pp. 48

Author(s):

Bingqiang He ◽

Honghua Song ◽

Yongjun Wang

Keyword(s):

Wound Healing ◽

Inflammatory Responses ◽

Tissue Injury ◽

Therapeutic Strategies ◽

Self Control ◽

Organ Injury ◽

Antibacterial Peptides ◽

Tail Regeneration ◽

Inflammatory Activation ◽

Fibrotic Scar

Lizards can spontaneously regenerate their lost tail without evoking excessive inflammation at the damaged site. In contrast, tissue/organ injury of its mammalian counterparts results in wound healing with a formation of a fibrotic scar due to uncontrolled activation of inflammatory responses. Unveiling the mechanism of self-limited inflammation occurring in the regeneration of a lizard tail will provide clues for a therapeutic alternative to tissue injury. The present review provides an overview of aspects of rapid wound healing and roles of antibacterial peptides, effects of leukocytes on the tail regeneration, self-blocking of the inflammatory activation in leukocytes, as well as inflammatory resistance of blastemal cells or immature somatic cells during lizard tail regeneration. These mechanistic insights of self-control of inflammation during lizard tail regeneration may lead in the future to the development of therapeutic strategies to fight injury-induced inflammation.

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Inhibition of poly (ADP-ribose) Synthetase Attenuates Neutrophil Recruitment and Exerts Antiinflammatory Effects

Journal of Experimental Medicine ◽

10.1084/jem.186.7.1041 ◽

1997 ◽

Vol 186 (7) ◽

pp. 1041-1049 ◽

Cited By ~ 216

Author(s):

Csaba Szabó ◽

Lina H.K. Lim ◽

Salvatore Cuzzocrea ◽

Stephen J. Getting ◽

Basilia Zingarelli ◽

...

Keyword(s):

Systemic Inflammation ◽

Inflammatory Responses ◽

Oxidant Stress ◽

Multiple Organ ◽

Neutrophil Recruitment ◽

Organ Injury ◽

Endothelial Integrity ◽

Antiinflammatory Effects ◽

Rats And Mice

A cytotoxic cycle triggered by DNA single-strand breakage and poly (ADP-ribose) synthetase activation has been shown to contribute to the cellular injury during various forms of oxidant stress in vitro. The aim of this study was to investigate the role of poly (ADP-ribose) synthetase (PARS) in the process of neutrophil recruitment and in development of local and systemic inflammation. In pharmacological studies, PARS was inhibited by 3-aminobenzamide (10–20 mg/kg) in rats and mice. In other sets of studies, inflammatory responses in PARS−/− mice were compared with the responses in corresponding wild-type controls. Inhibition of PARS reduced neutrophil recruitment and reduced the extent of edema in zymosan- and carrageenan-triggered models of local inflammation. Moreover, inhibition of PARS prevented neutrophil recruitment, and reduced organ injury in rodent models of inflammation and multiple organ failure elicited by intraperitoneal injection of zymosan. Inhibition of PARS also reduced the extent of neutrophil emigration across murine mesenteric postcapillary venules. This reduction was due to an increased rate of adherent neutrophil detachment from the endothelium, promoting their reentry into the circulation. Taken together, our results demonstrate that PARS inhibition reduces local and systemic inflammation. Part of the antiinflammatory effects of PARS inhibition is due to reduced neutrophil recruitment, which may be related to maintained endothelial integrity.

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