A<sub>2A</sub>Adenosine Receptor Activation Improves Survival in Mouse Models of Endotoxemia and Sepsis

Sullivan, Gail W.; Fang, Guodong; Linden, Joel; Scheld, W. Michael

doi:10.1086/386311

Cited by 98 publications

(92 citation statements)

References 44 publications

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“…In mice lacking the A 2A AR, protection by ATL-146e is lost and ischaemic injury of short duration is exacerbated, which contrasts with the results obtained in wild-type mice, suggesting a protective role for endogenous adenosine 185 . The A 2A AR agonist ATL-146e is also of interest for the treatment of sepsis 186 , inflammatory bowel disease 187 and for inclusion in drug-eluting stents to prevent restenosis after angioplasty. Selective activation of the A 2A AR has also been shown to reduce skin pressure, ulcer formation and inflammation 188 , and wound healing is accelerated 189 .…”

Section: Ars As Targets In Inflammatory Disordersmentioning

confidence: 99%

Adenosine receptors as therapeutic targets

Jacobson

Gao

2006

Nat Rev Drug Discov

1,276

1,361

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Adenosine receptors are major targets of caffeine, the most commonly consumed drug in the world. There is growing evidence that they could also be promising therapeutic targets in a wide range of conditions, including cerebral and cardiac ischaemic diseases, sleep disorders, immune and inflammatory disorders and cancer. After more than three decades of medicinal chemistry research, a considerable number of selective agonists and antagonists of adenosine receptors have been discovered, and some have been clinically evaluated, although none has yet received regulatory approval. However, recent advances in the understanding of the roles of the various adenosine receptor subtypes, and in the development of selective and potent ligands, as discussed in this review, have brought the goal of therapeutic application of adenosine receptor modulators considerably closer.

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Section: Ars As Targets In Inflammatory Disordersmentioning

confidence: 99%

Adenosine receptors as therapeutic targets

Jacobson

Gao

2006

Nat Rev Drug Discov

1,276

1,361

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“…Moreover, current antimicrobial approaches also often fail to treat infectious diseases. In these cases, a rational pharmacological targeting of stress and damage responses controlling tissue damage control may act therapeutically through the establishment of disease tolerance to infection, as illustrated for pharmacological targeting of adenosine receptors 109 or labile heme 16 , which establish disease tolerance to sepsis 16,109 or malaria 20,21,30 in mice.…”

Section: Pharmacological Modulation Of Disease Tolerancementioning

confidence: 99%

“…Catabolism of extracellular ATP/ADP into AMP and subsequently into adenosine, by the nucleoside triphosphate dephosphorylase CD39 and the ecto-5'-nucleotidase CD73, respectively 160 , exerts immunoregulatory effects, promoting the establishment of disease tolerance Toxoplasma gondii 161 or Helicobacter 162 infections in mice. Presumably these effects are mediated via adenosine-driven signaling through transmembrane adenosine G proteincoupled cell surface receptors 109,163 . Lipid peroxidation is countered by several damage responses 50 that induce HO-1 31 , a heme catabolizing enzyme that degrades the lipophilic pro-oxidant heme into biliverdin, which is converted by biliverdin reductase into the lipophilic anti-oxidant bilirubin 164 and promotes disease tolerance to bloodstream infections 16,20,21,[29][30][31] .…”

Section: Box 3 Microbiota and Disease Tolerancementioning

confidence: 99%

Disease tolerance and immunity in host protection against infection

2017

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The immune system has most likely evolved to limit the negative impact exerted by pathogens on host homeostasis. This defense strategy relies on the concerted action of innate and adaptive components of the immune system, which sense and target pathogens for containment, destruction or expulsion. Resistance to infection refers to these immune functions, which reduce the pathogen load of an infected host as the means to preserve homeostasis. Immune-driven resistance to infection is coupled to an additional, and arguably as important, defense strategy that limits the extent of dysfunction imposed to host parenchyma tissues during infection, without exerting a direct negative impact on pathogens.This defense strategy, called disease tolerance, relies on tissue damage control mechanisms that prevent the deleterious effects of pathogens, while uncoupling immunedriven resistance mechanisms from immunopathology and disease. Here we provide a unifying view of resistance and disease tolerance within the framework of immunity to infection.

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“…In a rat meningitis model, a selective adenosine AlA receptor agonist decreased WBC chemotaxis and blood brain barrier permeability in response to a lipopolysaccharide (LPS) challenge [41]. Adenosine agonists have also been shown to reduce the mortality associated with peritonitis in a mouse model [42].…”

Section: Introductionmentioning

confidence: 99%

Reducing joint destruction due to septic arthrosis using an adenosine_2A receptor agonist

Cohen

Gill

Baer

et al. 2004

Journal Orthopaedic Research

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We assessed the efficacy of a new adenosine AZA agonist ATL146e, a potent inhibitor of white blood cell chemotaxis, to reduce cartilage damage in the treatment of septic arthrosis. A live septic arthrosis model was created using Staphylococcus aureus in rabbit knees. Animals were divided into five treatment groups: (1) untreated infected control, (2) antibiotics control, and antibiotics plus ATL146e for (3) 24, (4) 48, or (5) 72 h and assessed at I , 4, and 7 days.Knees in all ATL 146e treated animals exhibited no detectable effusion, and histologic examination revealed near normal cartilage and diminished synovial inflammatory response. Synovial WBC counts decreased with the addition of ATL146e when compared to infected and antibiotic controls. Histologic grading of osteochondral specimens demonstrated improved scores for animals treated with ATLl46e compared to infected (p < 0.00004) and antibiotics controls (p < 0.05). Analysis of glycosaminoglycan content revealed significantly decreased loss of articular cartilage following infection in the ATL 146e groups when compared to infected (p < 0.03) and antibiotics controls (p < 0.05).Addition of an adenosine AZA agonist to antibiotic therapy decreases joint inflammation and articular cartilage destruction without compromising bacterial clearance in rabbit knees following intraarticular bacterial infection. The use of adenosine agonists selective to the AZA receptor to augment conventional treatment of joint sepsis may be chondroprotective and ultimately help prevent arthrosis.

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A_2AAdenosine Receptor Activation Improves Survival in Mouse Models of Endotoxemia and Sepsis

Abstract: AR agonists increase mouse survival in endotoxemia and sepsis via A(2A) AR-mediated mechanisms and reduce the number of live bacteria in blood.

Cited by 98 publications

References 44 publications

Adenosine receptors as therapeutic targets

Adenosine receptors as therapeutic targets

Disease tolerance and immunity in host protection against infection

Reducing joint destruction due to septic arthrosis using an adenosine_2A receptor agonist

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A2AAdenosine Receptor Activation Improves Survival in Mouse Models of Endotoxemia and Sepsis

Abstract: AR agonists increase mouse survival in endotoxemia and sepsis via A(2A) AR-mediated mechanisms and reduce the number of live bacteria in blood.

Cited by 98 publications

References 44 publications

Adenosine receptors as therapeutic targets

Adenosine receptors as therapeutic targets

Disease tolerance and immunity in host protection against infection

Reducing joint destruction due to septic arthrosis using an adenosine2A receptor agonist

Contact Info

Product

Resources

About

A_2AAdenosine Receptor Activation Improves Survival in Mouse Models of Endotoxemia and Sepsis

Reducing joint destruction due to septic arthrosis using an adenosine_2A receptor agonist