The Antifibrotic Effect of A<sub>2B</sub> Adenosine Receptor Antagonism in a Mouse Model of Dermal Fibrosis

Karmouty‐Quintana, Harry; Molina, Jose G.; Philip, Kemly; Bellocchi, Chiara; Gudenkauf, Brent; Wu, Minghua; Chen, Ning Yuan; Collum, Scott D.; Ko, Junsuk; Agarwal, Sandeep K.; Assassi, Shervin; Zhong, Hongshan; Blackburn, Michael R.; Weng, Tingting

doi:10.1002/art.40554

Cited by 19 publications

(16 citation statements)

References 40 publications

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“…Elevated levels of 1-methyl-adenosine 29 have so far been associated with proliferative and/or metastatic tumors 35 , 36 . Non-modified adenosine, generated extracellularly from ATP/ADP breakdown 29 , is a well-known pro-fibrotic mediator 37 – 41 and its inhibition was beneficial in in fibrotic animal models 37 , 39 , 40 . As previously observed in lung fibrosis and SSc 14 , there was a tendency towards lower adenosine monophosphate (AMP) levels in progressing SSc-ILD patients.…”

Section: Discussionmentioning

confidence: 99%

Serum metabolites as biomarkers in systemic sclerosis-associated interstitial lung disease

Meier

Freiburghaus

Bovet

et al. 2020

Sci Rep

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Systemic sclerosis (SSc) is a severe multi-organ disease with interstitial lung disease (ILD) being the major cause of death. While targeted therapies are emerging, biomarkers for sub-stratifying patients based on individual profiles are lacking. Herein, we investigated how levels of serum metabolites correlated with different stages of SSc and SSc-ILD. Serum samples of patients with SSc without ILD, stable and progressive SSc-ILD as well as of healthy controls (HC) were analysed using liquid targeted tandem mass spectrometry. The best discriminating profile consisted of 4 amino acids (AA) and 3 purine metabolites. l-tyrosine, l-tryptophan, and 1-methyl-adenosine distinguished HC from SSc patients. l-leucine, l-isoleucine, xanthosine, and adenosine monophosphate differentiated between progressing and stable SSc-ILD. In SSc-ILD, both, l-leucine and xanthosine negatively correlated with changes in FVC% predicted. Additionally, xanthosine was negatively correlated with changes in DLco% predicted and positively with the prognostic GAP index. Validation of l-leucine and l-isoleucine by an enzymatic assay confirmed both the sub-stratification of SSc-ILD patients and correlation with lung function and prognosis score. Serum metabolites may have potential as biomarkers for discriminating SSc patients based on the presence and severity of ILD. Confirmation in larger cohorts will be needed to appreciate their value for routine clinical care.

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Section: Discussionmentioning

confidence: 99%

Serum metabolites as biomarkers in systemic sclerosis-associated interstitial lung disease

Meier

Freiburghaus

Bovet

et al. 2020

Sci Rep

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“…Multiple sclerosis Pro-inflammatory actions [84] Experimental autoimmune uveitis Pro-inflammatory actions [86] Systemic sclerosis Pro-fibrotic regulator in vivo [89] Type 1 diabetes Inhibition of pro-inflammatory cytokine release [90] Inflammatory bowel disease Pro-inflammatory actions [92] Autoimmune liver disorders Among the vast number of available and sometimes contradictory evidence, the most promising results are currently related to the A 3 AR subtype, possibly due to two fundamental issues: the characteristic upregulation of this receptor subtype in autoimmune pathologies, which allows its prevalent activation in affected tissues only, and the fundamental contribution of medicinal chemists who have made selective agonists and antagonists available for pre-clinical and clinical studies. Additionally, A 3 ARs could also be exploited as biomarkers of therapeutic efficacy, thus paving the way for personalized patient-centered therapy.…”

Section: Receptor Autoimmune Disease Hypothesized Role Referencesmentioning

confidence: 99%

“…While no significant changes in A 2A AR binding parameters or expression levels are detected, a significant decrease in the maximum density of A 2B AR binding sites occurs in SSc neutrophils, in parallel with decreased A 2B ARs-mediated activation of adenylyl cyclase activity [ 88 ]. These data were recently confirmed in a murine model of SSc, where the administration of the orally active A 2B AR antagonist 3-Ethyl-3,9-dihydro-1-propyl-8-[1-[[3-(trifluoromethyl)phenyl]methyl]-1 H -pyrazol-4-yl]-1 H -purine-2,6-dione (GS-6201) reduces the production of pro-fibrotic mediators in the skin, attenuates dermal fibrosis, and reduces the number of arginase-expressing macrophages and myofibroblasts and the levels of extracellular matrix proteins, suggesting A 2B ARs as potential pro-fibrotic regulators [ 89 ].…”

Section: Towards New Ado-based Immunomodulatory Approaches: Preclimentioning

confidence: 99%

Adenosine Signaling in Autoimmune Disorders

Magni

Ceruti

2020

Pharmaceuticals

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The molecular components of the purinergic system (i.e., receptors, metabolizing enzymes and membrane transporters) are widely expressed in the cells of the immune system. Additionally, high concentrations of adenosine are generated from the hydrolysis of ATP in any “danger” condition, when oxygen and energy availability dramatically drops. Therefore, adenosine acts as a retaliatory metabolite to counteract the nucleotide-mediated boost of the immune reaction. Based on this observation, it can be foreseen that the recruitment with selective agonists of the receptors involved in the immunomodulatory effect of adenosine might represent an innovative anti-inflammatory approach with potential exploitation in autoimmune disorders. Quite surprisingly, pro-inflammatory activity exerted by some adenosine receptors has been also identified, thus paving the way for the hypothesis that at least some autoimmune disorders may be caused by a derailment of adenosine signaling. In this review article, we provide a general overview of the roles played by adenosine on immune cells with a specific focus on the development of adenosine-based therapies for autoimmune disorders, as demonstrated by the exciting data from concluded and ongoing clinical trials.

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“…There is a growing body of evidence indicating that adenosine has an important role in tissue remodeling and dermal fibrosis (Chan et al, 2013;Hu et al, 2013;Perez-Aso et al, 2014;Zhang et al, 2017a;Karmouty-Quintana et al, 2018). A 2A receptor activation causes dermal wound closure and increased dermal matrix deposition in vitro (Montesinos et al, 2004;Cronstein, 2006a;Scheibner et al, 2009).…”

Section: E Sclerodermamentioning

confidence: 99%

“…Subcutaneous treatment of mice with bleomycin upregulates A 2B receptor transcript levels in the skin (Karmouty-Quintana et al, 2018). Pharmacological blockade of A 2B receptors by GS-6201 reduced the production of profibrotic mediators (fibronectin, MCP1, IL-6, and a-SMA) in the skin and attenuated dermal fibrosis of mice in bleomycin-induced as well as genetic [mutant tight-skin (TSK1/+) mice] models of human scleroderma (Karmouty-Quintana et al, 2018).…”

Section: E Sclerodermamentioning

confidence: 99%

The Purinergic System as a Pharmacological Target for the Treatment of Immune-Mediated Inflammatory Diseases

Antonioli¹,

Blandizzi²,

Pacher³

et al. 2019

Pharmacol Rev

132

108

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Immune-mediated inflammatory diseases (IMIDs) encompass a wide range of seemingly unrelated conditions, such as multiple sclerosis, rheumatoid arthritis, psoriasis, inflammatory bowel diseases, asthma, chronic obstructive pulmonary disease, and systemic lupus erythematosus. Despite differing etiologies, these diseases share common inflammatory pathways, which lead to damage in primary target organs and frequently to a plethora of systemic effects as well. The purinergic signaling complex comprising extracellular nucleotides and nucleosides and their receptors, the P2 and P1 purinergic receptors, respectively, as well as catabolic enzymes and nucleoside transporters is a major regulatory system in the body. The purinergic signaling complex can regulate the development and course of IMIDs. Here we provide a comprehensive review on the role of purinergic signaling in controlling immunity, inflammation, and organ function in IMIDs. In addition, we discuss the possible therapeutic applications of drugs acting on purinergic pathways, which have been entering clinical development, to manage patients suffering from IMIDs.

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The Antifibrotic Effect of A_2B Adenosine Receptor Antagonism in a Mouse Model of Dermal Fibrosis

Abstract: These findings identify ADORA2B as a potential profibrotic regulator in dermal fibrosis and suggest that ADORA2B antagonism may be a useful approach for the treatment of SSc.

Cited by 19 publications

References 40 publications

Serum metabolites as biomarkers in systemic sclerosis-associated interstitial lung disease

Serum metabolites as biomarkers in systemic sclerosis-associated interstitial lung disease

Adenosine Signaling in Autoimmune Disorders

The Purinergic System as a Pharmacological Target for the Treatment of Immune-Mediated Inflammatory Diseases

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The Antifibrotic Effect of A2B Adenosine Receptor Antagonism in a Mouse Model of Dermal Fibrosis

Abstract: These findings identify ADORA2B as a potential profibrotic regulator in dermal fibrosis and suggest that ADORA2B antagonism may be a useful approach for the treatment of SSc.

Cited by 19 publications

References 40 publications

Serum metabolites as biomarkers in systemic sclerosis-associated interstitial lung disease

Serum metabolites as biomarkers in systemic sclerosis-associated interstitial lung disease

Adenosine Signaling in Autoimmune Disorders

The Purinergic System as a Pharmacological Target for the Treatment of Immune-Mediated Inflammatory Diseases

Contact Info

Product

Resources

About

The Antifibrotic Effect of A_2B Adenosine Receptor Antagonism in a Mouse Model of Dermal Fibrosis