Can Adenosine Fight COVID-19 Acute Respiratory Distress Syndrome? (original) (raw)
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Efficacy and Effect of Inhaled Adenosine Treatment in Hospitalized COVID-19 Patients
Frontiers in Immunology, 2021
Lack of specific antiviral treatment for COVID-19 has resulted in long hospitalizations and high mortality rate. By harnessing the regulatory effects of adenosine on inflammatory mediators, we have instituted a new therapeutic treatment with inhaled adenosine in COVID-19 patients, with the aim of reducing inflammation, the onset of cytokine storm, and therefore to improve prognosis. The use of inhaled adenosine in COVID19 patients has allowed reduction of length of stay, on average 6 days. This result is strengthened by the decrease in SARS-CoV-2 positive days. In treated patients compared to control, a clear improvement in PaO2/FiO2 was observed together with a reduction in inflammation parameters, such as the decrease of CRP level. Furthermore, the efficacy of inhaled exogenous adenosine led to an improvement of the prognosis indices, NLR and PLR. The treatment seems to be safe and modulates the immune system, allowing an effective response against the viral infection progression,...
Therapeutic effects of adenosine in high flow 21% oxygen aereosol in patients with Covid19-pneumonia
PLOS ONE
Background SARS-Cov2 infection may trigger lung inflammation and acute-respiratory-distress-syndrome (ARDS) that requires active ventilation and may have fatal outcome. Considering the severity of the disease and the lack of active treatments, 14 patients with Covid-19 and severe lung inflammation received inhaled adenosine in the attempt to therapeutically compensate for the oxygen-related loss of the endogenous adenosine!A2A adenosine receptor (A2AR)-mediated mitigation of the lung-destructing inflammatory damage. This off label-treatment was based on preclinical studies in mice with LPS-induced ARDS, where inhaled adenosine/A2AR agonists protected oxygenated lungs from the deadly inflammatory damage. The treatment was allowed, considering that adenosine has several clinical applications. Patients and treatment Fourteen consecutively enrolled patients with Covid19-related interstitial pneumonitis and PaO 2 /FiO 2 ratio<300 received off-label-treatment with 9 mg inhaled adenosine every 12 hours in the first 24 hours and subsequently, every 24 days for the next 4 days. Fifty-two patients with analogue features and hospitalized between February and April 2020, who did not receive adenosine, were considered as a historical control group. Patients monitoring also included hemodynamic/hematochemical studies, CTscans, and SARS-CoV2-tests.
Possible Role of Adenosine in COVID-19 Pathogenesis and Therapeutic Opportunities
Frontiers in Pharmacology, 2020
The outbreak of the novel coronavirus disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) requires urgent clinical interventions. Crucial clinical needs are: 1) prevention of infection and spread of the virus within lung epithelia and between people, 2) attenuation of excessive lung injury in Advanced Respiratory Distress Syndrome, which develops during the end stage of the disease, and 3) prevention of thrombosis associated with SARS-CoV-2 infection. Adenosine and the key adenosine regulators adenosine deaminase (ADA), adenosine kinase (ADK), and equilibrative nucleoside transporter 1 may play a role in COVID-19 pathogenesis. Here, we highlight 1) the non-enzymatic role of ADA by which it might out-compete the virus (SARS-CoV-2) for binding to the CD26 receptor, 2) the enzymatic roles of ADK and ADA to increase adenosine levels and ameliorate Advanced Respiratory Distress Syndrome, and 3) inhibition of adenosine transporters to reduce plat...
bioRxiv (Cold Spring Harbor Laboratory), 2022
Effective and available therapies for the treatment of COVID-19 disease are limited. Apadenoson is a highly potent selective anti-inflammatory adenosine A2A receptor (A2AR) agonist and potential treatment option for COVID-19 patients. Apadenoson, when administered after infection with SARS CoV-2, was found to decrease weight loss, improve clinical symptoms, reduce levels of a several proinflammatory cytokines and chemokines in bronchial lavage (BAL) fluid, and promote increased survival in K18hACE2 transgenic mice. Of note, administering apadenoson after, but not prior to Covid-19 infection, caused a rapid decrease in lung viral burden. The work presented provides the foundation for further examination of these drugs as a therapy option for COVID-19.
Adenosine: An endogenous modulator of innate immune system with therapeutic potential
European Journal of Pharmacology, 2009
Adenosine is a purine nucleoside, which is produced inside the body under metabolic stress like hypoxic conditions, acute or chronic inflammatory tissue insults. The synthesis of adenosine involves the catabolism of adenine nucleotides (ATP, ADP and AMP) by the action of extracellular ectonucleotidases i.e. CD39 or nucleoside triphosphate dephosphorylase (NTPD) and CD73 or 5′-ectonucleotidase. Once adenosine is released in the extracellular environment, it binds to different types of adenosine (i.e. adenosine A 1 , A 2A , A 2B and A 3 receptors) receptors expressed on various innate immune cells [Neutrophils, macrophages, mast cells, dendritic cells and natural killer cells]. Thus, depending on the type of adenosine receptor to which it binds, adenosine modulates innate immune response during various inflammatory conditions [i.e. chronic (cancer, asthma) as well as acute (sepsis, acute lung injury) inflammatory diseases]. This review summarizes the effect of adenosine on innate immunity and the use of adenosine receptor specific agonists or antagonists in various immunologic disorders (asthma, cancer, HIV-1 infection) as future immunomodulatory therapeutics.
Modulation of innate immunity by adenosine receptor stimulation
Shock (Augusta, Ga.)
In the past decades, increased concentrations of the signaling molecule adenosine have been shown to play an important role in the prevention of tissue damage evoked by several stressful circumstances. During systemic inflammation, the circulating adenosine concentration increases rapidly, even up to 10-fold in septic shock patients. By binding to specific adenosine receptor subtypes, designated A1, A2a, A2b, and A3, adenosine exerts a wide variety of immunomodulating and (cyto)protective effects. Only recently, several specific adenosine receptor agonists and other drugs that modulate adenosine metabolism have been developed for human use. Importantly, correct interpretation of the effects of adenosine is highly related to the model of inflammation used, e.g., administration of endotoxin or live bacteria. This review will discuss the potential role for adenosine as an immunomodulating and cytoprotective signaling molecule and will discuss its potential role in the treatment of the ...
Inhibition of Adenosine Kinase Attenuates Acute Lung Injury*
Critical Care Medicine, 2015
Objective-Extracellular adenosine has tissue protective potential in several conditions. Adenosine levels are regulated by a close interplay between nucleoside transporters and adenosine kinase (ADK). Based on evidence of the role of ADK in regulating adenosine levels during hypoxia, we evaluated the effect of ADK on lung injury. Furthermore, we tested the influence of a pharmacological approach to blocking ADK on the extent of lung injury. Design-Prospective experimental animal study. Setting-University based research laboratory. Subjects-In vitro cell lines, wildtype (Wt) and ADK +/− mice. Methods-We tested the expression of ADK during inflammatory stimulation in vitro and in a model of lipopolysaccharide (LPS) inhalation in vivo. Studies using the ADK promoter were performed in vitro. Wt and ADK +/− mice were subjected to LPS inhalation.
A protective role for the A1 adenosine receptor in adenosine-dependent pulmonary injury
Journal of Clinical Investigation, 2005
Adenosine is a signaling nucleoside that has been implicated in the regulation of asthma and chronic obstructive pulmonary disease. Adenosine signaling can serve both pro- and anti-inflammatory functions in tissues and cells. In this study we examined the contribution of A(1) adenosine receptor (A(1)AR) signaling to the pulmonary inflammation and injury seen in adenosine deaminase-deficient (ADA-deficient) mice, which exhibit elevated adenosine levels. Experiments revealed that transcript levels for the A(1)AR were elevated in the lungs of ADA-deficient mice, in which expression was localized predominantly to alveolar macrophages. Genetic removal of the A(1)AR from ADA-deficient mice resulted in enhanced pulmonary inflammation along with increased mucus metaplasia and alveolar destruction. These changes were associated with the exaggerated expression of the Th2 cytokines IL-4 and IL-13 in the lungs, together with increased expression of chemokines and matrix metalloproteinases. These findings demonstrate that the A(1)AR plays an anti-inflammatory and/or protective role in the pulmonary phenotype seen in ADA-deficient mice, which suggests that A(1)AR signaling may serve to regulate the severity of pulmonary inflammation and remodeling seen in chronic lung diseases by controlling the levels of important mediators of pulmonary inflammation and damage.
Role of A2B adenosine receptor signaling in adenosine-dependent pulmonary inflammation and injury
Journal of Clinical Investigation, 2006
Adenosine has been implicated in the pathogenesis of chronic lung diseases such as asthma and chronic obstructive pulmonary disease. In vitro studies suggest that activation of the A 2B adenosine receptor (A 2B AR) results in proinflammatory and profibrotic effects relevant to the progression of lung diseases; however, in vivo data supporting these observations are lacking. Adenosine deaminase-deficient (ADA-deficient) mice develop pulmonary inflammation and injury that are dependent on increased lung adenosine levels. To investigate the role of the A 2B AR in vivo, ADA-deficient mice were treated with the selective A 2B AR antagonist CVT-6883, and pulmonary inflammation, fibrosis, and airspace integrity were assessed. Untreated and vehicle-treated ADAdeficient mice developed pulmonary inflammation, fibrosis, and enlargement of alveolar airspaces; conversely,