Adenosine A2A Receptor (A2AR) agonists improve survival in K28-hACE2 mice following SARS CoV-2 infection (original) (raw)
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Can Adenosine Fight COVID-19 Acute Respiratory Distress Syndrome?
Some COVID-19 patients develop interstitial pneumonia that can evolve into Acute Respiratory Distress Syndrome (ARDS). This is accompanied by an inflammatory cytokine storm. SarS-CoV has proteins capable of promoting cytokine storm, especially in patients with comorbidities, including obesity. Since there is currently no resolutive therapy for ARDS and given the scientific literature regarding the use of adenosine, its application has been hypothesized. Adenosine through its receptors is able to inhibit the acute inflammatory process, increase the protection capacity of the epithelial barrier and reduce the damage due to an overactivation of the immune system, such as in cytokine storms. These features are known in ischemia / reperfusion models and could also be exploited in acute lung injury, with hypoxia. In light of these hypotheses, for compassionate use, a COVID-19 patient, with unresponsive respiratory failure, was treated with adenosine. The results showed a rapid and clear i...
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...
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,...
Regadenoson for the treatment of COVID-19: A five case clinical series and mouse studies
PLOS ONE
Background Adenosine inhibits the activation of most immune cells and platelets. Selective adenosine A2A receptor (A2AR) agonists such as regadenoson (RA) reduce inflammation in most tissues, including lungs injured by hypoxia, ischemia, transplantation, or sickle cell anemia, principally by suppressing the activation of invariant natural killer T (iNKT) cells. The anti-inflammatory effects of RA are magnified in injured tissues due to induction in immune cells of A2ARs and ecto-enzymes CD39 and CD73 that convert ATP to adenosine in the extracellular space. Here we describe the results of a five patient study designed to evaluate RA safety and to seek evidence of reduced cytokine storm in hospitalized COVID-19 patients. Methods and findings Five COVID-19 patients requiring supplemental oxygen but not intubation (WHO stages 4–5) were infused IV with a loading RA dose of 5 μg/kg/h for 0.5 h followed by a maintenance dose of 1.44 μg/kg/h for 6 hours, Vital signs and arterial oxygen sat...
Possible therapeutic options and management of COVID-19
Research, Society and Development
Currently, there is no effective therapy against Coronavirus disease 2019 (COVID-19). Thus, there is crucial requirement for effective therapy against COVID-19. To our knowledge, few investigations have been conducted on AT2 progenitor cells as target for the (SARS-CoV-2). Hence, alveolar type 2 progenitor cells may be a possible therapeutic agent against COVID19. This review focused on the pathogenesis and pathophysiology of COVID19 disease on AT2 cells and explored potential mechanisms to prevent infection and death of AT2 progenitor cells as possible therapy against COVID-19. We propose that inhibition of IL-1 receptor, IL 1, NFkB and JNK signalling pathway may serve as therapeutic target for COVID-19
Drug Development Research, 2020
A highly contagious coronavirus disease COVID-19 caused by a recently identified severe acute respiratory syndrome CoV-2 (SARS-CoV-2) initially detected in Wuhan, China has spread worldwide and become a major health crisis in the absence of specific vaccine or antiviral drugs. SARS-CoV-2 infection has resulted in overwhelming number of reported deaths. Unfortunately it is still spreading uncontrollably despite implementing stringent protective measures. Rapid development of effective therapeutic strategies for treatment and prevention of infection is crucially required. Although genomic characterization has assisted in unfolding various aspects of SARS-CoV-2 but development of specific antiviral drugs and vaccine against COVID-19 is still a worldwide challenge. Understanding the disease pathological course underlying the clinical manifestations of COVID-19 is imperative to identify the vital targets for drug development. SARS-CoV-2 uses angiotensin converting enzyme 2 (ACE2) receptor to enter the host cell and primarily target type II alveolar cells. COVID-19 disease progression is associated with distressed immune functions and hyper active inflammatory system leading to development of cytokine storm which is a vital factor involved in disease advancement. The current review elucidates the disease pathology and summarizes the possible therapeutic options to battle against COVID-19 on the basis of current state of understanding about SARS-CoV-2 pathogenic pathways and knowledge gained from previous SARS and MERS-CoV epidemics. Therapeutic strategies to treat and prevent infection as well as to suppress the disease progression to reduce severity and mortality rate is discussed. Drug candidates currently under consideration and undergoing clinical trials for COVID-19 treatment are highlighted. K E Y W O R D S anti-inflammatory, antiviral, disease pathology, pharmacologic treatment, SARS-CoV-2, viral entry blockers 1 | INTRODUCTION COVID 19 is a highly contagious respiratory tract infection caused by recently identified severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) originated from Wuhan, China (Wang et al., 2020). Unrestrained global spread of SARS-CoV-2 has resulted in 42,58,666 infected cases with ample number of reported deaths (2,94,190) across the world as on May 15, 2020 as per WHO report. Its extraordinary human to human transmission efficiency leading to irrepressibly increasing global incidents on such an alarming rate exhibited high potential for a pandemic (Chan et al., 2020; Li et al., 2020). The lack of specific antiviral medication or vaccine against SARS-CoV-2 poses
Journal of virology, 2014
We have shown that bronchoalveolar epithelial A1-adenosine receptors (A1-AdoR) are activated in influenza A virus-infected mice. Alveolar macrophages and neutrophils also express A1-AdoRs, and we hypothesized that activation of A1-AdoRs on these cells will promote macrophage and neutrophil chemotaxis and activation and thereby play a role in the pathogenesis of influenza virus-induced acute lung injury. Wild-type (WT) C57BL/6 mice, congenic A1-AdoR knockout (A1-KO) mice, and mice that had undergone reciprocal bone marrow transfer were inoculated intranasally with 10,000 PFU/mouse influenza A/WSN/33 (H1N1) virus. Alternatively, WT mice underwent daily treatment with the A1-AdoR antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) from 1 day prior to inoculation. Infection increased bronchoalveolar lining fluid (BALF) adenosine comparably in WT and A1-KO mice. Infection of WT mice resulted in reduced carotid arterial O2 saturation (hypoxemia), lung pathology, pulmonary edema, reduced...
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.
Comparison of transgenic and adenovirus hACE2 mouse models for SARS-CoV-2 infection
Emerging Microbes & Infections
Severe acute respiratory syndrome CoV-2 (SARS-CoV-2) is currently causing a worldwide pandemic with high morbidity and mortality. Development of animal models that recapitulate important aspects of coronavirus disease 2019 (COVID-19) is critical for the evaluation of vaccines and antivirals, and understanding disease pathogenesis. SARS-CoV-2 has been shown to use the same entry receptor as SARS-CoV-1, human angiotensin-converting enzyme 2 (hACE2) [1-3]. Due to amino acid differences between murine and hACE2, inbred mouse strains fail to support high titer viral replication of SARS-CoV-2 virus. Therefore, a number of transgenic and knock-in mouse models, as well as viral vector-mediated hACE2 delivery systems have been developed. Here we compared the K18-hACE2 transgenic model to adenovirusmediated delivery of hACE2 to the mouse lung. We show that K18-hACE2 mice replicate virus to high titers in the nasal turbinates, lung and brain, with high lethality, and cytokine/chemokine production. In contrast, adenovirusmediated delivery results in viral replication to lower titers limited to the nasal turbinates and lung, and no clinical signs of infection. The K18-hACE2 model provides a stringent model for testing vaccines and antivirals, whereas the adenovirus delivery system has the flexibility to be used across multiple genetic backgrounds and modified mouse strains.