P2X7 purinergic receptor: A potential target in heart diseases (Review).

The P2X7 purinergic receptor (P2X7R) is a non­selective cation channel activated by high levels of adenosine triphosphate that are commonly present in serious conditions. Activation of this purinergic receptor is closely related to the development of various disease states including inflammatory and neurodegenerative disorders, orthopedic diseases and types of cancer. Accumulating evidence has shown that the P2X7R plays a crucial role in the development of various heart diseases. For example, activation of P2X7Rs may alleviate myocardial ischemia­reperfusion injury by releasing endogenous cardiac protective substances. In contrast to these findings, activation of P2X7Rs can promote the development of acute myocardial infarction and myocarditis by inducing inflammatory responses. Activation of these receptors can also contribute to the development of different types of cardiomyopathies including diabetic cardiomyopathy, dilated cardiomyopathy and hypertrophic cardiomyopathy by inducing cardiac hypertrophy, fibrosis and apoptosis. Notably, inhibition of P2X7Rs can improve cardiac structure and function abnormalities following acute myocardial infarction, reduction of inflammatory responses following myocarditis and attenuation of the cardiomyopathy process. Furthermore, recent evidence has demonstrated that P2X7Rs are highly active in patients infected with coronavirus disease­2019 (COVID­19). Hyperactivation of P2X7Rs in COVID­19 may induce severe myocardial injury through the activation of several signaling pathways. The present study reviewed the important role of the P2X7R in cardiac dysfunctions and discusses its use as a possible new therapeutic approach for the prevention and treatment of several myocardial diseases.

A novel definition and treatment of hyperinflammation in COVID-19 based on purinergic signalling.

Hyperinflammation plays an important role in severe and critical COVID-19. Using inconsistent criteria, many researchers define hyperinflammation as a form of very severe inflammation with cytokine storm. Therefore, COVID-19 patients are treated with anti-inflammatory drugs. These drugs appear to be less efficacious than expected and are sometimes accompanied by serious adverse effects. SARS-CoV-2 promotes cellular ATP release. Increased levels of extracellular ATP activate the purinergic receptors of the immune cells initiating the physiologic pro-inflammatory immune response. Persisting viral infection drives the ATP release even further leading to the activation of the P2X7 purinergic receptors (P2X7Rs) and a severe yet physiologic inflammation. Disease progression promotes prolonged vigorous activation of the P2X7R causing cell death and uncontrolled ATP release leading to cytokine storm and desensitisation of all other purinergic receptors of the immune cells. This results in immune paralysis with co-infections or secondary infections. We refer to this pathologic condition as hyperinflammation. The readily available and affordable P2X7R antagonist lidocaine can abrogate hyperinflammation and restore the normal immune function. The issue is that the half-maximal effective concentration for P2X7R inhibition of lidocaine is much higher than the maximal tolerable plasma concentration where adverse effects start to develop. To overcome this, we selectively inhibit the P2X7Rs of the immune cells of the lymphatic system inducing clonal expansion of Tregs in local lymph nodes. Subsequently, these Tregs migrate throughout the body exerting anti-inflammatory activities suppressing systemic and (distant) local hyperinflammation. We illustrate this with six critically ill COVID-19 patients treated with lidocaine.

SARS-CoV-2 vs. SARS-CoV-1 management: antibiotics and inflammasome modulators potential.

The coronavirus SARS-CoV-2 at the origin of COVID-19 shares more than 70% genetic similarity with SARS-CoV-1 that was at the origin of 2003 SARS. Infection-associated symptoms are very similar between SARS and COVID-19 diseases and are the same as community-acquired pneumonia symptoms. Antibiotics were empirically given to SARS patients in the early stages of the pathology whereas a different strategy has been decided in the management of COVID-19 pandemic with a worldwide shutdown. The cytokine storm, both identified in SARS and COVID-19 severe cases, is generated through inflammasome activation, which opens therapeutic perspectives to counteract the pathogenic inflammation. As corticoids have numerous side effects that limit their use, focusing on anti-inflammasome agents could represent a safer alternative for patients with severe COVID-19.