1. A novel definition and treatment of hyperinflammation in COVID-19 based on purinergic signalling.
- Author
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Hasan D, Shono A, van Kalken CK, van der Spek PJ, Krenning EP, and Kotani T
- Subjects
- Anti-Inflammatory Agents therapeutic use, Critical Care, Cytokine Release Syndrome drug therapy, Humans, Inflammation drug therapy, Infusions, Subcutaneous, Lidocaine administration & dosage, Lidocaine pharmacology, Lymph Nodes immunology, Lymphatic System immunology, Male, Maximum Tolerated Dose, Middle Aged, Models, Immunological, Purinergic P2X Receptor Antagonists administration & dosage, Purinergic P2X Receptor Antagonists pharmacology, Receptors, Purinergic drug effects, Receptors, Purinergic P1 drug effects, Receptors, Purinergic P1 physiology, Receptors, Purinergic P2X7 physiology, Respiratory Distress Syndrome drug therapy, Respiratory Distress Syndrome etiology, Signal Transduction, T-Lymphocytes, Regulatory immunology, Adenosine Triphosphate metabolism, COVID-19 immunology, Cytokine Release Syndrome etiology, Inflammation etiology, Lidocaine therapeutic use, Purinergic P2X Receptor Antagonists therapeutic use, Receptors, Purinergic physiology
- Abstract
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., (© 2021. The Author(s).)
- Published
- 2022
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