ATP, the molecule of life, is dangerous when accumulates outside the cells

In severely ill Covid‐19 patients, a cytokine storm syndrome causing severe pneumonia has been observed that fulfils some of the Berlin criteria of acute respiratory distress syndrome (ARDS). In addition, in the lungs of Covid‐19 patients a massive infiltration by inflammatory cells (neutrophils and monocytes/macrophages) with increased blood levels of pro‐inflammatory cytokines, chemokines and of pro-coagulant factors has also been observed. It is believed that an essential component of preventing extensive lung injury caused by severe acute respiratory syndrome‐Coronavirus‐2 (Sars‐Cov‐2) is macrophage inhibition. Therefore, a promising target to down-regulate the responses of macrophages might be the P2X7 receptor.

In a new study published in the British Journal of Pharmacology, University of Ferrara scientists Professor Francesco Di Virgilio and Dr Alba Clara Sarti together with Dr. Yong Tang, Chengdu University of Traditional Chinese Medicine, and Dr. Marco Rossato from the University of Padova,  propose a hypothesis that the P2X7 receptor might be an ideal therapeutic target in Covid-19-associated severe pneumonia.  The P2X7 receptor is a plasma membrane receptor gated by extracellular ATP. ATP, the well-known and ubiquitous intracellular energy currency, is also the most ubiquitous and earliest damage‐associated molecular pattern (DAMP) released at all inflammatory sites, including the lungs. The P2X7 receptor is one of the most powerful stimulators of PYD domain‐containing protein 3 (NLRP3) inflammasome, and therefore of secretion of the potent inflammatory cytokines IL-1β and IL-18. There is evidence that SARS‐Cov, the aetiological agent of SARS epidemic in 2002 directly activates NLRP3 inflammasome through a mechanism dependent on Ca²⁺. Furthermore, P2X7 receptor stimulation promotes release of several other cytokines and chemokines, and sustained production of reactive oxygen species (ROS).

“Injured tissues release large amounts of ATP that, once in the extracellular space, ligates the P2X7 receptor and acts as a very powerful inflammatory agent. We are just starting to identify the multiple pathways set in motion by ATP/P2X7, and to learn to mitigate the dire effects caused by  their activation. There is an immense room here for the development of innovative anti-inflammatory drugs”, says Professor Di Virgilio.

Studies have shown that the genetic ablation or pharmacological inhibition of P2X7 receptors causes a marked reduction in cytokine levels, inflammatory cell infiltration and lung damage in in acute lung injury (ALI) caused by the inhalation of endotoxin (lipopolysaccharide, LPS), an experimental model of acute respiratory distress syndrome (ARDS). P2X7 receptor deficiency also caused a reduction in pro‐IL‐1α release  and alveolar macrophage death in the lungs of mice undergoing ALI.

Of interest, P2X7 receptor‐deficient mice displayed markedly reduced lung inflammation in bleomycin‐ or silica‐induced lung fibrosis models. This suggests that the use of P2X7 receptor antagonists might be beneficial for Covid‐19 patients who might have less severe pneumonia and do not need intensive care units’ admission, but will later develop lung fibrosis. Overactivation of the P2X7 receptor in Covid-19 might also be responsible of “exhaustion” of lymphocyte functions, likely due to inhibition of mitochondrial metabolism, as seen in monocytes during sepsis.

Extensive pulmonary oedema, mostly dependent on the release of VEGF is a key feature of ARDS. Increased blood levels of VEGF have been reported in Covid‐19 patients. The P2X7 receptor induces the release of VEGF and neo‐angiogenesis in vivo, accordingly, VEGF‐dependent increase in vascular permeability is suppressed by the blockade of P2X7 receptors. It might therefore be beneficial to target the P2X7 receptor to fight the early exudative phase in ARDS. Furthermore, P2X7 receptor stimulation is also a powerful trigger for the release of tissue factor (TF), and therefore for the activation of intravascular coagulation.

Till date, no test has been conducted to explore therapeutic effects of P2X7 receptor blockade in a disease condition associated with uncontrolled hyperinflammation, as in Covid‐19. The authors propose that the administration of P2X7 receptor antagonists might be beneficial in patients with severe pneumonia, especially those admitted to intensive care units who need intubation. The aim will be to reduce hyperinflammation, thrombosis and the possible side effects of ventilation, and to prevent development of lung fibrosis.

To validate this hypothesis, identification of a marker of receptor engagement will be required. To assess the extent of P2X7 receptor blockade, blood levels of P2X7 receptor can be easily measured. On the basis of the above considerations, the authors believe that P2X7 receptor antagonism could be a promising strategy to treat Covid‐19 patients with rapidly evolving ARDS.