Excitotoxicity (Immunoexcitotoxicity) as a Critical Component of the Cytokine Storm Reaction in Pulmonary Viral Infections, Including SARS-Cov-2

A hyperimmune state secondary to dysregulation of the immune system during lower pulmonary viral infections, sepsis and in some cases non-infectious disorders, is now considered to be the principle event leading to clinical deterioration and eventual death in these patients. While most studies have attributed the pathological damage to the lung to be primarily due to high levels of cytokines and chemokines along with massive infiltration of principally neutrophils and macrophages, there is compelling evidence that overactivation of glutamate receptors is also playing a significant, if not critical role in this process. Functional glutamate receptors, along with two important glutamate transport systems, have now been described in epithelial and endothelial cells in the pulmonary airways as well as all involved immune cells. Experimental studies using cytokine models have shown considerable protection against pathological damage to pulmonary tissues by reducing the activation of these glutamate receptors.