Carbon dioxide and MAPK signalling: towards therapy for inflammation

Inflammation, although necessary to fight infections, becomes a threat when it exceeds the capability of the immune system to control it. In addition, inflammation is a cause and/or symptom of many different disorders, including metabolic, neurodegenerative, autoimmune and cardiovascular diseases. Comorbidities and advanced age are typical predictors of more severe cases of seasonal viral infection, with COVID-19 a clear example. The primary importance of mitogen-activated protein kinases (MAPKs) in the course of COVID-19 is evident in the mechanisms by which cells are infected with SARS-CoV-2; the cytokine storm that profoundly worsens a patient's condition; the pathogenesis of diseases, such as diabetes, obesity, and hypertension, that contribute to a worsened prognosis; and post-COVID-19 complications, such as brain fog and thrombosis. An increasing number of reports have revealed that MAPKs are regulated by carbon dioxide (CO2); hence, we reviewed the literature to identify associations between CO2 and MAPKs and possible therapeutic benefits resulting from the elevation of CO2 levels. CO2 regulates key processes leading to and resulting from inflammation, and the therapeutic effects of CO2 (or bicarbonate, HCO3-) have been documented in all of the abovementioned comorbidities and complications of COVID-19 in which MAPKs play roles. The overlapping MAPK and CO2 signalling pathways in the contexts of allergy, apoptosis and cell survival, pulmonary oedema (alveolar fluid resorption), and mechanical ventilation-induced responses in lungs and related to mitochondria are also discussed.F1FfzyNebiAnmgfybRMuY1Video Abstract

Automated summary

Inflammation becomes a threat when it exceeds the immune system's control, and it is a cause and/or symptom of many diseases. Advanced age and comorbidities lead to more severe cases of viral infections, such as COVID-19. Mitogen-activated protein kinases (MAPKs) play a crucial role in COVID-19, affecting the infection mechanisms, cytokine storm, disease pathogenesis, and post-COVID-19 complications. Carbon dioxide (CO2) regulates MAPKs and may have therapeutic benefits for COVID-19 and related comorbidities.