Abstract
Mitogen-activated protein kinase (MAPK) signalling pathways are crucial for developmental processes, oncogenesis, and inflammation, including the production of proinflammatory cytokines caused by reactive oxygen species and upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. There are no drugs that can effectively prevent excessive inflammatory responses in endothelial cells in the lungs, heart, brain, and kidneys, which are considered the main causes of severe coronavirus disease 2019 (COVID-19). In this work, we demonstrate that human MAPKs, i.e. extracellular signal-regulated kinases 1 and 2 (ERK1/2), are CO2 sensors and CO2 is an efficient anti-inflammatory compound that exerts its effects through inactivating ERK1/2 in cultured endothelial cells when the CO2 concentration is elevated. CO2 is a potent inhibitor of cellular proinflammatory responses caused by H2O2 or the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2. ERK1/2 activated by the combined action of RBD and cytokines crucial for the development of severe COVID-19, i.e. interferon-gamma (IFNγ) and tumour necrosis factor-α (TNFα), are more effectively inactivated by CO2 than by dexamethasone or acetylsalicylic acid in human bronchial epithelial cells. Previously, many preclinical and clinical studies showed that the transient application of 5–8% CO2 is safe and effective in the treatment of many diseases. Therefore, our research indicates that CO2 may be used for the treatment of COVID-19 as well as the modification of hundreds of cellular pathways.
Highlights
The physiological importance of carbon dioxide (CO2) in tissues, organs and the body is well understood
Since inactive plant Mitogen-activated protein kinase (MAPK) are activated upon CO2 binding, and active MAPKs are inactivated by C O2 [9], we investigated MAPK susceptibility to CO2 in vitro and in human cells
We focused on endothelial cell (EC) to test hypotheses regarding the potential role of CO2 in regulating extracellular signalregulated kinases 1 and 2 (ERK1/2) activity, because ECs in the lungs, heart and brain are strongly affected in COVID-19, and COVID-19 is considered a form of inflammatory endothelialitis [14, 15]
Summary
The physiological importance of carbon dioxide (CO2) in tissues, organs and the body is well understood. The influence of this common gas on the functioning and components of cells is poorly understood, even though all cells in which organic substances are oxidised in the processes of oxidative cellular respiration produce C O2. The widespread presence of carbonic anhydrases in bacteria, archaea and eukaryotes and the existence of additional C O2 and HCO3− transporters indicate the benefits of rapid regulation of C O2 levels in cells, further suggesting the importance of CO2 for cell functions. It is, expected that there are mechanisms of C O2 sensing that are common to different groups of organisms. Several families of proteins are considered HCO3− receptors, including protein tyrosine phosphatases, which are inactivated by HCO3−-assisted oxidation using H 2O2 [1], adenylyl cyclases (ACs) [2] and guanylyl cyclases (GCs) [3]
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