COVID-19 pathogenesis and potential of methylxanthines use for therapeutic purpose
Existing research recognizes the critical role played by ”cytokine storm” in pathology associated with coronaviruses. It is now well established from a variety of studies; this condition is one of the primary underlying mechanism of the disease aggravation (Mehta et al. 2020). One of the very early publications about COVID-19 reported a suppressed immune system followed by lymphopenia, neutropenia, hypo-albuminemia, as well as a decrease in CD8+ T cells (Chen et al. 2020). Further analysis of blood from COVID-19 patients showed high levels of inflammatory factors, including interleukin 1β (IL-1β), interferon γ (IFN-γ), interferon-inducible protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), and also IL-4, IL-7, IL-8, IL-9, IL-10 and Tumour Necrosis Factor (TNF) α and overproduction of these inflammatory cytokines and chemokines may contribute to the progression of the disease (Huang et al. 2020). In SARS disease models, the cytokine storm associated disease pathology in Acute Lung Injury (ALI) was accompanied by increased expression of inflammatory genes (Channappanavar et al. 2016). Furthermore, decreasing the inflammatory monocytes/macrophages or ablation of the IFN-α/β receptor resulted in increased survival of the coronavirus host (Smits et al. 2010; Channappanavar et al. 2016). In both cases, a potential amplifying of the inflammation is involved underlying the CoV induced lung diseases. Hence, it could conceivably be hypothesized that cytokine storm, inflammation, and repressed immune function seemed to be a major feature in all COVID-19 patients, and mitigation of disease progression may potentially be achieved by focusing the therapies on these major disease features.
Methylxanthines are well known as respiratory stimulants and used as one of the commonly used therapies for bronchial asthma. Methylxanthines are a unique class of drugs prescribed for asthmatic lung in humans because of their role in reversing the airflow obstruction and reducing airway hyperresponsiveness and airway inflammation. Methylxanthines also exert their effect via additional mechanisms, which include inhibition of immune cell activation, reduction of proinflammatory gene expression via induction of the histone deacetylase (HDAC) activity, and also via its effect on mucociliary transport (Tilley 2011). Methylxanthines have shown to lower allergic inflammations in several species like rats, rabbits, and guinea pigs (Pauwels 1987; Ali et al. 1992; Manzini et al. 1993). The anti-inflammatory properties of methylxanthines were eventually established in a series of clinical studies that showed a significant decrease in EG2+ eosinophils (which correlates to decreased airway inflammation during asthma), reduction of CD4+ lymphocytes in the bronchial wall (Sullivan et al. 1994). Ever since, methylxanthines have been efficiently used therapeutically for respiratory diseases.