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.