4.2.1 JAK inhibitors for COVID-19 induced ARDS
JAK inhibitors could be considered an option for treating
COVID-19-related ARDS or pneumonia patients for two reasons. On the one
hand, JAKs are involved in JAK/STAT signaling which is associated with
the receptors of a large variety of cytokines(Convertino et al., 2020),
as the major patients of ARDS showed a phenomenon of “cytokine storm”,
related to the severity of disease, that high circulating levels of
interleukins (IL)-2, IL-6, IL-7, IL-10, granulocyte colony-stimulating
factor (G-CSF), 10kDa interferon-gamma-induced protein (IP-10), monocyte
chemo-attractant protein-1 (MCP-1), macrophage inflammatory protein 1α
(MIP-1α), and tumor necrosis factor (TNF) (Guo et al., 2020; McGonagle,
Sharif, O’Regan & Bridgewood, 2020). Especially, in ARDS patients, a
strong depletion of peripheral blood T cells, along with a decreased
recruitment of lymphocytes and neutralizing antibodies and an increased
production of cytokines, was detected in the lungs(Qin et al., 2020). On
the other, the selective JAK1/2 inhibitor, baricitinib, is shown to
hinder the endocytosis and assembly of the SARS-CoV-2 to the host cell
by inhibiting AP2-associated protein kinase 1 (AAK1) (Aslan & Akova,
2021; Saber-Ayad et al., 2021). So far, there are over dozens of
clinical trials for JAK inhibitors (including ruxolitinib, baricitinib,
tofacitinib, nezulcitinib (TD-0903)) and their combined application with
other anti-viral drugs like remdesivir treating the COVID related
pneumonia around worldwide(Giudice et al., 2020). And therapeutic
strategy ranges from oral administration to inhalation(Aslan & Akova,
2021; Saber-Ayadet al., 2021; Singh et al., 2021).
Recently, a meta-analysis about JAK-inhibitors for coronavirus
disease-2019 enrolled 2367 subjects found that the usage of
JAK-inhibitors decreased the invasive mechanical ventilation (RR = 0.63;
[95% Confidence Interval (CI), 0.47, 0.84]; P = 0.002) and had
borderline impact on rates of intensive care unit (ICU) admission (RR =
0.24 [0.06, 1.02]; P = 0.05) and acute respiratory distress
syndrome. did not decrease interval of hospitalization. The risk of
death was decreased, most convincingly for baricitinib(Chen, Wang, Li,
Yuan, Gale & Liang, 2021; Patoulias, Doumas, Papadopoulos &
Karagiannis, 2021). JAK-inhibitors play a potential role in reducing the
risk of death in persons with COVID-19. While, the underling mechanism
of therapeutic benefits is not clearly studied.
In the in vivo mouse model of SARS-CoV-2 spike protein induced ARDS
cytokine storm, the JAK1/2 inhibitor, baricitinib and febratinib have
the different outcomes, JAK1/2 inhibitor baricitinib significantly
reduced the production of IL-6, but the JAK2 inhibitor febratinib did
not and baricitinib led to obvious decrease in neutrophilic inflammation
and interstitial edema(Gu et al., 2020).
While there are also other natural products, which are convinced inhibit
the JAK/STAT, are potential candidates of treating COVID or COVID
related ARDS. The flavonolignan silibinin is a direct inhibitor of
STAT3, regulate inflammatory cytokine signaling and immune response,
thus may play a combination role of IL-6-targeted monoclonal antibodies
and pan-JAK1/2 inhibitors in treating COVID(Bosch-Barrera,
Martin-Castillo, Buxo, Brunet, Encinar & Menendez, 2020).