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).