Pentoxifylline:
There is a growing body of literature that recognizes various activities
of pentoxifylline on immune cells (Figure 1). The
immunomodulatory effect of this molecule has been studied extensively in
both animal models and human clinical trials.
The anti-apoptotic activity of pentoxifylline has been demonstrated in
human cell lines (Gupta et al. 1999).
Pentoxifylline increases immune memory in CD4 and CD8 T cells by
suppressing the activation of mediated T cell apoptosis, which is
attributed to the cAMP-PKA-mediated pathway
(Suresh et al. 2002). Besides,
pentoxifylline was able to attenuate the apoptosis induced by TNF-α,
IFN-δ, and nitric oxide (NO) (Mensah-Brown
et al. 2002). In a randomized, double-blind, controlled clinical trial,
pentoxifylline significantly decreased the serum concentrations of TNFα
and IL-6 (González-Espinoza et al. 2012).
IL-6 is a mortality predictor of COVID-19 patients
(Ruan et al. 2020b), and in severely
affected COVID-19 patients, IL-6 levels are increased
(Qin et al. 2020). Therefore, the idea of
pentoxifylline to significantly bring down IL-6 levels to dampen the
cytokine storm in COVID -19 patients is captivating. As mentioned
earlier, due to the high level of cytokines and risks of apoptosis of
epithelial and endothelial cells along with the infected cells,
pentoxifylline may propose a safer therapeutic option in COVID-19
patients.
Furthermore, pentoxifylline suppressed the expression of surface T cell
antigen, including CD25, CD69, and CD98. In line with this study, it has
been shown that pentoxifylline interferes with T cell proliferation via
the CD3/T-cell receptor complex
(González-Amaro et al. 1998). Further
immunomodulatory activity of pentoxifylline has been shown in animal
models. In a murine model, pentoxifylline administration reduced the
airway hyperresponsiveness due to Th1 cytokine IFN δ
(Fleming et al. 2001). In line with
aforementioned study, the reversal of arthritic changes and attenuation
of the Th1 (IFN- δ) and Th2 (IL-4) cytokine have been also observed in a
rheumatoid arthritis rat model following administration of
pentoxifylline (Pal et al. 2016).
Elevated levels of Th1 and Th2 cytokines have been found in SARS-CoV
patients (Josset et al. 2013), and Th1,
as well as Th17, was reported to contribute to the cytokine storm in
SARS-CoV-2 induced pulmonary viral infection
(Wu et al. 2020a). Therefore, the
attenuating impact of pentoxifylline on Th1 and Th2 cytokine levels can
be utilized for its potential role in COVID-19 patients.
There is emerging evidence showing the beneficial effects of
pentoxifylline in chronic heart failure due to its immunomodulatory
effects and suppression of TNFα (Shaw et
al. 2009). In addition to that, it has been described that
pentoxifylline contributes to the suppression of TNFα and IL-1β induced
by Toll-like receptors (TLRs). This suppression role of TNFα and IL-1β
by pentoxifylline can be exploited as a therapeutic potential because in
COVID-19 patients, as SARS-CoV-2 also induces lung inflammation, fever,
and fibrosis by inducing active production of TNFα and IL-1β
(Conti et al. 2020). TNFα has always been
involved in SARS-CoV induced severe immune-based pulmonary injury, which
suggests that TNFα inhibitors could be a potential treatment for the
respiratory symptoms caused by the coronavirus
(Tobinick and opinion 2004). Collecting
the aforementioned evidence regarding the immunomodulatory activity of
pentoxifylline suggests a potential therapeutic value of this agent in
COVID-19 patients.