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.