Pentoxifylline:
Prior studies have reported that alveolar macrophages release inflammatory cytokines such as TNF-α that plays an important role in the prognosis of inflammatory pulmonary diseases (Kelley 1990; Sibille and Reynolds 1990). Consistent with the literature, it has been shown that pentoxifylline elicited a significant reduction in the production of TNF-α in cultured cells of LPS -stimulated alveolar macrophages and peripheral blood monocytes isolated from patients with an indication for bronchoalveolar lavage (Poulakis et al. 1999). This finding was also reported by Tong et al. (Tong et al. 2003). The results of this study indicate that pentoxifylline suppressed TNF-α production in a dose-dependent manner in alveolar macrophages in sarcoidosis, which is mainly driven by proinflammatory and anti-inflammatory mediators. Data from another study demonstrated that pentoxifylline suppressed cytokine-induced neutrophil chemoattractant, nuclear factor kappa B (NF-κB), Matrix metalloproteinase-2 (MMP-2), MMP-9 and myeloperoxidase content in Sprague Dawley rat model (Deree et al. 2007). As mentioned in the literature review, MMPs are well-known inflammatory mediators that contribute to the aggravation of ALI and ARDS by accelerating the secretion of neutrophils into the lung (Torii et al. 1997; Corbel et al. 2000). This action is correlated with the proteolytic activity of MMPs.
The efficacy of pentoxifylline in improving the survival rate during hyperoxia has been shown in neonatal rats (Almario et al. 2012). Shreds of evidence suggested that pentoxifylline enhanced the pulmonary antioxidant activity in enzymes such as glutathione peroxidase, catalase, and superoxide dismutase. Another important finding was that pentoxifylline treatment enhanced vascularization through increasing the vascular endothelial growth factor (VEGF) protein expression (Almario et al. 2012). It is well established that VEGF involved in alveolar structures (Thébaud and Abman 2007). Subsequently, it has been shown that pentoxifylline not only suppresses proinflammatory macrophages but also enhances both wound healing and anti-inflammatory macrophage in nitrogen mustard -induced lung injury and inflammation (Sunil et al. 2014). Clinical trial in patients with acute coronary syndromes has shown the meaningful reduction in pro-inflammatory and elevation of the anti-inflammatory response following administration of pentoxifylline 400 mg TDS for 6 months. These results suggest the potential therapeutic efficacy of pentoxifylline in cardiovascular events (Fernandes et al. 2008).
Considering the extensive evidence on anti-inflammatory and antioxidant properties of pentoxifylline (Figure 1) , this molecule may have beneficial clinical effects in COVID-19 patients suffering from the severe inflammatory response.