Anti-proteolitic, antioxidant and immunomodulatory activities
Tetracycline’s immunomodulatory and anti-inflammatory properties may even be of greater relevance for their protective effect against COVID-19 than their anti-infectious activity described above (Figure 1 C-E). At the time of intervention, the damaging consequences of the host response may overcome the infection itself. The lung is particularlly susceptible to the outcome of wide-spread inflammation, sequestering neutrophils and monocytes into the pulmonary tissue. In this regard, doxycycline has shown to reduce nitric oxide and chemokine production by lung epithelial cells (Hoyt et al., 2006; Raza et al., 2006), and to reduce neutrophil chemotaxis into the airspaces of the lung in vivo (Moon et al., 2012) (Figure 1C). Tetracyclines are effective in reducing the proteolytic activity derived from neutrophilic inflammation in COPD (Maisi et al., 1999), which can prevent fibrosis sequalae in ARDS survivors (Figure 1D). Of note, a retrospective multi-institutional cohort study concluded that minocycline or doxycycline treatment within a year prior to ARDS was associated with a 75% reduced likelihood for mechanical ventilation and reduced duration of mechanical ventilation and ICU stay (Byrne et al., 2020). Given the interest of tetracycline’s activity for lung protection, the application of chemically modified tetracyclines (CMTs) to ARDS is not completely novel. Prophylactic CMT-3 has shown to prevent the development of ARDS in models induced by sepsis (Steinberg et al., 2005) and cardiopulmonary bypass (Carney David E. et al., 1999). Therapeutic benefit has also been achieved with CMT-3 in lung injury upon established inflammation/septic events (Roy et al., 2012; Sadowsky et al., 2015) as well as other models of lung injury. In these contexts, CMT-3 treatment was associated with a reduction in inflammation, collagen deposition and the histological lesions of ARDS (Roy et al., 2012). Mechanistically, their effects could derive from the reduction in neutrophil transmigration and neutrophil-mediated inflammation, and the direct inhibition of elastases, MMPs and oxygen radical species produced by the immune system during the inflammatory reaction, which damage alveolar-capillary basement membranes and the extracellular matrix (Figure 1D). Tetracyclines also display immunomodulatory actions in other relevant populations, such as T cells and macrophages. Regarding the later, in contrast to their immunosuppressive effect observed in peritoneal macrophages, it has been described that tetracyclines could potentiate the response of alveolar macrophages (Bonjoch et al., 2015). We have observed a similar effect in intestinal inflammation, where tetracyclines enhanced macrophage recruitment and response, but this resulted in accelerated differentiation into the homeostatic phenotype and improved mucosal healing (Garrido-Mesa et al., 2018). Considering that both intestinal and alveolar macrophages reside at mucosal sites and share this particular response to immunomodulatory tetracyclines, we believe that a similar protective outcome could be expected. In fact, no adverse effects have been observed upon their evaluation in ARDS. Finally, CMT-3 has also shown to prevent coagulopathy associated to ARDS, an important pathological feauture of COVID-19, which could derive from its inhibitory effects in PLA2 and COX-2, essential for platelet function (Roy et al., 2012) (Figure 1E). This synergic combination of anti-proteolitic, antioxidant and immunomodulatory activities adds to the well-known mechanisms described above, including antibiotic protection from secondary bacterial pneumonia.
In addition to these direct immunomodulatory effects, tetracyclines can also impact altered responses of the stromal compartment (Figure 1F). On the basis that ACE2 inhibition due to viral entry could contribute to lung injury in COVID-19, a recent study has shown that CMT-3 is a great candidate to reverse the altered gene expression pattern of lung cells upon ACE2 inhibition (He and Garmire, 2020). Finally, for a complete understanding of the mechanisms behind the effects observed for tetracyclines in ARDS and their potential for COVID-19, it is also worth mentioning their ability to concentrate at sites of inflammation and tissue injury, which might potentiate tetracycline’s pharmacological effects. This is explained by the increased tetracycline uptake observed with increasing temperature, as well as in specific cell types, such as neutrophils and alveolar macrophages, where tigecycline can be found up to 78-times more concentrated than in blood.