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.