2.3 - Resolvins and bacterial infections
A wide range of studies have demonstrated the effects of resolvins in
various model of bacterial infections. For example, treatment with RvD1
reduced inflammation and neutrophil infiltrates during P.
aureoginosa infection in mice (Lee et al., 2022). In the case ofCitrobacter rodentium (C. rodentium ) infection,
post-infection treatment with RvD1 plus RvD5 decreased bacterial loads,
reduced inflammation, and rescued mice from lethality (Diaz et al.,
2017). Accordingly, administration of RvD2 limited neutrophil
infiltration, enhanced phagocytosis and bacteria clearance, and
expedited inflammation resolution in Escherichia coli (E.
coli ) and S. aureus infections (Chiang et al., 2015). RvD3
treatment improved bacterial clearance, efferocytosis, and accelerated
resolution during peritonitis induced by E. coli infection,
making it a promising agent against E. coli (Norris et al.,
2018). Additionally, treatment with approximately 0.1nM concentrations
of RvD4 proved effective against S. aureus infection in mice
(Winkler et al., 2016). In vitro studies also demonstrated the
immune modulation of RvD1, RvD2, and RvD5 during E. coliinfection in human macrophages, resulting in a decrease in the
production of pro-inflammatory cytokines (Palmer et al., 2011; Werz et
al., 2018).
Resolvins have shown efficacy in both sepsis and sepsis-like models. For
instance, in a murine model of sepsis induced by cecal ligation and
puncture (CLP), delayed systemic treatment with RvD1 increased bacterial
clearance, improved mouse survival, and decreased neutrophil influx and
cytokine production, such as TNF (Chen et al., 2014). In a model of
sepsis induced by D-galactosamine (GalN), mice treated with RvD1
concurrently with D-GalN injection exhibited a lower number of
neutrophil accumulations and decreased levels of HMGB1 and CCL2 in serum
(Murakami et al., 2011). Other studies have demonstrated the potential
of RvD1, RvD2, RvE1, and AT-RvD1 treatment, as well as the protective
effect of endogenous levels of these lipids, in various sepsis models.
These treatments increased mouse survival, reduced bacterial load, and
suppressed pro-inflammatory cytokine production (Chiang et al., 2012;
Chen et al., 2020; Silva et al., 2021; Svahn et al., 2016, see Table 1
and Supplementary Table 1). Importantly, administration of RvD1 in
conjunction with antibiotics expedited the resolution of peritonitis,
indicating the potential of resolvins to be used as adjutants in
traditional bacterial infection and septic condition treatments (Chiang
et al., 2012).
RvD1 has garnered significant attention in pre-clinical models of lung
infection due to its ability to ameliorate lung damage, reduce
inflammation, and decrease bacterial loads. Studies conducted in mice
have demonstrated the positive effects of RvD1 or AT-RvD1 treatment in
response to various pathogens such as E. coli , P.
aeruginosa , and Nontypeable Haemophilus influenzae (NTHi) (Codagnone et
al., 2018; Croasdell et al., 2016; Abdulnour et al., 2016; Wang et al.,
2017; Sekheri et al., 2020; Isopi et al., 2020; Bhat et al., 2021).
These effects of RvD1 were primarily attributed to a significant
decrease in neutrophil accumulation. Additionally, RvD1 could accelerate
the resolution phase in the lungs, either alone or in combination with
antibiotics against P. aureoginosa (Gao et al., 2020). Other
classes of resolvins, such as RvE1 and RvD2, also demonstrated
beneficial effects. RvD2 decreased bacterial load in the lungs duringP. aeruginosa infection (Walker et al., 2022; Sundarasivarao et
al., 2022). Treatment with RvE1 in mice decreased neutrophil
accumulation, improved E. coli clearance, and dampened cytokine
production (Seki et al., 2010).
In summary, these results demonstrate that resolvins, especially RvD1,
show promise as therapeutic candidates against a range of bacterial
infections, either alone or in combination with antibiotic treatments.