EDITORIAL
Coronavirus disease‐19 (COVID‐19) is a new disease caused by SARS‐CoV2.
Since the beginning of 2020, it has become one of the main challenges of
our times, causing a high incidence of severe pneumonia, acute
respiratory distress syndrome (ARDS), multiorgan failure and
death1. At the root of
COVID-19 lies the sudden development of ‘cytokine storms’,
hyper-inflammatory responses involving the release of pro-inflammatory
cytokines (e.g., TNF-α, IL-6, IL-1, IL-8, and MCP-1) that impair the gas
exchange function of the lung and lead in select patients, mostly with
underlying comorbidities, to multiorgan failure and
death1,2.
Additional complications triggered by ‘cytokine storms’ include
endothelial dysfunction and hypercoagulation, increasing the risk of
thromboembolytic events, and life-threatening cardiovascular
complications. Anti-inflammatory therapies are thus being considered for
alleviating the damaging side effects of hyper-inflammation with many
trials including anti-cytokine biologicals, disease-modifying
antirheumatic drugs (DMARDs) and corticosteroids being
ongoing3. Surprisingly,
among them dexamethasone has taken center stage as initial results from
the RECOVERY trial, a large multicenter randomized open-label
trial for hospitalized patients run in the United Kingdom, revealed
notable efficacy in the treatment of critically ill COVID-19
patients4.
Dexamethasone is one of the oldest synthetic glucocorticoid agonists
synthesized in 1957 and introduced into the clinic in 1961. When
administered at 6 mg daily, either orally or intravenously for 10 days,
dexamethasone was shown in the RECOVERY trial to improve survival
rates of hospitalized patients with severe COVID-19 receiving oxygen or
being on mechanical ventilation by a remarkable
30%4. Benefit was
restricted to patients requiring respiratory support whereas in milder
cases this was not clear. This notable efficacy of dexamethasone
treatment goes against the current view of corticosteroid use in
respiratory viral infections which remains contradictory. Although
corticosteroids improve ventilator weaning and can lower the intensity
of the host response to the virus, tempering the ‘cytokine storm’ and
limiting immunopathology, they can also reduce viral clearance and lead
to more severe disease. Understanding therefore how dexamethasome
mediates its effects is of paramount importance.
Dexamethasone, as other corticosteroids, is held to mediate its
anti-inflammatory and immunosuppressive effects via the glucocorticoid
receptor. Upon ligand binding, the receptor-corticosteroid molecule
complex moves into the cell nucleus, where it dimerizes and binds to
glucocorticoid response elements (GRE), acting as transcriptional
repressor or transactivator of diverse sets of genes. This results in
the inhibition of inflammatory cell activity, including neutrophils,
macrophages and lymphocytes, and the suppression of pro-inflammatory
cytokines such as TNF and interleukins and other genes such as
cyclooxygenase-2 and inducible nitric oxide
synthase5. However, we
have recently uncovered that dexamethasone can also induce the D-series
proresolving lipid mediator pathway leading to the production of 17-HDHA
and the protectins D1 and
DX6. These are potent
major players of the molecular machinery driving the resolution of
inflammation, i.e. the proper regulated termination of pro-inflammatory
responses involving the catabolism of pro-inflammatory mediators, the
removal of inflammatory cells and the restoration of the tissue in a
timely and highly coordinated
manner7. Although
resolution of inflammation has long been considered to occur
spontaneously as a result of the waning of pro-inflammatory responses,
this is now known to be an ordered and highly regulated process
involving the timely production of enzymatically oxygenated
lipid-derived mediators such as protectins, D-series resolvins and
maresins derived from the omega-3 fatty acid docosahexaenoic acid (DHA),
E-series resolvins derived from eicosapentaenoic acid (EPA), and
lipoxins biosynthesized from omega-6 fatty acids following eicosanoid
class switching7.
Interestingly, certain lipid mediators have been shown to exert
additional non-conventional functions; resolvin D4 can attenuate
pathologic thrombosis, reduce NETosis and promote clot removal8 which is now
recognized as a key pathology of COVID-19 infection, while resolvin E4
(RvE4) stimulates efferocytosis of senescent erythrocytes in hemorrhagic
exudates especially under hypoxic conditions that characterize
COVID-199. Moreover,
corticosteroids have been reported to reduce fibrinogen and procoagulant
factors under pro-inflammatory conditions and increase anticoagulant
factors10.
The ability of viral infections to induce proresolving lipids has been
reported earlier. Toll-like receptor 7 (TLR7), a major pattern
recognition receptor of viral RNA, activates PD1 and PDX
production11. Moreover,
influenza virus infection has been demonstrated to drive proresolving
lipid mediator networks including the production of PD1 which limits
influenza pathogenicity by directly interacting with the RNA replication
machinery to inhibit viral RNA nuclear
export12,13.
Notably, in particularly virulent strains of influenza virus such as the
H5N1 avian strain, PD1 formation is not sufficiently upregulated,
leading to more efficient viral replication and host
demise12. It is
therefore plausible that the efficacy of dexamethasone in COVID-19 is
due at least in part to its ability to induce proresolving lipid
mediators that possess multiple anti-inflammatory and proresolving
actions tempering down inflammation and promoting its resolution,
preventing coagulation and enhancing viral and bacterial clearance
(Figure 1) yet are not immunosuppressive . Whether other corticosteroids
beyond dexamethasone can also mediate such effects, and to what extent,
is not known. Whether inhalable corticosteroids, such as those given to
asthmatic patients, can also induce proresolving lipid mediator networks
locally and thus prevent the development of severe SARS‐CoV‐2 infection
remains to be determined. There is evidence that asthmatic patients
exhibit reduced incidence of severe and/or critical
COVID-1914.
Recently, COVID-19 patients showed increased association of serum
arachidonate-derived proinflammatory lipid mediators, e.g.
prostaglandins, in severe COVID -19 infections while some pro-resolving
mediators such as resolvin E3 were up-regulated in the moderate COVID-19
group suggesting that an imbalance in lipid mediators with a swift
toward pro-inflammatory mediators in severe disease may contribute to
COVID-19 disease
severity15. Although
the involvement of proresolving lipid mediator pathways in COVID-19 is
an attractive hypothesis, further evidence from human trials is needed
as there are no studies at present reporting the induction or modulation
of such networks in the context of the various disease stages and
treatments. It is thus of uttermost priority to investigate proresolving
lipid mediators in COVID-19, in a temporal and longitudinal manner, as
modulating these networks either through drug treatment or direct
administration of resolvin and protectins agonists has the potential to
affect this highly lethal and devastating disease in a way other
approaches cannot. Such studies are therefore eagerly awaited.