Figure legends
Figure 1 . Eicosanoid biosynthesis and signalling
pathways are therapeutic targets of medications used in the treatment of
infections, acute and chronic inflammatory diseases (including asthma
and allergy) and pain. Glucocorticosteroids (GCs), non-steroidal
anti-inflammatory drugs (NSAIDs), leukotriene receptor antagonists
(LTRAs; eg. montelukast, zafirlukast, pranlukast), 5-lipoxygenase
(5-LOX) inhibitor, zileuton, as well as still clinically tested,
timapiprant and setitpiprant act directly on the synthesis of eicosanoid
mediators or their signalling molecules and receptors. Biosynthesis of
endocannabinoids (2-AG, AEA) interfere with eicosanoids metabolic
pathways.2-AG- 2-Arachidonoyl-glycerol (endocannabinoid);
AEA-arachidonyl- ethanolamide (endocannabinoid); COX– cyclooxygenase;
Cyt-cytochrome; EET- epoxyeicosatrienoic acid; GC- glucocorticoids;
HETE- hydroxyeicosatetraenoic acid; HPETE- hydroperoxyeicosatetraenoic
acid; LOX – lipoxygenase; LTE4 – leukotriene; LTRA -
leukotriene receptor antagonists; LX – lipoxin; PLA – phospholipase;
PG – prostaglandin; TX-thromboxane
Figure 2. Eicosanoid pathways in viral infections and allergic
inflammation of the respiratory airways are affected by several groups
of medications. Eicosanoids are important immune mediators coordinating
the inflammatory response to viral infections and allergen challenges
between bronchial epithelial cells, airway-resident and -infiltrating
immune cells. Several groups of drugs used in the treatment of allergic
diseases and respiratory tract infections interfere with eicosanoid
production and signalling pathways. Glucocorticoids (GCs) reduce the
activity of phospholipase A2 (PLA2) and
COX-2, therefore restricting both the upstream substrate for eicosanoid
production and subsequent enzyme. NSAIDs block COX-1 and COX-2 -mediated
synthesis of prostaglandins by both bronchial epithelial cells and
immune cells. This reduces tissue inflammation and alleviates the
symptoms of infection, but at the same time affects the anti-viral
response. LTRAs block eicosanoid leukotriene signalling at the receptor
level, reducing activation of granulocytes. Biologicals used in the
treatment of allergic diseases (anti-IL-5, anti-IL-5Rα, anti-IL-4Rα and
anti-IgE) interfere with the eicosanoid signalling in a non-direct
manner, by preventing undue activation of eosinophils and Th2 cells, as
well as degranulation of basophils and mast cells. BAS – basophil;
COX-1 – cyclooxygenase 1; CysLTs – cysteinyl leukotrienes; DC –
dendritic cell; EOS – eosinophil; GCs – glucocorticoids; IFN –
interferon; IL – interleukin; LOX – lipoxygenase; LTE4– leukotriene E4; LTRA - leukotriene receptor antagonists;
LXA4 – lipoxin A4; MC – mast cell; MO – monocyte; Mθ
– macrophage; NEU – neutrophil; NSAIDs – non-steroidal
anti-inflammatory drugs; PLA2 – phospholipase A2; PGD2 – prostaglandin
D2; PGE2 – prostaglandin E2; PGD2-inh – prostaglandin D2 inhibitors;
PUFA – polyunsaturated fatty acids; TSLP – thymic stromal
lymphopoietin;
Figure 3. Non-steroidal anti-inflammatory drugs and leukotriene
antagonists in SARS-CoV-2 infection. Increased levels of eicosanoids
have been found in bronchoalveolar lavage fluid of patients with severe
COVID-19, with predominance of prostaglandins and thromboxane. There are
strong grounds to explore eicosanoid inhibition as a potential
therapeutic target in SARS-CoV-2 infections. Prostaglandins amplify
innate immune responses to pathogen- and damage-associated molecular
patterns, enhance the cascade of proinflammatory cytokine release,
activate Th1 and Th17 cells and contribute to recruitment of macrophages
and T cells. Moreover, studies in mouse adapted to SARS-CoV-2 infection
showed that PGD2 inhibition protected from severe
disease. Despite the initial mixed reports on the use of NSAIDs in
COVID-19, it has been concluded that these medications can be safely
used to alleviate the symptoms of SARS-CoV-2 infection. This effect is
attributed to the disruption of inflammatory circuits. Other effects of
NSAIDs in COVID-19 are being investigated and preliminary studies
suggest that a non-selective NSAID naproxen could negatively influence
SARS-CoV-2 replication. Furthermore, the efficacy of leukotriene
antagonist montelukast is being evaluated in a series of clinical
trials. The hypothesised mode of action in COVID-19 includes inhibition
of leukotriene signalling, as well as direct anti-viral effect (damage
to the viral lipid membrane and genome), as reported for other viruses.
Figure 4. The effect of biologicals used in the
treatment of allergic diseases on eicosanoid pathways.
Biologicals have revolutionized therapeutic algorithms for patients with
the most severe form of allergic diseases. Currently, 5 monoclonal
antibodies have been approved for the treatment of severe asthma. Their
use has been associated with a decrease in the concentration of
proinflammatory lipid mediators. This is most probably an indirect
effect of inhibition of immune cells which are the main eicosanoid
producers in allergic inflammation.
Omalizumab (anti IgE) binds to free IgE and inhibits their binding to
IgE receptors, which results in a downregulation of FcεRI expression on
mast cells, basophils and dendritic cells. This leads to a significant
decrease in biosynthesis and release of proinflammatory eicosanoids from
these cells, and prevents expansion of eosinophils and ILC2. Dupilumab
(anti IL-4Rα) binds to the α subunit of the IL-4 receptor, which is
shared by IL-4 and IL-13 receptor complexes. Therefore it blocks the
effect of these cytokines on cells contributing to type 2 immune
reaction. This results in an inhibition of IgE production, mast cell
activation and eicosanoid production, goblet cell metaplasia and mucus
production. Mepolizumab, reslizumab (anti-IL-5) and benralizumab (anti
IL-5Rα) block IL-5 activity on different levels, therefore inhibiting
the maturation, activation and proliferation of eosinophils, as well as
basophil activation. Monoclonal antibodies targeting IL-5Rα moreover
leads to antibody-dependent cell-mediated cytotoxicity of NK cells
against eosinophils and basophils, vast producers of proinflammatory
eicosanoids such as prostaglandin D2 and cysteinyl
leukotrienes. While no direct effect of biologicals on eicosanoid
biosynthesis has been reported, these medicines disrupt the cascade of
immune events leading to type 2 inflammatory responses and the
concomitant overproduction of proinflammatory lipid mediators.