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.