Abstract. Phosphorilated polyprenols (PP) isolated from different sources are known to exert immunomodulating and antiviral activities. In this paper possible anti-inflammatory action of PP were studied using sensitive models of 5-lypoxigenase and 15-lypoxigenase activity inhibition, as well as a model of the hypostasis induced by the complete Freundt’s adjuvant, or carraginan. Also in vitro model of bronchospasm was used to study prospective broncholytic activity of PP. The latter was found to exert dose-dependent inhibitory effect upon both 5-lypoxigenase and 15-lypoxigenase activity. In the suspension cell culture significant inhibitory effect of PP upon leukotriens production was found even at a concentration of 5 mcg/ml; at concentration of 100 mkg/ml activity of the enzyme was suppressed almost to zero. In neutrophil cells cultivated on a collagenic substrate the significant inhibitory effect was also found at the concentration of 5 mcg/ml; 20 mcg/ml of PP reduced 5-LOX activity approximately 20-fold. In another protocol PP significantly inhibited 15-LOX activity. Thus, PP may be regarded as active inhibitor of both lipoxygenases. The PP exerted anti-inflammatory activity at both models of hypostasis, though it was weaker compared with indomethacin. Also PP was found to possess broncholytic activity in vitro in the bronchospasm model. Taking into account early established findings proving that PP may function as a physiological counterregulator of MIF (macrophage inhibitory factor), a major pro-inflammatory cytokine, our data prove that PP possess anti-inflammatory and broncholytic activities, which might be used for development of novel drugs for preventive care and treatment of bronchial asthma, inflammatory diseases and other pathologies.

The viruses most commonly affecting the human respiratory tract include rhinoviruses, respiratory syncytial virus (RSV), influenza viruses, and coronaviruses (CoVs). The virus infection of the epithelial cells of the respiratory tract triggers an inflammation accompanied by the release of pro-inflammatory cytokines and chemokines including IL6, IL8(CXCL8), IL1β, and tumor necrosis factor α (TNFα). A subsequent acute inflammatory response in the lungs is accompanied by an increase in the production of cytokines and chemokines − CXCR3 receptor ligands – that are key players of acute inflammatory response that induce an influx of neutrophils and T cells into the lungs.We studied the pharmacodynamic activity of the new compound XC221GI to suppress the IL6 and IL8 of an experimental RSV infection in vitro in human lung carcinoma cells A549 and in vivo in the lungs of cotton rats. We also studied the effect of XC221GI on the production of the chemokines CXCL10, CXCL9, and CXCL11 in mouse bronchoalveolar lavage as well as on the influx of neutrophils into the mouse lungs after the intranasal administration of interferon γ (IFNγ).The obtained results demonstrate the anti-inflammatory activity of XC221GI, which suppresses the production of excessive levels of the key inflammatory markers IL6, IL8, CXCL10, CXCL9, and CXCL11 as well as the influx of neutrophils into the lungs thereby reducing lung pathology. These data confirm the effectiveness of XC221GI as a means of preventive anti-inflammatory therapy during a viral infection of the respiratory tract.

The major feature of COVID-19 is intensive virus-induced inflammation in vital body organs and spatiotemporal dysregulation of pro- and anti-inflammatory cytokines and chemokines synthesis. All this leads to unpredicted clinical progression and high risk of "cytokine storm" development. The "cytokine storm" is the pathogenetic basis for further development of life-threatening complications. Thus, there is a huge need to select effective and safe approaches that allow to control virus-induced inflammation as a part of preventive anti-inflammatory therapy. This article presents toxicological characteristics of the original low-molecular compound XC221GI (1-[2-(1-methylimidazole-4-yl)-ethyl]perhydroazin-2,6-dione) from pre-clinical studies. The obtained results demonstrate that the XC221GI does not have any toxic effect in repeated long-term administration. The compound was well tolerated by all animals. The no-observed-adverse-effect level (NOAEL) was 30 mg/kg per day for dogs and 450 mg/kg per day for rats. There were no effects of XC221GI on blood count, hematopoiesis and hemostasis. As well as no cytotoxic, mutagenic, genotoxic, carcinogenic properties or anaphylactogenic and immunotoxic activity were revealed for XC221GI. All known data enable to classify XC221GI as a low toxic compound and consider its safety profile as reasonably favorable.

Вирусы, наиболее часто поражающие респираторный тракт человека, включают риновирусы, респираторно-синцитиальный вирус (РСВ), вирусы гриппа и коронавирусы (CoV). Инфицирование вирусом эпителиальных клеток респираторного тракта запускает воспалительный процесс, сопровождающийся выбросом провоспалительных цитокинов и хемокинов, основными из которых являются интерлейкины IL6, IL8(CXCL8), IL1β и фактор некроза опухоли (tumor necrosis factor α, TNFα). Переход инфекции в фазу острой воспалительной реакции в легких сопровождается увеличением продукции цитокинов, притоком в легкие нейтрофилов и Т-клеток и индукцией хемокинов – лигандов рецептора CXCR3, – основных участников генерализованного воспаления. В настоящей работе мы изучили фармакодинамическую активность нового соединения XC221GI в отношении IL6 и IL8 в условиях экспериментальной РСВ инфекции in vitro в клетках карциномы легкого человека А549 и in vivo в легких хлопковых крыс. Мы также изучили влияние XC221GI на приток нейтрофилов в легкие мышей и индукцию хемокинов CXCL10, CXCL9 и CXCL11 в бронхоальвеолярном лаваже после интраназального введения животным интерферона γ (IFNγ). В ходе исследования была продемонстрирована противовоспалительная активность препарата XC221GI, выражающаяся в снижении избыточной продукции ключевых маркеров воспаления в легких, включающих цитокины и хемокины IL6, IL8, CXCL10, CXCL9, CXCL11 и нейтрофилы, приводя к снижению легочной патологии. Полученные результаты подтверждают эффективность препарата XC221GI в качестве средства упреждающей противовоспалительной терапии при вирусной инфекции респираторного тракта.

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