Настоящая работа посвящена изучению эффектов лейтрагина, аналога эндогенного гексапептида динорфина 1-6, на экспрессию провоспалительных цитокинов и интерферонов I типа в экспериментальной фатальной модели острого респираторного дистресс-синдрома (ОРДС) у мышей C57BL/6Y. Экспрессию интерлейкина-1β (IL-1β), интерлейкина-6 (IL-6), фактора некроза опухоли (TNF-α), интерферонов α (IFN-α) и β (IFN-β) в легких оценивали методом ПЦР в реальном времени. Индукция ОРДС α-галактозилцерамидом и липополисахаридом E. coli приводила к многократному повышению экспрессии цитокинов в легких. Введение лейтрагина в сочетанном режиме, внутримышечная инъекция плюс ингаляция, приводило к статистически значимому снижению уровней мРНК цитокинов в легких уже через 3 ч после начала введения. При этом средний уровень мРНК IL-6, ключевого цитокина в развитии тяжелого ОРДС, снижался в 4,7 раза (p<0,01) до значений, близких к наблюдаемым у интактных животных. С учетом особой роли повышенных концентраций IL-6 в развитии тяжелых форм COVID-19 использование лейтрагина для подавления «цитокинового шторма» может быть эффективным подходом к лечению коронавирусной инфекции.
COVID-19 is a respiratory infection caused by the SARS-CoV-2 virus that can rapidly escalate to life-threatening pneumonia and acute respiratory distress syndrome (ARDS). Recently, extracellular high mobility group box 1 (HMGB1) has been identified as an essential component of cytokine storms that occur with COVID-19; HMGB1 levels correlate significantly with disease severity. Thus, the modulation of HMGB1 release may be vital for treating COVID-19. HMGB1 is a ubiquitous nuclear DNA-binding protein whose biological function depends on posttranslational modifications, its redox state, and its cellular localization. The acetylation of HMGB1 is a prerequisite for its translocation from the nucleus to the cytoplasm and then to the extracellular milieu. When released, HMGB1 acts as a proinflammatory cytokine that binds primarily to toll-like receptor 4 (TLR4) and RAGE, thereby stimulating immune cells, endothelial cells, and airway epithelial cells to produce cytokines, chemokines, and other inflammatory mediators. In this study, we demonstrate that inhaled [D-Ala2]-dynorphin 1-6 (leytragin), a peptide agonist of δ-opioid receptors, significantly inhibits HMGB1 secretion in mice with lipopolysaccharide- (LPS-) induced acute lung injury. The mechanism of action involves preventing HMGB1’s hyperacetylation at critical lysine residues within nuclear localization sites, as well as promoting the expression of sirtuin 1 (SIRT1), an enzyme known to deacetylate HMGB1. Leytragin’s effects are mediated by opioid receptors, since naloxone, an antagonist of opioid receptors, abrogates the leytragin effect on SIRT1 expression. Overall, our results identify leytragin as a promising therapeutic agent for the treatment of pulmonary inflammation associated with HMGB1 release. In a broader context, we demonstrate that the opioidergic system in the lungs may represent a promising target for the treatment of inflammatory lung diseases.
The Ministry of Health of the Russian Federation jointly with professional association and experts in the field of pediatrics, infectious diseases and resuscitation has revised guidelines “Clinical Features and Management of the Disease Caused by New Coronaviral Infection (COVID-19) in Children” in order to provide the child population with effective medical care during the pandemic of the new coronaviral infection. The practical experience of specialists from various countries was considered during the development of this document. Special attention should be given to the evidence base of the presented data, as well as to the efficiency and safety issues of medications used in treatment of coronaviral infection and its complications. The authors highlight the problems of prevention, diagnostics and management of pathological conditions caused by COVID-19 in the article according to the presented guidelines. Patient’s management is presented depending on the age and severity of the disease itself. The therapy is considered with regard to etiological, pathogenetic and symptom focus.
This study was aimed at developing an experimental model of fatal acute lung injury and acute respiratory distress syndrome (ARDS) based on the intratracheal administration of bacterial lipopolysaccharide (LPS) in combination with muramylpeptide and Freund’s complete adjuvant to C57Bl/6Y mice sensitized with α-galactosylceramide. The developed model is characterized by diffuse alveolar damage to the lungs and high mortality rates, as well as by a multifold increase in the mRNA level of interleukin-6 in the lungs. The model can be used for assessing the efficacy of drug candidates in the treatment of acute lung injury and ARDS, including in COVID-19.
This study aims to investigate effects of tocilizumab, a monoclonal antibody to interleukin-6 (IL-6) receptors, on cytokine expression and animal survival in a model of fatal acute respiratory distress syndrome (ARDS) characterized by high mortality rates and increased IL-6 production in the lungs. The expression of interleukin-1β (IL-1β), interleukin-6 (IL-6), tumour necrosis factor (TNF-α) and interferons α (IFN-α) and β (IFN-β) in the lungs was assessed by real-time PCR. Cytokine production was assessed by enzyme immunoassay. Although tocilizumab did not affect the expression of the studied cytokines in the lungs of animals with ARDS, it changed the profiles of their release. An acute multifold increase in the levels of IL-6 in the lungs was observed in the first two hours after the administration of tocilizumab, followed by a decrease of IL-6 to lower values similar to those observed in intact animals. Tocilizumab did not reduce mortality in treated animals with ARDS compared to those without treatment. Thus, the inhibition of the IL-6 receptor signaling pathway alone does not provide an effective solution to the problem of reducing mortality from ARDS associated with the development of a “cytokine storm”.
A unique clinical case of a combination of malformations of the anterior abdominal wall (omphalocele of large size) and malformation of the lymphatic system (congenital chyloperitoneum) is presented. Each of these defects can lead to a fatal outcome, and the combination of them has greatly increased the risk of developing an unfavourable outcome. The use of immunosuppressive therapy with Sirolimus used for the first time during the newborn period made it possible to completely stop the chyloperitoneum. This clinical example shows that in the treatment of surgical patients with multiple congenital malformations, a multidisciplinary approach and observation is necessary for timely response to the patient’s condition.
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