COVID-19: cytokine storm and anticytokine therapy

This review describes in detail one of the key links in the pathogenesis of COVID-19 — the overproduction of pro-inflammatory cytokines that play a key role in the formation of acute respiratory distress syndrome, disseminated intravascular coagulation, multiple organ dysfunction syndromes, and causes high mortality among patients infected with COVID-19. The article deals with the basic directions of intensive therapy for the prevention of development as well as the treatment of cytokine storm and drugs for anti-cytokine therapy. Among drugs with anti-cytokine and anti-inflammatory properties, corticosteroids have the highest evidence base for efficacy and safety. The most promising drugs that require further clinical studies are those that inhibit the activity of the main intracellular regulator of the production of proinflammatory cytokines, the nuclear transcription factor kappa B of immunocompetent cells. These include turmeric-based preparations, which are now at the final stages of the pre-registration studies.

Immunopathogenesis and perspectives for immunotherapy of coronavirus infection

Highly pathogenic coronavirus SARS-CoV-2 is the cause of COVID-19 in humans sometimes with severe clinical manifestations and death. COVID-19 immunopathogenesis is linked with dysregulated immune response with decreased interferon synthesis at the beginning of infection followed by inflammatory cytokines hyperproduction, resulting in an exuberant lung inflammation and respiratory distress syndrome. Perspective immunotherapy directions for COVID-19 could be: intranasal recombinant interferon application in the initial stage of disease, anticytokine therapy at the stage of severe pneumonia and cytokine storm development, passive immunization with blood plasma of recovered patients or therapeutic monoclonal antibodies, prophylactic vaccination.

NEW APPROACHES TO POSTOPERATIVE TREATMENT PERITONITIS

A significant role in the pathogenesis of peritonitis is attributed to free radical mechanisms of tissue damage. Due to inhibition of a number of membrane-bound enzymes and FRO of lipids of plasma membranes, foci of secondary necrosis appear in the peritoneum. Oxidized lipids have antigenic properties, and therefore stimulate autoimmune processes of tissue damage. In the pathogenesis of peritonitis, an important role is played by inflammatory mediators - cytokines. Their biological activity is manifested by the action on highly specific receptors located on cells. At the same time, interleukins and tumor necrosis factor act on all cells, exhibiting a systemic effect. It was found that the activity of ceruloplasmin in the blood plasma of patients in the control group progressively decreased from the first to the fifth day of the postoperative period, from 77.2 ± 5.61 to 59.32 ± 4.42 o.o. / g of protein, and in the patients of the experimental group it increased highly reliably - from 77.2 ± 5.61 to 97.31 ± 4.42 o.o. / h protein (p <0.001). The same pattern is characteristic of catalase activity. The activity of glutathione peroxidase in patients of both groups significantly decreased up to 3 days after the operation and increased on the fifth day, and it was more pronounced in the patients of the experimental group. When studying the level of cytokines, it was found that the expression of proinflammatory cytokines IL-1b, IL-8, TNFa exceeded the control values, while the expression of anti-inflammatory cytokines IL-1Ra was "delayed" (almost twofold). The highest expression of IL-1b, IL-8 potentiated further chain of pro-inflammatory reactions indicates the adequacy of the anti-inflammatory response and the relative balance between pro-inflammatory and anti-inflammatory cytokines and the adequacy of anticytokine therapy. The total number of septic complications (PBS) in the control group was 82.4%, and in the experimental group it was 66.7%. In dynamics study of pro- and antioxidant systems and serum concentra-tions of cytokine in the patients with acute peritonitis was high prognostic significance of results this study, which allows defining treatment tactic of these patients. To include in complex post-operative treatment of these pa-tients with evaluated antioxidant and anticytokine therapy allowed reducing the development of purulent-septic complications from 82.4 to 66.7%, which increased effectively of treatment in such patients and reduced the term of hospitality.

Targeting miR-18a sensitizes chondrocytes to anticytokine therapy to prevent osteoarthritis progression

Inflammation participates in the development of OA and targeting inflammatory signaling pathways is a potential strategy for OA treatment. IL-1β is one of the most important inflammatory factors to trigger the activation of NF-κB signaling and accelerate OA progression, whereas OA patients could hardly benefit from inhibiting IL-1β in clinic, suggesting the importance to further explore the details of OA inflammation. We here showed that expression of miR-18a in chondrocytes was specifically induced in response to IL-1β in vitro as well as in rat model of OA during which NF-κB signaling was involved, and that nuclear-translocated p65 directly upregulated miR-18a expression at transcriptional level. Further, increased miR-18a mediated hypertrophy of chondrocytes, resulting in OA degeneration, by targeting TGFβ1, SMAD2, and SMAD3 and subsequently leading to repression of TGF-β signaling. And the level of serum miR-18a was positively correlated to severity of OA. Interestingly, other than IL-1β, pro-inflammation cytokines involving TNFα could also remarkably upregulate miR-18a via activating NF-κB signaling and subsequently induce chondrocytes hypertrophy, suggesting a pivotal central role of miR-18a in inflammatory OA progression. Thus, our study revealed a novel convergence of NF-κB and TGF-β signaling mediated by miR-18a, and a novel mechanism underlying inflammation-regulated OA dependent of NF-κB/miR-18a/TGF-β axis. Notably, in vivo assay showed that targeting miR-18a sensitized OA chondrocytes to IL-1β inhibitor as targeting IL-1β and miR-18a simultaneously had much stronger inhibitory effects on OA progression than suppressing IL-1β alone. Therefore, the diagnostic and therapeutic potentials of miR-18a for OA were also revealed.

Visfatin and Rheumatoid Arthritis: Pathogenetic Implications and Clinical Utility

Objective: Analysis and generalization of data related to visfatin involvement in the pathogenesis of inflammation at various stages of rheumatoid arthritis. Data Synthesis: Visfatin is an adipocytokine which has also been identified in non-adipose tissues. It influences directly on the maturation of B cells, which are involved in autoantibody production and T cell activation. Visfatin can promote inflammation via regulation of pro-inflammatory cytokines including TNF, IL-1β and IL-6. The concentration of circulating visfatin in rheumatoid arthritis patients is higher compared to healthy individuals. Several studies suggest that visfatin level is associated with rheumatoid arthritis activity, and its elevation may precede clinical signs of the relapse. In murine collagen-induced arthritis, visfatin levels were also found to be elevated both in inflamed synovial cells and in joint vasculature. Visfatin blockers have been shown to confer fast and long-term attenuation of pathological processes; however, most of their effects are transient. Other factors responsible for hyperactivation of the immune system can participate in this process at a later stage. Treatment of rheumatoid arthritis with a combination of these blockers and inhibitors of other mediators of inflammation can potentially improve treatment outcomes compared to current therapeutic strategies. Recent advances in the treatment of experimental arthritis in mice as well as the application of emerging treatment strategies obtained from oncology for rheumatoid arthritis management could be a source of novel adipokine-mediated anti-rheumatic drugs. Conclusion: The ongoing surge of interest in anticytokine therapy makes further study of visfatin highly relevant as it may serve as a base for innovational RA treatment.

tocilizumab in the treatment of systemic inflammatory response in a patient with CoVID-19 (clinical case)

Improving the approaches to treating COVID-19 infection opens up the possibility for using previously known groups of drugs that demonstrate their effectiveness in the pathogenetic treatment of this disease. Significant clinical experience in the field of treatment of COVID-19 have been accumulated in Clinical Infectious Diseases Hospital named after S.P. Botkin, Saint-Petersburg, Russia. The case study demonstrates the timeliness and effectiveness of anticytokine therapy with COVID-19, the possibility of using a recombinant humanized monoclonal antibody to the human receptor for interleukin-6 (IL-6) (tocilizumab).

Immune Immunomodulation in Coronavirus Disease 2019 (COVID-19): Strategic Considerations for Personalized Therapeutic Intervention

We are learning that the host response to severe acute respiratory syndrome coronavirus 2 ( SARS-CoV-2) infection is complex and highly dynamic. Effective initial host defense in the lung is associated with mild symptoms and disease resolution. Viral evasion of the immune response can lead to refractory alveolar damage, ineffective lung repair mechanisms, and systemic inflammation with associated organ dysfunction. The immune response in these patients is highly variable and can include moderate to severe systemic inflammation and/or marked systemic immune suppression. There is unlikely to be a “one size fits all” approach to immunomodulation in patients with coronavirus disease 2019 (COVID-19). We believe that a personalized, immunophenotype-driven approach to immunomodulation that may include anticytokine therapy in carefully selected patients and immunostimulatory therapies in others is the shortest path to success in the study and treatment of patients with critical illness due to COVID-19.