Inflammation-Induced Coagulopathy Substantially Differs Between COVID-19 and Septic Shock: A Prospective Observational Study

Critical COVID-19, like septic shock, is related to a dysregulated systemic inflammatory reaction and is associated with a high incidence of thrombosis and microthrombosis. Improving the understanding of the underlying pathophysiology of critical COVID-19 could help in finding new therapeutic targets already explored in the treatment of septic shock. The current study prospectively compared 48 patients with septic shock and 22 patients with critical COVID-19 regarding their clinical characteristics and outcomes, as well as key plasmatic soluble biomarkers of inflammation, coagulation, endothelial activation, platelet activation, and NETosis. Forty-eight patients with matched age, gender, and co-morbidities were used as controls. Critical COVID-19 patients exhibited less organ failure but a prolonged ICU length-of-stay due to a prolonged respiratory failure. Inflammatory reaction of critical COVID-19 was distinguished by very high levels of interleukin (IL)-1β and T lymphocyte activation (including IL-7 and CD40L), whereas septic shock displays higher levels of IL-6, IL-8, and a more significant elevation of myeloid response biomarkers, including Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) and IL-1ra. Subsequent inflammation-induced coagulopathy of COVID-19 also differed from sepsis-induced coagulopathy (SIC) and was characterized by a marked increase in soluble tissue factor (TF) but less platelets, antithrombin, and fibrinogen consumption, and less fibrinolysis alteration. In conclusion, COVID-19 inflammation-induced coagulopathy substantially differs from SIC. Modulating TF release and activity should be evaluated in critical COVID-19 patients.

The Significance of Toll-Like Receptors in the Neuroimmunologic Background of Alcohol Dependence

Toll-like receptors (TLR) are a group of protein belonging to the family of Pattern Recognition Receptors (PRR) which have the ability to distinguish between an organism's own antigens and foreign ones and to induce immunological response. TLR play a significant part in non-specific immunity but at the same time they are also a vital element linking non-specific response to the specific one. A growing number of data seems to indicate that the non-specific immunity mechanisms affect the development and sustenance of alcohol addiction. Alcohol damages the organism's cells not only directly but also through an increase inintestinal permeability which induces innate immune response of peripheral blood cells. The signaling pathway of Toll-like receptors located on the surface of brain immune cells intensifies the inflammatory reaction and, through modifying gene expression of proinflammatory factors, unnaturally supports it. This overly protracted “sterile inflammatory reaction” positively correlates with alcohol craving affecting also the functioning of the reward system structures and increasing the risk of relapse of alcoholism. Recurrent alcoholic binges sensitize the microglia and cause an escalation in inflammatory reaction which also leads to neurodegeneration. The induction of innate immunity signaling pathways exposes clinical symptoms of alcohol addiction such as increased impulsivity, loss of behavioral control, depressive-anxiety symptoms and cognitive dysfunctions. Traditional methods of treating alcohol addiction have tended to focus predominantly on reducing symptoms which—given the frequency of relapses—seems insufficient. The aim of the present paper is to discuss the role of toll-like receptors as elements of the immunity system which, together with the nervous system, plays a crucial part in the pathogenesis of alcohol addiction. We also wish to present pharmacotherapeutic perspectives targeted at the neuroimmunological mechanisms of alcohol addiction.

Steroid-Responsive Post-Traumatic Persistent Neutrophilic Meningitis

Post-traumatic meningitis is a potentially fatal condition that presents as a diagnostic and therapeutic challenge. The vast majority of post-traumatic meningitides are caused by infectious pathogens, most commonly multi-drug-resistant (MDR) bacterial pathogens. However, aseptic meningitis occurs less frequently due to tissue response to injury or stimulation by noninfectious agents, such as blood breakdown products or chemicals. Here, we present a case of post-traumatic persistent neutrophilic meningitis who was found to be steroid responsive. Diagnostic evaluation in our patient did not reveal any infectious pathogen, and the patient did not respond to broad-spectrum antimicrobial treatment. We suggest that physicians who treat patients with post-traumatic meningitis should consider steroid-responsive post-traumatic persistent neutrophilic meningitis (SPNM) in the list of differential diagnosis particularly when no infectious etiology is found and the patient does not respond to empirical antimicrobial treatment. Brain injury-induced immune dysregulation causing exaggerated inflammatory reaction might play a role in the pathogenesis of SPNM; however, further neuropathological studies are absolutely necessary to evaluate and characterize trauma-induced immune dysregulation.

c-Fos is a mechanosensor that regulates inflammatory responses and lung barrier dysfunction during ventilator-induced acute lung injury

Background As one of the basic treatments performed in the intensive care unit, mechanical ventilation can cause ventilator-induced acute lung injury (VILI). The typical features of VILI are an uncontrolled inflammatory response and impaired lung barrier function; however, its pathogenesis is not fully understood, and c-Fos protein is activated under mechanical stress. c-Fos/activating protein-1 (AP-1) plays a role by binding to AP-1 within the promoter region, which promotes inflammation and apoptosis. T-5224 is a specific inhibitor of c-Fos/AP-1, that controls the gene expression of many proinflammatory cytokines. This study investigated whether T-5224 attenuates VILI in rats by inhibiting inflammation and apoptosis. Methods The SD rats were divided into six groups: a control group, low tidal volume group, high tidal volume group, DMSO group, T-5224 group (low concentration), and T-5224 group (high concentration). After 3 h, the pathological damage, c-Fos protein expression, inflammatory reaction and apoptosis degree of lung tissue in each group were detected. Results c-Fos protein expression was increased within the lung tissue of VILI rats, and the pathological damage degree, inflammatory reaction and apoptosis in the lung tissue of VILI rats were significantly increased; T-5224 inhibited c-Fos protein expression in lung tissues, and T-5224 inhibit the inflammatory reaction and apoptosis of lung tissue by regulating the Fas/Fasl pathway. Conclusions c-Fos is a regulatory factor during ventilator-induced acute lung injury, and the inhibition of its expression has a protective effect. Which is associated with the antiinflammatory and antiapoptotic effects of T-5224.

Ezetimibe prevents IL-1β-induced inflammatory reaction in mouse chondrocytes via modulating NF-κB and Nrf2/HO-1 signaling crosstalk

Background: Osteoarthritis, a type of age-related, chronic, degenerative joint disease. Ezetimibe, a cholesterol absorption inhibitor, is widely used for the treatment of various diseases. The role of ezetimibe in osteoarthritis remains unclear. Objective: This study aimed to explored the anti-inflammation effect of ezetimibe on mouse chondrocytes. Method: In the present study, ELISA, qPCR and western blot analysis were performed to evaluate the anti-inflammatory effects of ezetimibe. In addition, enzymes that are highly associated with the anabolism and catabolism of the extracellular matrix of the articular cartilage were also evaluated. Results: Treatment with ezetimibe attenuated the IL-1β-induced degradation of the extracellular matrix, including aggrecan and collagen II. Ezetimibe also attenuated the IL-1β-induced expression levels of MMP3, MMP13 and ADAMTS5, thus exerting protective effects against IL-1β-induced extracellular matrix degradation. The complex mechanism of the anti-inflammatory reaction contributed to the activation of the Nrf2/HO-1 pathway and the suppression of the NF-κB pathway. Conclusion: On the whole, the present study demonstrates that ezetimibe may be a promising agent for further osteoarthritis therapy

Overcoming Immune Depletion is the Main Goal of Developing New Therapies

In recent years, immunotherapy has revolutionized the treatment of cancer; However, inflammatory reactions in healthy tissues often have side effects that can be serious and lead to permanent discontinuation of treatment. This toxicity is not yet well understood and is a major obstacle to the use of immunotherapy. When the immune system is so severely activated, the resulting inflammatory reaction can have detrimental effects and sometimes serious damage to healthy tissue. We wanted to know if there was a difference between an optimal immune response that aims to kill cancer and an unwanted response that could affect healthy tissue. Identifying the distinctive elements between these two immune responses allows the development of new, more effective and less toxic therapeutic approaches. Keywords: Cancer; Cells; Tissues; Tumors; Prevention; Prognosis; Diagnosis; Imaging; Screening, Treatment; Management

Clinical importance of determination of procalcitonin in diagnosis of sepsis

The review presents an assessment of the dynamics of the change in procalcitonin as the main marker of bacterial inflammation in patients with the syndrome of systemic inflammatory reaction, sepsis and septic shock, clarification of the practical and predictive significance of PCT in patients with an identified and not identified focus of infection.

ON THE ISSUE OF DIFFERENTIAL DIAGNOSIS OF BACTERIAL INFECTIONS AND PEDIATRIC MULTISYSTEM INFLAMMATORY SYNDROME DURING THE COVID-19 PANDEMIC

During the COVID-19 pandemic, it is necessary to be wary of the development of pediatric multisystem inflammatory syndrome in children (PMIS) who have had a COVID-19 and had antibodies to the SARS-CoV-2 virus. The aim of this work is to describe two clinical cases in children with antibodies to SARS-CoV-2 against the background of yersiniosis in a 12-year-old child and salmonellosis in a 3-year-old child, which proceeded with a pronounced inflammatory reaction and required a differential diagnosis with multisystem inflammatory syndrome. These bacterial infections proceeded with severe intoxication and fever, had a polymorphic clinical picture with exanthema syndrome, conjunctivitis/scleritis, swelling of the palms/feet, diarrhea and toxic kidney damage, with a pronounced systemic inflammatory reaction – high leukocytosis with neutrophilia and lymphopenia, a significant increase in C-reactive protein, procalcitonin, hypercoagulability (increased fibrinogen, D-dimer). Etiotropic antibiotic therapy led to recovery in both cases. Conclusions: During the COVID-19 pandemic, if antibodies to the SARS-CoV-2 virus are detected in children in the presence of signs of systemic inflammation and corresponding symptoms, the alertness of doctors and a timely comprehensive examination are necessary to exclude bacterial infections, also characterized by signs of systemic inflammation, for the purpose of differential diagnosis of PMIS.

The Effects of Moxibustion on PD-1/PD-L1-Related Molecular Expression and Inflammatory Cytokine Levels in RA Rats

Objective. Rheumatoid arthritis (RA) is an autoimmune disease that starts with inflammation of the synovium. The pain and joint dysfunction caused by RA urgently need an effective treatment to alleviate the inflammatory reaction and delay the progression of the disease. The pathological damage of RA is proposed to associate with the dysfunction of the programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) pathway. Moxibustion, as a main complementary therapy of traditional Chinese medicine (TCM), has been proved effective to reduce chronic inflammatory reaction on RA, but whether the anti-inflammatory effects are mediated by PD-1/PD-L1 pathway is still unclear. Therefore, moxibustion was conducted in the rats with RA to investigate its effect on PD-1/PD-L1. Methods. The rats' right hind paws were injected with Freundʼs complete adjuvant (FCA) to establish the model of RA. Seven days after the injection of FCA, moxibustion therapy was performed on the acupoints of Shenshu (BL23) and Zusanli (ST36) once a day for three weeks. Then, ELISA and immunohistochemical methods were used to analyze the influence of moxibustion on the expression of PD-1/PD-L1. If the moxibustion had an effect on the expression of PD-1/PD-L1-related molecules, we would knock down PD-1 with adenovirus vector. After moxibustion therapy, ELISA and histological analysis were performed to observe the anti-inflammatory effect of moxibustion. Results. The results demonstrated that moxibustion had an effect on the expression of PD-1-related molecules. The results of ELISA manifested that moxibustion decreased the level of IFN-γ and increased the level of IL-4 and IL-10. HE staining revealed that moxibustion alleviated the proliferation of synovial tissue. However, the anti-inflammatory effect and pathological improvement were weakened when PD-1 was blocked. Conclusions. The results indicate that moxibustion affected the expression of PD-1/PD-L1-related molecules and can effectively treat RA damage. The anti-inflammatory effect of moxibustion was weakened when PD-1 was knocked down.