Compensatory Anti-inflammatory Response Research Articles

Natural Killer Cell Infiltration in Prostate Cancers Predict Improved Patient Outcomes.

Natural killer (NK) cells are non-antigen specific innate immune cells that can be redirected to targets of interest using multiple strategies, although none are currently FDA-approved. We sought to evaluate NK cell infiltration into tumors to develop an improved understanding of which histologies may be most amenable to NK cell-based therapies currently in the developmental pipeline. DNA (targeted/whole-exome) and RNA (whole-transcriptome) sequencing was performed from tumors from 45 cancer types (N = 90,916 for all cancers and N = 3365 for prostate cancer) submitted to Caris Life Sciences. NK cell fractions and immune deconvolution were inferred from RNA-seq data using quanTIseq. Real-world overall survival (OS) and treatment status was determined and Kaplan-Meier estimates were calculated. Statistical significance was determined using X2 and Mann-Whitney U tests, with corrections for multiple comparisons where appropriate. In both a pan-tumor and prostate cancer (PCa)-specific setting, we demonstrated that NK cells represent a substantial proportion of the total cellular infiltrate (median range 2-9% for all tumors). Higher NK cell infiltration was associated with improved OS in 28 of 45 cancer types, including (PCa). NK cell infiltration was negatively correlated with common driver mutations and androgen receptor variants (AR-V7) in primary prostate biopsies, while positively correlated with negative immune regulators. Higher levels of NK cell infiltration were associated with patterns consistent with a compensatory anti-inflammatory response. Using the largest available dataset to date, we demonstrated that NK cells infiltrate a broad range of tumors, including both primary and metastatic PCa. NK cell infiltration is associated with improved PCa patient outcomes. This study demonstrates that NK cells are capable of trafficking to both primary and metastatic PCa and are a viable option for immunotherapy approaches moving forward. Future development of strategies to enhance tumor-infiltrating NK cell-mediated cytolytic activity and activation while limiting inhibitory pathways will be key.

The Hepatic Nerves Regulated Inflammatory Effect in the Process of Liver Injury: Is Nerve the Key Treating Target for Liver Inflammation?

Liver injury is a common pathological basis for various liver diseases. Chronic liver injury is often an important initiating factor in liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Currently, hepatitis A and E infections are the most common causes of acute liver injury worldwide, whereas drug toxicity (paracetamol overdose) in the USA and part of Western Europe. In recent years, chronic liver injury has become a common disease that harms human health. Meanwhile, the main causes of chronic liver injury are viral hepatitis (B, C) and long-term alcohol consumption worldwide. During the process of liver injury, massive inflammatory cytokines are stimulated by these hazardous factors, leading to a systemic inflammatory response syndrome, followed by a compensatory anti-inflammatory response, which causes immune cell dysfunction and sepsis, subsequent multi-organ failure. Cytokine release and immune cell infiltration-mediated aseptic inflammation are the most important features of the pathobiology of liver failure. From this perspective, diminishing the onset and progression of liver inflammation is of clinical importance in the treatment of liver injury. Although many studies have hinted at the critical role of nerves in regulating inflammation, there largely remains undetermined how hepatic nerves mediate immune inflammation and how the inflammatory factors released by these nerves are involved in the process of liver injury. Therefore, the purpose of this article is to summarize previous studies in the field related to hepatic nerve and inflammation as well as future perspectives on the aforementioned questions. Our findings were presented in three aspects: types of nerve distribution in the liver, how these nerves regulate immunity, and the role of liver nerves in hepatitis and liver failure.

During Sepsis and COVID-19, the Pro-Inflammatory and Anti-Inflammatory Responses Are Concomitant.

The most severe forms of COVID-19 share many features with bacterial sepsis and have thus been considered to be a viral sepsis. Innate immunity and inflammation are closely linked. While the immune response aims to get rid of the infectious agent, the pro-inflammatory host response can result in organ injury including acute respiratory distress syndrome. On its side, a compensatory anti-inflammatory response, aimed to dampen the inflammatory reaction, can lead to immunosuppression. Whether these two key events of the host inflammatory response are consecutive or concomitant has been regularly depicted in schemes. Initially proposed from 2001 to 2013 to be two consecutive steps, the concomitant occurrence has been supported since 2013, although it was proposed for the first time in 2001. Despite a consensus was reached, the two consecutive steps were still recently proposed for COVID-19. We discuss why the concomitance view could have been initiated as early as 1995.

Mild Cognitive Impairment Is Associated with Enhanced Activation of Th17 Lymphocytes in Non-Alcoholic Fatty Liver Disease.

Patients with nonalcoholic fatty liver disease (NAFLD) may show mild cognitive impairment (MCI). The mechanisms involved remain unclear. The plasma concentrations of several cytokines and chemokines were measured in 71 NAFLD patients (20 with and 51 without MCI) and 61 controls. Characterization and activation of leukocyte populations and CD4+ sub-populations were carried out and analyzed by flow cytometry. We analyzed the cytokines released from CD4+ cell cultures and the mRNA expression of transcription factors and receptors in peripheral blood mononuclear cells. The appearance of MCI in NAFLD patients was associated with increased activation of CD4+ T lymphocytes, mainly of the Th17 subtype, increased plasma levels of pro-inflammatory and anti-inflammatory cytokines such as IL-17A, IL-23, IL-21, IL-22, IL-6, INF-γ, and IL-13, and higher expression of the CCR2 receptor. Constitutive expression of IL-17 was found in cultures of CD4+ cells from MCI patients, reflecting Th17 activation. High IL-13 plasma levels were predictive of MCI and could reflect a compensatory anti-inflammatory response to the increased expression of pro-inflammatory cytokines. This study identified some specific alterations of the immune system associated with the appearance of neurological alterations in MCI patients with NAFLD that could be the basis to improve and restore cognitive functions and quality of life in these patients.

Elevation of neutrophil-derived factors in patients after multiple trauma.

Trauma represents one of the leading causes of death worldwide. Traumatic injuries elicit a dynamic inflammatory response with systemic release of inflammatory cytokines. Disbalance of this response can lead to systemic inflammatory response syndrome or compensatory anti-inflammatory response syndrome. As neutrophils play a major role in innate immune defence and are crucial in the injury-induced immunological response, we aimed to investigate systemic neutrophil-derived immunomodulators in trauma patients. Therefore, serum levels of neutrophil elastase (NE), myeloperoxidase (MPO) and citrullinated histone H3 (CitH3) were quantified in patients with injury severity scores above 15. Additionally, leukocyte, platelet, fibrinogen and CRP levels were assessed. Lastly, we analysed the association of neutrophil-derived factors with clinical severity scoring systems. Although the release of MPO, NE and CitH3 was not predictive of mortality, we found a remarkable increase in MPO and NE in trauma patients as compared with healthy controls. We also found significantly increased levels of MPO and NE on Days 1 and 5 after initial trauma in critically injured patients. Taken together, our data suggest a role for neutrophil activation in trauma. Targeting exacerbated neutrophil activation might represent a new therapeutic option for critically injured patients.

Resolving sepsis-induced immunoparalysis via trained immunity by targeting interleukin-4 to myeloid cells

Immunoparalysis is a compensatory and persistent anti-inflammatory response to trauma, sepsis or another serious insult, which increases the risk of opportunistic infections, morbidity and mortality. Here, we show that in cultured primary human monocytes, interleukin-4 (IL4) inhibits acute inflammation, while simultaneously inducing a long-lasting innate immune memory named trained immunity. To take advantage of this paradoxical IL4 feature in vivo, we developed a fusion protein of apolipoprotein A1 (apoA1) and IL4, which integrates into a lipid nanoparticle. In mice and non-human primates, an intravenously injected apoA1-IL4-embedding nanoparticle targets myeloid-cell-rich haematopoietic organs, in particular, the spleen and bone marrow. We subsequently demonstrate that IL4 nanotherapy resolved immunoparalysis in mice with lipopolysaccharide-induced hyperinflammation, as well as in ex vivo human sepsis models and in experimental endotoxemia. Our findings support the translational development of nanoparticle formulations of apoA1-IL4 for the treatment of patients with sepsis at risk of immunoparalysis-induced complications.

Dynamics of immune responses are inconsistent when trauma patients are grouped by injury severity score and clinical outcomes

The injury severity score (ISS) is used in daily practice to evaluate the severity of trauma patients; however, the score is not always consistent with the prognosis. After injury, systemic inflammatory response syndrome (SIRS) and compensatory anti-inflammatory response syndrome (CARS) are related to the prognosis of trauma patients. We aimed to evaluate the associations between the immune response and prognosis in trauma patients. Patients who admitted to the Trauma Intensive Care Unit (ICU) were eligible. Whole blood samples were collected at admission, and then 6, 12, 24, 48 and 72 h after admission. Natural killer (NK) cells, lymphocyte subset population and cytokines release were identified using flow cytometry. We grouped patients by their ISS (≤ 25 and > 25 as very severe injury) and ICU stay (≤ 10 days as a short ICU stay and > 10 days as a long ICU stay) for evaluation. Fifty-three patients were enrolled. ICU stay but not ISS was close correlated with activity daily living (ADL) at discharge. Patients with a long ICU stay had an immediate increase in NK cells followed by lymphopenia which persisted for 48 h. Immediate activation of CD8+ T cells and then exhaustion with a higher programmed cell death-1 (PD-1) expression and suppression of CD4+ T cells with a shift to an anti-inflammatory Th2 phenotype were also observed in the patients with a long ICU stay. When the patients were grouped by ISS, the dynamics of immune responses were inconsistent to those when the patients were grouped by ICU stay. Immune responses are associated with the prognosis of trauma patients, however the currently used clinical parameters may not accurately reflect immune responses. Further investigations are needed to identify accurate predictors of prognosis in trauma patients.

Identification of novel immune-related targets mediating disease progression in acute pancreatitis.

Acute pancreatitis (AP) is an inflammatory disease with very poor outcomes. However, the order of induction and coordinated interactions of systemic inflammatory response syndrome (SIRS) and compensatory anti-inflammatory response syndrome (CARS) and the potential mechanisms in AP are still unclear. An integrative analysis was performed based on transcripts of blood from patients with different severity levels of AP (GSE194331), as well as impaired lung (GSE151572), liver (GSE151927) and pancreas (GSE65146) samples from an AP experimental model to identify inflammatory signals and immune response-associated susceptibility genes. An AP animal model was established in wild-type (WT) mice and Tlr2-deficient mice by repeated intraperitoneal injection of cerulein. Serum lipase and amylase, pancreas impairment and neutrophil infiltration were evaluated to assess the effects of Tlr2 in vivo. The numbers of anti-inflammatory response-related cells, such as M2 macrophages (P = 3.2 × 10-3), were increased with worsening AP progression, while the numbers of pro-inflammatory response-related cells, such as neutrophils (P = 3.0 × 10-8), also increased. Then, 10 immune-related AP susceptibility genes (SOSC3, ITGAM, CAMP, FPR1, IL1R1, TLR2, S100A8/9, HK3 and MMP9) were identified. Finally, compared with WT mice, Tlr2-deficient mice exhibited not only significantly reduced serum lipase and amylase levels after cerulein induction but also alleviated pancreatic inflammation and neutrophil accumulation. In summary, we discovered SIRS and CARS were stimulated in parallel, not activated consecutively. In addition, among the novel susceptibility genes, TLR2might be a novel therapeutic target that mediates dysregulation of inflammatory responses during AP progression.

CRITERIA IN THE PROGNOSTIC OF GENERALIZATION OF BACTERIOSES IN DOGS WITH UTERINE INFLAMMATION

A common complication in purulent endometritis is septicemia and septic shock, leading to the death of the animal. To prevent the development of complications, an early diagnosis is carried out. For this purpose, a proprietary variation of the scoring models (scales PRO (P = predisposition, I = infection, K = response, O = organ dysfunction) and PYOMETRA) is proposed. An algorithm of actions has been developed for making operational decisions on the prognosis of possible septic complications in animals, including an assessment of the clinical manifestation of the inflammatory response SIRS, the syndrome of multiple organ insufficiency MODS and the syndrome of compensatory anti-inflammatory response CARS. The algorithm at the first stage provides for the determination of the PIRO score. If necessary, if the PIRO data indicate a doubtful, cautious or unfavorable prognosis, an assessment of the cellular and humoral blood parameters of dogs is carried out on a PIOMETRA scale. This makes it possible to determine the degree of development of the clinical manifestation of the inflammatory response (SIRS) and the level of expenditure of the body's protective resources because of the anti-inflammatory response (CARS). The indicator of the severity of the general condition of the sick animal also affects the reliability of the prognosis regarding the outcome of the disease. When evaluating the PIRO and PYOMETRA scales in the study, some animals had a mild degree; others had a medium, severe or critical degree of severity of the disease, which allowed us to confirm the importance of using additional scales when developing strategies and tactics for treating animals.

Management of Acute Liver Failure: Update 2022.

Abbreviated pathogenesis and clinical course of the acute liver failure syndrome. The pathogenesis and clinical course of the syndrome of acute liver failure (ALF) differs depending upon the etiology of the primary liver injury. In turn, the severity of the liver injury and resulting synthetic failure is often the primary determinant of whether a patient is referred for emergency liver transplantation. Injuries by viral etiologies trigger the innate immune system via pathogen-associated molecular patterns (PAMPs), while toxin-induced (and presumably ischemia-induced) injuries do so via damage-associated molecular patterns (DAMPs). The course of the clinical syndrome further depends upon the relative intensity and composition of cytokine release, resulting in an early proinflammatory phenotype (SIRS) and later compensatory anti-inflammatory response phenotype (CARS). The outcomes of overwhelming immune activation are the systemic (extrahepatic) features of ALF (cardiovascular collapse, cerebral edema, acute kidney injury, respiratory failure, sepsis) which ultimately determine the likelihood of death.Acute liver failure (ALF) continues to carry a high risk of mortality or the need for transplantation despite recent improvements in overall outcomes over the past two decades. Optimal management begins with identifying that liver failure is indeed present and its etiology, since outcomes and the need for transplantation vary widely across the different etiologies. Most causes of ALF can be divided into hyperacute (ischemia and acetaminophen) and subacute types (other etiologies), based on time of evolution of signs and symptoms of liver failure; the former evolve in 3 to 4 days and the latter typically in 2 to 4 weeks. Both involve intense release of cytokines and hepatocellular contents into the circulation with multiorgan effects/consequences.Management involves optimizing fluid balance and cardiovascular support, including the use of continuous renal replacement therapy, vasopressors, and pulmonary ventilation. Early evaluation for liver transplantation is advised particularly for acetaminophen toxicity, which evolves so rapidly that delay is likely to lead to death.Vasopressor support, high-grade hepatic encephalopathy, and unfavorable (subacute) etiologies heighten the need for urgent listing for liver transplantation. Prognostic scores such as Kings Criteria, Model for End-Stage Liver Disease, and the Acute Liver Failure Group prognostic index take these features into account and provide reasonable but imperfect predictive accuracy. Future treatments may include liver support devices and/or agents that improve hepatocyte regeneration.

Clinical Laboratory Justification of Early Diagnosis and Prognosis on Surgical Sepsis Using Simple Laboratory Criteria in the Elderly

Introduction. Clinical and laboratory criteria of the Sepsis-2 Consensus disregard organ dysfunction manifestations and compensatory anti-inflammatory response in septic complications. The aim of the study was to develop a laboratory parameter detecting sepsis at different periods of its course based on a detailed complete blood test considering the degree of pro-inflammatory response to infection, an anti-inflammatory component, presence of a particular sign of the multiple organ failure. Materials and methods. A statistical study included 152 patients with clinical and laboratory manifestations of surgical sepsis who underwent inpatient treatment at the surgical clinical base of the North-Western State Medical University. In the group of patients who had signs of endogenous intoxication, but the diagnosis of sepsis was not confirmed, frequency of verification of septicopyemia at autopsy was identified in every 4th case. Variants of sepsis scoring were determined in accordance with the parameters of the complete blood test.Results. The correlation between the procalcitonin level and the scoring system was noted at 0,5019309, the correlation between the blood lactate level and the scoring system did not exceed 0,542726115. Findings. With a score higher than 7, the diagnosis of severe sepsis is very likely. With a score lower than 4, the presence of severe sepsis, including the development of septicopyemia, is unlikely. Under the condition when a score is equal 5-6 and combined with long periods of the disease, the search for distant foci of septicopyemia and assessment of the prognosis for the secondary sepsis development are priority. Conclusion. The scoring assessment of a simple laboratory investigation (detailed complete blood test), in our opinion, indirectly reflects the presence and period of septic complications. The use of a score system in practical healthcare can improve screening of patients with surgical infection complicated by the development of sepsis at all stages of medical care.

41 Peripheral Mononuclear Cell Expression of IL-10, IL-12, ARG1, & NOS2 Correlates with Outcomes After Burn

IntroductionIn the burned patient, clinical outcomes are inextricably linked with immune function. Patients are subject to an early pro-inflammatory response and a subsequent compensatory anti-inflammatory response syndrome. This dysregulation can lead to infection, multiple organ dysfunction syndrome, and death. Despite continuing efforts, a profile of immune gene expression from burn patients that can be transformed into an “immune suppression index”, which accurately reflects the underlying degree of immune insult and significantly correlates with the degree compromise, has yet to be developed. The development of such an approach that can predict graft failure, susceptibility to infection, length-of-stay in the hospital, and/or that can inform a provider on how to better manage the timing of surgical interventions would be transformative.ObjectiveTo determine a set of peripheral biomarkers that correlates with clinical outcomes of burn patients.MethodsThis observational study enrolled two participant cohorts within a single burn center. Initial unbiased analysis compared 23 burn patients and 6 healthy controls. Confirmatory outcomes analysis was performed in 109 burn patients and 19 healthy controls. We employed multiplex gene expression analysis to identify differential peripheral blood mononuclear cells (PBMC) immune gene expression. qPCR was used to validate these findings, identify, and model associations with outcomes.ResultsWe identified 149 genes with a significant difference in expression within PBMCs from burn patients compared to controls (Figure 1a). Pathway analysis identified pathways related to IL-10 and inducible nitric oxide synthase (iNOS) signaling (Figure 1b). qPCR analysis of IL-10, IL-12, arginase-1 (ARG1), and iNOS demonstrated that burn injury was associated with increased expression of ARG1 and IL-10, and decreased expression of NOS2 and IL-12. Burn severity, acute lung injury (ALI), development of infection, failure of skin autograft, and mortality significantly correlated with expression of one or more of these genes. Ratios of IL-10/IL-12, ARG1/NOS2 and (ARG1+IL-10)/(NOS2+IL-12) transcript levels further improved the correlation with outcomes. A multivariate regression model, adjusting for confounders, demonstrated that (ARG1+IL-10)/(NOS2+IL-12) significantly correlated with burn severity and development of ALI (Table 1).ConclusionsWe present a robust model to predict patient outcomes early after burn injury using non-invasive methods, allowing early identification of underlying immune dysfunction.

Роль та місце ω-3 жирних кислот у регуляції синдрому системної відповіді на запалення в пацієнтів, які отримують інтенсивну терапію

У статті проаналізовано сучасні наукові дані про роль ω-3 жирних кислот у комплексі нутритивної підтримки у хворих у критичному стані, їх вплив на динаміку синдрому системної відповіді на запалення (SIRS), синдрому протизапальної відповіді (CARS), а також синдрому змішаної антагоністичної дії (MАRS), що розвивається при взаємодії різноспрямованої (запальної/протизапальної) відповіді (SIRS/САRS). Призначення замісної імунокорекції в комплексі інтенсивної терапії критичних станів патогенетично обґрунтоване і показане як компонент цілеспрямованої органопротективної терапії. Наявність у пацієнтів синдромів SIRS або CARS повинно визначати вибір ліпідної емульсії в комплексі парентерального харчування з уключенням емульсій МСТ/ЛСТ з ω-3 жирними кислотами у хворих у клініці інтенсивної терапії. Використання ліпідних емульсій, збагачених риб’ячим жиром, сприяє зменшенню тривалості лікування в стаціонарі пацієнтів із критичними станами.

Profile and role of immune function changes of T lymphocytes in patients with acute pancreatitis

In recent decades, with the development of the pathogenesis of Acute severe pancreatitis (SAP) and the improvement of clinical treatment techniques, the mortality rate of SAP is still over 10% . Recent studies have shown that immune dysregulation plays an important role in the pathogenesis of AP, especially in SAP. A meta-study points to widespread concern for the discovery of immunosuppression by networked cytokines in the course of AP. In the early stages of AP, high cytokine levels play a leading role in the development of SIRS pathological conditions, which result in a cascade of inflammatory cytokines that induce the release of immunocompetent cells, leading to an excessive immune response. In the later stages of Compensatory anti-inflammatory response syndrome (CARS), the body over-releases anti-inflammatory agents and has an immunosuppressive process, but contributes to the development of the risk of secondary infection and increases the likelihood of Multiple organ disfunction syndrome (MODS). The study was aimed to measure T-lymphocyte immune function changes of patients with acute pancreatitis and to explore BISAP scoring system in clinical applications.

Early Diagnosis and Prognosis of Surgical Sepsis with Simple Laboratory Criteria in the Elderly Patients: Clinical and Laboratory Substantiation

Introduction. Clinical and laboratory criteria of the 2nd Consensus on Sepsis do not consider manifestations of the organ dysfunction and compensatory anti-inflammatory response in septic complications.
 The aim of study was to develop laboratory parameters that reflect presence of sepsis at different stages of its course based on a detailed complete blood count; take into account the degree of pro-inflammatory response to infection, an anti-inflammatory component, presence of a particular sign of the multiple organ failure.
 Materials and methods. This was a statistical study involving 152 patients with clinical and laboratory manifestations of surgical sepsis who underwent inpatient treatment at the surgical department of the NWSMU clinical hospital. In patients with signs of edogenic intoxication, whose diagnosis sepsis was not confirmed, septicopyemia was verified on autopsy in every 4 cases. The patterns of the score assessment of the sepsis process were determined in accordance with the complete blood count parameters.
 Results. The degree of correlation between the level of procalcitonin and the scores" was noted at the level of 0.5019309, the degree of correlation between the level of blood lactate and the scores did not exceed 0.542726115.
 Conclusions. If the total score is more than 7, the diagnosis of severe sepsis is highly probable. If the total score is less than 4 - presence of severe sepsis including the development of septicopiemia is improbable. If the total score is at the level of 5 -6 combined with long-term disease, the search for distant foci of septicopiemia and assessment of the prognosis of secondary sepsis is a priority.
 In our opinion, the score assessment of simple laboratory parameters (detailed complete blood count), reflects, though indirectly, presence and stages of septic complications. The use of the score assessment in practical health care can improve screening of patients with surgical infection complicated by the sepsis development at all stages of medical care.

IL-1β, IL-17A, and IL-10: A Novel Axis Linked to Immunological Dysfunction May Pre-Empt Early Diagnosis of Sepsis after Cardiac Surgery

INTRODUCTIONSepsis caused by a dysregulated host response to infection, is a serious healthcare problem that results in very high mortality every year-round the globe. When left untreated, sepsis can potentially turn fulminant, making early diagnosis and intervention an essential component of the therapeutic strategy. Proinflammatory cytokines are necessary for initiating an effective inflammatory response against infection, whereas their excess production has been associated with tissue injury in multiple organ systems leading to increased mortality. In contrast, anti-inflammatory cytokines seem to be a prerequisite for controlling and down regulating the initial inflammatory response. But a sustained release of these biomolecules leads to a turn-down of immune activation within the host organism. In the clinical conundrums associated with sepsis, it was often observed that pathogen-responsive cells were exposed to a complex cytokine milieu. The excess production of proinflammatory cytokines is essential for the survival, replication and activation of phagocytic and cytotoxic immune cells. In conjunction with this proinflammatory activity, anti-inflammatory cytokines are also released which are involved in the occurrence of cellular anergy and impaired response to aetiologic agents, causing a compensatory anti-inflammatory response syndrome (CARS).Current practice in cardiac surgery is to review laboratory test results (CRP, PCT, blood culture) and clinical criteria (SOFA and STS) 48 h after surgery to diagnose sepsis. CRP and PCT lack sensitivity and specificity, whereas blood culture requires a long turnaround time and lacks sensitivity. Sepsis being an interplay between pro and anti-inflammatory response, the relative expression of immune biomarkers may provide a useful criterion for early diagnosis of sepsis. Thus, we aimed at investigating the variations in circulating levels of prominent cytokines and their potential use as a diagnostic marker of adult sepsis post cardiac surgery.MATERIALS AND METHODSIn this double-blinded cohort study, blood samples of adult patients undergoing cardiac surgery were collected before surgery (D -1), and on the post-operative day 1 (D +1) after the approval from the appropriate Institutional Ethics Committee. Patients who were deemed risky by EuroSCORE II risk stratification were included and immuno-compromised as well as patients with active infection before surgery were excluded. Plasma levels of IL-1β, IL-5, IL-6, IL-10, IL-17A and TNFα were determined using cytometric bead assay by flow cytometry and the results were analyzed using FCAP Array™ software. The data sets were analyzed (GraphPad Prism 5.02) and a p value of < 0.05 was considered statistically significant.RESULTSThe study was conducted with 34 patients (n=34) and un-blinded after retrieval of data. The cohort has 8 patients diagnosed with sepsis and 26 without sepsis based on STS criteria. Demographic details for both groups are summarized in Table 1. Cytokine and other biomarker expression levels before (D-1) and after (D+1) Surgery is summarized in Table 2. At D +1, IL-1β, TNF-α, IL-17A and IL-10 showed significantly higher concentration in sepsis group compared to non-sepsis group (Fig 1B). CRP, PCT, WBC and differential blood count were not showing any discriminatory potential between sepsis and non-sepsis patients at D +1. The ROC curves of the above four cytokine expression levels at D+1 was analyzed between sepsis and non-sepsis groups. A plasma IL-1β level of 0.25 pg/ml had a sensitivity of 87.5 % and a specificity of 53.8 % and a plasma IL-17A level of 1.78 pg/ml had a sensitivity of 75 % and specificity of 46.2 %. In addition, IL-10 level of 8.99 pg/ml in plasma showed a diagnostic sensitivity of 87.5 % and a specificity of 53.8% (Fig 1C). Based on the current observation we proposed a model of inflammatory cytokine dynamics involving IL-1β, IL-17A and IL-10 suggesting their role, which may lead to the development of sepsis (Fig 1D).CONCLUSIONWe identified a significant up regulation of circulating inflammatory cytokines at 24 h in patients who developed sepsis after cardiac surgery, earlier than any noticeable changes in conventional sepsis biomarkers. These results suggest the possibility of inflammatory cytokines as a diagnostic marker and may be a potential therapeutic target as well. The study needs to be validated further on a larger cohort of patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Особливості формування імунної відповіді на термічну травму

To study the effect of thermal trauma on the immune response formation, 43 patients aged 16 to 58 with body surface area of burns 20-60% were examined. The neutrophilic granulocytes (NG) and monocytes functional activity, the content of myeloperoxidase and substances with a positive reaction to Schiff’s periodic acid (PAS- stained substances), the cytokines content were determined: interleukin-1β (IL-1β), IL-2, IL-4, IL- 6, tumor necrosis factor-α (TNF-α). Thermal damage caused changes in the immune response, which were characterized by a pro-inflammatory phase in which innate immunity cells (neutrophilic granulocytes, monocytes) acquired high functional activity, producing a higher content of proinflammatory cytokines. On the 2-3rd day after the burn injury in the peripheral blood, the interleukin-1β (IL-1β) content was 133.5 ± 21.1 pg/ml, the tumor necrosis factor α (TNF-α) content was 265 ± 115.5 pg/ml, which exceeded the reference values by 5.1 and 10.9 times, respectively. The content of IL-6 on the 2-3rd day was 85.30 ± 13.10 pg/ml. Also a concomitant syndrome of compensatory anti-inflammatory response developed with increasing production of anti-inflammatory IL-4: on the 2-3rd day after burn injury, its content was 268.5 pg/ml, exceeding the reference values by 8.2 times. The content of anti-inflammatory IL-10 was decreased. This suggests that anti-inflammatory cytokines do not compensate for the high content of pro-inflammatory factors. On the 7th-8th day after the burn injury, there was a tendency to further increase the content of pro-inflammatory cytokines IL- 1β and TNF-α to 148.0 ± 27.0, and 281.2 ± 146.7 pg/ml, respectively, while the content of IL-6 on the 7-8th day was 131.0 ± 11.1 pg/ml, the anti-inflammatory cytokine IL-10 increased slightly, and the content of IL-4 decreased. These changes in the early period of burn disease dynamics, as well as reduced activity of myeloperoxidase and PAS- stained substances NG, point for a functional deficiency of NG, reduced enzymatic activity and cells energy resources decompensation. These changes could clinically lead to SIRS progression and multiorgan dysfunction.

Immune Function in Critically Ill Septic Children.

The inflammatory response in pediatric sepsis is highly dynamic and includes both pro- and anti-inflammatory elements that involve the innate and adaptive immune systems. While the pro-inflammatory response is responsible for the initial clinical signs and symptoms of sepsis, a concurrent compensatory anti-inflammatory response often results in an occult, but highly clinically relevant, form of acquired immunodeficiency. When severe, this is termed “immunoparalysis” and is associated with increased risks for nosocomial infection, prolonged organ dysfunction, and death. This review focuses on the pathophysiology and clinical implications of both over- and under-active immune function in septic children. Host-, disease-, and treatment-specific risk factors for immunoparalysis are reviewed along with immune phenotype-specific approaches for immunomodulation in pediatric sepsis which are currently the subject of clinical trials.

Endocytosis of peroxiredoxin 1 links sterile inflammation to immunoparalysis in pediatric patients following cardiopulmonary bypass

After cardiopulmonary bypass (CPB), the occurrence of systemic inflammatory response is often accompanied by a persistent compensatory anti-inflammatory response syndrome that can lead to a compromised immune competence termed immunoparalysis, rendering the patients susceptible to infections which is a leading complication following cardiac surgery. However, the underlying mechanisms of CPB-elicited immunoparalysis remain obscure. In this study we showed that peroxiredoxin 1 (Prdx1), a putative cytosolic antioxidant, was released immediately after CPB in a cohort of pediatric patients receiving congenital cardiac surgery. This increased Prdx1 was correlated to a reduced human leukocyte antigen-DR expression and an elevated interleukin-10 (IL-10) production, as well as a hypo-responsiveness of macrophages to endotoxin and a higher incidence of nosocomial infection. We demonstrated that substitution of Ser83 for Cys83 prevented Prdx1 from oligomerization and subsequent binding and internalization to macrophages. These effects mitigated Prdx1-induced IL-10 induction and endotoxin tolerance. Furthermore, after engagement with toll-like receptor (TLR) 4, clathrin-dependent endocytosis is crucial for Prdx1 to elicit IL-10 production in phagocytes. Congruently, inhibition of Prdx1/TLR4 endocytosis in phagocytes reversed the Prdx1/IL-10-mediated hypo-responsiveness to endotoxin. Our findings unveiled the possible mechanisms by which Prdx1 undertakes to cause immunoparalysis, and targeting endocytosis of Prdx1 could be a novel therapeutic approach for postoperative infections associated with CPB.

Epigenetic Regulation in Sepsis, Role in Pathophysiology and Therapeutic Perspective.

Sepsis is characterized by an initial hyperinflammatory response, with intense cell activation and cytokine storm. In parallel, a prolonged compensatory anti-inflammatory response, known as immunological tolerance, can lead to immunosuppression. Clinically, this condition is associated with multiple organ failure, resulting in the patient's death. The mechanisms underlying the pathophysiology of sepsis are not yet fully understood, but evidence is strong showing that epigenetic changes, including DNA methylation and post-translational modifications of histones, modulate the inflammatory response of sepsis. During the onset of infection, host cells undergo epigenetic changes that favor pathogen survival. Besides, epigenetic changes in essential genes also orchestrate the patient's inflammatory response. In this review, we gathered studies on sepsis and epigenetics to show the central role of epigenetic mechanisms in various aspects of the pathogenesis of sepsis and the potential of epigenetic interventions for its treatment.