The influence of sepsis as a complication after trauma on immune response to injury

Introduction. Mortality rate in trauma complicated with sepsis is exceeding 50%. Outcome is not determined only by infection or trauma, but also by the intensity of immuno-inflammatory response. Objective. The aim of this study was to determine the influence of sepsis on the immuno-inflammatory response, in the group of 35 traumatized men, of which in 25 cases trauma was complicated with sepsis. Methods. Cytokines were measured by ELISA test in plasma. Blood samples were drown on the first, third and fifth day after ICU admission. Results. Proinflammatory cytokine IL-8 was 230-fold higher in trauma + sepsis group (1148.48 vs. 5.05 pg/ml; p<0.01), and anti- inflammatory cytokine IL-1ra was 4-fold higher (1138.3 vs. 310.05 pg/ml; p<0.01), whereas IL-12 and IL-4 showed no significant difference between the groups. Conclusion. We concluded that sepsis, as a complication after trauma, drastically enhances immuno-inflammatory response to insult, as indicated by IL-8 and IL-1ra, but not IL-12 and IL-4.

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Interleukin-35 inhibited production of histamine and pro-inflammatory cytokines through suppression MAPKs pathway in HMC-1 cells

10.21203/rs.3.rs-41258/v1 ◽

2020 ◽

Author(s):

Tao Chen ◽

Lixin Fu ◽

Qiaomei Sun ◽

Peimei Zhou ◽

Zai-pei Guo

Keyword(s):

Immune Response ◽

Inflammatory Cytokine ◽

Human Mast Cell ◽

Rt Pcr ◽

Effector Cells ◽

Response System ◽

Mast Cell Line ◽

Anti Inflammatory Cytokine ◽

Pro Inflammatory Cytokines

Abstract Background: IL-35 is a newly anti-inflammatory cytokine which belong to the IL-12 family. Mast cells, as one of the major effector cells in the immune response system, play important roles in the pathogenesis of chronic spontaneous urticarial (CSU). The aim of our study is to explore the inhibited role of IL-35 in HMC-1. Methods: The effects of IL-35 on cell proliferation, cytokine expression and histamine release in human mast cell line (HMC1) were investigated by CCK8, ELISA or RT-PCR. The phosphorylation of ERK1/2, p38 and JNK1/2, in PMA and A23187 induced HMC-1 cells were detected by Western Blot.Results: We found that IL-35 significantly inhibited the proliferation of HMC-1 cells stimulated by PMA and A23187. IL-35 also down-regulates the released of histamine and the mRNA expression of IL-6 and IL-17 in activated HMC-1. Furthermore, IL-35 markedly inhibited the phosphorylation of ERK1/2, p38 and JNK1/2, in PMA and A23187 induced HMC-1 cells. Conclusions: This study provides first observations on the inhibitory and anti-inflammtory effect of IL-35 on activated HMC-1 cells. We suggest that IL35 may play an inhibited role in the pathogenesis of CSU.

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Type I and III IFNs produced by the nasal epithelia and dimmed inflammation are key features of alpacas resolving MERS-CoV infection

10.1101/2020.11.23.395301 ◽

2020 ◽

Author(s):

Nigeer Te ◽

Jordi Rodon ◽

Maria Ballester ◽

Mónica Pérez ◽

Lola Pailler-García ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Nasal Mucosa ◽

Inflammatory Cytokine ◽

Innate Immune ◽

Type I ◽

Innate Immune Responses ◽

Interferon Stimulated Genes ◽

Anti Inflammatory ◽

Anti Inflammatory Cytokine

ABSTRACTWhile MERS-CoV (Middle East respiratory syndrome Coronavirus) provokes a lethal disease in humans, camelids, the main virus reservoir, are asymptomatic carriers, suggesting a crucial role for innate immune responses in controlling the infection. Experimentally infected camelids clear infectious virus within one week and mount an effective adaptive immune response. Here, transcription of immune response genes was monitored in the respiratory tract of MERS-CoV infected alpacas. Concomitant to the peak of infection, occurring at 2 days post inoculation (dpi), type I and III interferons (IFNs) were maximally transcribed only in the nasal mucosa of alpacas, provoking the induction of interferon stimulated genes (ISGs) along the whole respiratory tract. Simultaneous to mild focal infiltration of leukocytes in nasal mucosa and submucosa, upregulation of the anti-inflammatory cytokine IL10 and dampened transcription of pro-inflammatory genes under NF-κB control were observed. In the lung, early (1 dpi) transcription of chemokines (CCL2 and CCL3) correlated with a transient accumulation of mainly mononuclear leukocytes. A tight regulation of IFNs in lungs with expression of ISGs and controlled inflammatory responses, might contribute to virus clearance without causing tissue damage. Thus, the nasal mucosa, the main target of MERS-CoV in camelids, is central in driving an efficient innate immune response based on triggering ISGs as well as the dual anti-inflammatory effects of type III IFNs and IL10.IMPORTANCEMiddle East respiratory syndrome coronavirus (MERS-CoV) is the etiological agent of a respiratory disease causing high mortality in humans. In camelids, the main MERS-CoV reservoir host, viral infection leads to subclinical disease. Our study describes transcriptional regulations of innate immunological pathways underlying asymptomatic clinical manifestations of alpacas in response to MERS-CoV. Concomitant to the peak of infection, these animals elicited a strong transient interferon response and induction of the anti-inflammatory cytokine IL10 in the nasal mucosa. This was associated to a dimmed regulation of pro-inflammatory cytokines and induction of interferon stimulated genes along the whole respiratory mucosa, leading to the rapid clearance of the virus. Thus, innate immune responses occurring in the nasal mucosa appear to be the key in controlling MERS-CoV disease by avoiding a cytokine storm. Understanding on how asymptomatic host reservoirs counteract MERS-CoV infection will aid in the development of antiviral drugs and vaccines.

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The Effect of Remote Ischaemic Preconditioning on the Immune Response

10.26686/wgtn.17009441 ◽

2021 ◽

Author(s):

◽

Jennifer Mae Williams-Spence

Keyword(s):

Immune Response ◽

Cardiac Surgery ◽

Immune System ◽

Inflammatory Response ◽

Direct Effect ◽

Peripheral Blood ◽

Serum Levels ◽

Ischaemic Preconditioning ◽

Significant Difference ◽

Remote Ischaemic Preconditioning

<p>Remote ischaemic preconditioning (RIPC) describes the phenomenon where brief intermittent periods of limb ischaemia are used to protect the heart and other organs from subsequent prolonged ischaemic insults. RIPC has been identified as a promising intervention for use during cardiac surgery and has consistently shown a beneficial effect in animal models; however, the results of early clinical trials have not been as successful. The exact mechanisms involved in mediating RIPC have not yet been characterised and a better understanding of the pathways through which RIPC exerts its protective effects will be essential in order to progress the translation of this intervention into the clinical setting. There is increasing evidence that RIPC modifies the inflammatory response, therefore the central aim of the research presented in this thesis was to investigate how RIPC affects the human immune system. We performed a double-blind randomised controlled trial of RIPC in 96 high-risk cardiac surgery patients and found no evidence that the intervention reduced myocardial injury or altered peri-operative expression levels of the key inflammatory cytokines, interleukin (IL)-6, IL-8, and IL-10, during simple or more complex procedures. There was a trend towards higher levels of IL-6 and IL-8 in the preconditioned patients; however, confounding variables in the trial design and the heterogeneous patient population limited our ability to interpret the results. We next conducted a paired-analysis trial with 10 healthy male volunteers to assess the direct effect of preconditioning on the early immune response, away from any form of ischaemic injury or comorbidities. We found that RIPC directly and significantly decreased serum levels of the chemokines MIP-1α and MIP-1β, but did not increase the serum concentrations of a range of key cytokines or alter the cytokine producing potential of peripheral blood leukocytes. These findings strongly suggest that a cytokine is not likely to be the humoral mediator associated with transmitting the RIPC protective signal. RIPC did not alter the immunophenotype or extravasation of peripheral leukocyte populations, or the proliferative and cytokine responses of peripheral blood mononuclear cells (PBMC) to pharmacological, physiological, and antigen-specific stimuli. However, preconditioning did appear to reduce the ability of monocytes and neutrophils to respond to activation signals, as indicated by lower levels of CD11b expression in stimulated cultures, and a significant increase in the basal production of IL-22 was also detected in PBMC cultured for 6 days following preconditioning. These alterations may reduce neutrophil and monocyte tissue infiltration and limit the inflammatory response during the early window of RIPC-induced protection and enhance tissue and wound repair several days later. A multivariate analysis confirmed that there was a significant difference in the response between the control and RIPC treatments and the main contributing factors were identified as changes in neutrophil and T cell activation, serum levels of MIP-1α and β, and production of IL-10 and IL-22 from PBMC cultured for 6 days. Overall, our results suggest that RIPC has a subtle but direct effect on the systemic innate immune response during the early window of protection in healthy volunteers, whereas the effects on the adaptive immune system seem to be considerably delayed. The changes detected following RIPC are likely to contribute to protection against ischaemia-reperfusion injury but not solely account for the extent of the beneficial effects of RIPC detected in animals. Our findings reinforce the safety profile of this intervention and have defined a number of immune parameters that are altered by preconditioning for focusing future research.</p>

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Type I and III IFNs produced by the nasal epithelia and dimmed inflammation are key features of alpacas resolving MERS-CoV infection

10.1101/2020.12.22.423939 ◽

2020 ◽

Author(s):

Nigeer Te ◽

Jordi Rodon ◽

Maria Ballester ◽

Mónica Pérez ◽

Lola Pailler-García ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Nasal Mucosa ◽

Inflammatory Cytokine ◽

Innate Immune ◽

Type I ◽

Innate Immune Responses ◽

Interferon Stimulated Genes ◽

Anti Inflammatory ◽

Anti Inflammatory Cytokine

AbstractWhile MERS-CoV (Middle East respiratory syndrome Coronavirus) provokes a lethal disease in humans, camelids, the main virus reservoir, are asymptomatic carriers, suggesting a crucial role for innate immune responses in controlling the infection. Experimentally infected camelids clear infectious virus within one week and mount an effective adaptive immune response. Here, transcription of immune response genes was monitored in the respiratory tract of MERS-CoV infected alpacas. Concomitant to the peak of infection, occurring at 2 days post inoculation (dpi), type I and III interferons (IFNs) were maximally transcribed only in the nasal mucosa of alpacas, provoking the induction of interferon stimulated genes (ISGs) along the whole respiratory tract. Simultaneous to mild focal infiltration of leukocytes in nasal mucosa and submucosa, upregulation of the anti-inflammatory cytokine IL10 and dampened transcription of pro-inflammatory genes under NF-κB control were observed. In the lung, early (1 dpi) transcription of chemokines (CCL2 and CCL3) correlated with a transient accumulation of mainly mononuclear leukocytes. A tight regulation of IFNs in lungs with expression of ISGs and controlled inflammatory responses, might contribute to virus clearance without causing tissue damage. Thus, the nasal mucosa, the main target of MERS-CoV in camelids, is central in driving an efficient innate immune response based on triggering ISGs as well as the dual anti-inflammatory effects of type III IFNs and IL10.Author summaryMiddle East respiratory syndrome coronavirus (MERS-CoV) is the etiological agent of a respiratory disease causing high mortality in humans. In camelids, the main MERS-CoV reservoir host, viral infection leads to subclinical disease. Our study describes transcriptional regulations of innate immunological pathways underlying asymptomatic clinical manifestations of alpacas in response to MERS-CoV. Concomitant to the peak of infection, these animals elicited a strong transient interferon response and induction of the anti-inflammatory cytokine IL10 in the nasal mucosa. This was associated to a dimmed regulation of pro-inflammatory cytokines and induction of interferon stimulated genes along the whole respiratory mucosa, leading to the rapid clearance of the virus. Thus, innate immune responses occurring in the nasal mucosa appear to be the key in controlling MERS-CoV disease by avoiding a cytokine storm. Understanding on how asymptomatic host reservoirs counteract MERS-CoV infection will aid in the development of antiviral drugs and vaccines.

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Can systemic inflammation at diagnosis predict benefit from primary resection in metastatic colorectal cancer (mCRC)?

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.4_suppl.410 ◽

2013 ◽

Vol 31 (4_suppl) ◽

pp. 410-410 ◽

Cited By ~ 1

Author(s):

Ben Tran ◽

Hui-Li Wong ◽

Jayesh Desai ◽

Jeanne Tie ◽

Kathryn Maree Field ◽

...

Keyword(s):

Immune Response ◽

Inflammatory Response ◽

Systemic Inflammation ◽

De Novo ◽

Primary Resection ◽

Rank Test ◽

Tumour Resection ◽

Prognostic Impact ◽

Neutrophil Lymphocyte Ratio ◽

Significant Difference

410 Background: In CRC, the tumor associated immune response can manifest as, (1) a good prognostic anti-tumor local (intra-tumoral) inflammatory response; or (2) a poor prognostic tumor promoting systemic inflammatory response. As suggested for renal cancer, the survival advantage associated with primary resection in mCRC patients (pts) might relate to modification of the tumor associated immune response, through reduction in tumor bulk and the resulting reduction in tumor promoting cytokines. We examine if systemic inflammation at diagnosis predicts benefit from primary resection in mCRC. Methods: A prospectively collected multi-disciplinary CRC database was used to explore clinicopathological data from pts diagnosed with de novo mCRC from Jan 2009 to Jul 2012. Evidence of systemic inflammation was defined as serum albumin (SA) <35g/L or neutrophil-lymphocyte ratio (NLR) >4 at diagnosis. Pts with primary resection >42 days from diagnosis were excluded. Survival analyses utilised the Kaplan-Meier method and log-rank test. Results: Of 212 pts diagnosed with mCRC, 154 (72%) had de novo mCRC. 92 (60%) of these underwent primary resection, 62 (40%) had primary left in situ. SA was available in 141 pts, 71 (50%) had SA <35g/L. NLR was available in all pts, 93 (60%) had NLR >4. Primary resection was associated with superior overall survival (OS): median 32.5mo v 8.4mo (HR 0.29, p<0.001). Systemic inflammation was associated with inferior OS using either SA <35g/L (median 8.4mo v 19.8mo, HR 2.54, p<0.001) or NLR >4 (median 16.8 mo v 13.1 mo, HR 1.59, p=0.03). There was no difference in OS advantages associated with primary resection in pts with SA <35g/L (HR 0.25, p<0.001) compared to normal SA (HR 0.28, p<0.001) at diagnosis; a non significant difference was observed for NLR ≤4 (HR 0.15, p<0.001) compared to NLR >4 (HR 0.42, p=0.001). Data regarding resolution of systemic inflammation following primary resection will be presented. Conclusions: Our study confirms the OS benefit from primary resection in mCRC and the adverse prognostic impact of systemic inflammation. Based on our current data, any benefit from primary tumour resection cannot be explained by an impact on the tumor associated immune response.

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The anti-inflammatory cytokine response characterized by elevated interleukin-10 is a stronger predictor of severe disease and poor outcomes than the pro-inflammatory cytokine response in coronavirus disease 2019 (COVID-19)

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2020-1284 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Brandon Michael Henry ◽

Stefanie W. Benoit ◽

Jens Vikse ◽

Brandon A. Berger ◽

Christina Pulvino ◽

...

Keyword(s):

Inflammatory Response ◽

Lymphocyte Count ◽

Inflammatory Cytokine ◽

Severe Disease ◽

Interleukin 10 ◽

Cytokine Response ◽

Inflammatory Cytokine Response ◽

Anti Inflammatory ◽

Poor Outcomes ◽

Anti Inflammatory Cytokine

AbstractObjectivesSevere coronavirus disease 2019 (COVID-19) is associated with a dysregulated immune state. While research has focused on the hyperinflammation, little research has been performed on the compensatory anti-inflammatory response. The aim of this study was to evaluate the anti-inflammatory cytokine response to COVID-19, by assessing interleukin-10 (IL-10) and IL-10/lymphocyte count ratio and their association with outcomes.MethodsAdult patients presenting to the emergency department (ED) with laboratory-confirmed COVID-19 were recruited. The primary endpoint was maximum COVID-19 severity within 30 days of index ED visit.ResultsA total of 52 COVID-19 patients were enrolled. IL-10 and IL-10/lymphocyte count were significantly higher in patients with severe disease (p<0.05), as well as in those who developed severe acute kidney injury (AKI) and new positive bacterial cultures (all p≤0.01). In multivariable analysis, a one-unit increase in IL-10 and IL-10/lymphocyte count were associated with 42% (p=0.031) and 32% (p=0.013) increased odds, respectively, of severe COVID-19. When standardized to a one-unit standard deviations scale, an increase in the IL-10 was a stronger predictor of maximum 30-day severity and severe AKI than increases in IL-6 or IL-8.ConclusionsThe hyperinflammatory response to COVID-19 is accompanied by a simultaneous anti-inflammatory response, which is associated with poor outcomes and may increase the risk of new positive bacterial cultures. IL-10 and IL-10/lymphocyte count at ED presentation were independent predictors of COVID-19 severity. Moreover, elevated IL-10 was more strongly associated with outcomes than pro-inflammatory IL-6 or IL-8. The anti-inflammatory response in COVID-19 requires further investigation to enable more precise immunomodulatory therapy against SARS-CoV-2.

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Determining controllability of sepsis using genetic algorithms on a proxy agent-based model of systemic inflammation

10.1101/153080 ◽

2017 ◽

Author(s):

Chase Cockrell ◽

Gary An

Keyword(s):

Immune Response ◽

Immune System ◽

Mortality Rate ◽

Inflammatory Response ◽

Disease Process ◽

The United States ◽

Innate Immune ◽

Agent Based ◽

Human Immune ◽

Inflammatory Response To Injury

AbstractSepsis, a manifestation of the body’s inflammatory response to injury and infection, has a mortality rate of between 28%-50% and affects approximately 1 million patients annually in the United States. Currently, there are no therapies targeting the cellular/molecular processes driving sepsis that have demonstrated the ability to control this disease process in the clinical setting. We propose that this is in great part due to the considerable heterogeneity of the clinical trajectories that constitute clinical “sepsis,” and that determining how this system can be controlled back into a state of health requires the application of concepts drawn from the field of dynamical systems. In this work, we consider the human immune system to be a random dynamical system, and investigate its potential controllability using an agent-based model of the innate immune response (the Innate Immune Response ABM or IIRABM) as a surrogate, proxy system. Simulation experiments with the IIRABM provide an explanation as to why single/limited cytokine perturbations at a single, or small number of, time points is unlikely to significantly improve the mortality rate of sepsis. We then use genetic algorithms (GA) to explore and characterize multi-targeted control strategies for the random dynamical immune system that guide it from a persistent, non-recovering inflammatory state (functionally equivalent to the clinical states of systemic inflammatory response syndrome (SIRS) or sepsis) to a state of health. We train the GA on a single parameter set with multiple stochastic replicates, and show that while the calculated results show good generalizability, more advanced strategies are needed to achieve the goal of adaptive personalized medicine. This work evaluating the extent of interventions needed to control a simplified surrogate model of sepsis provides insight into the scope of the clinical challenge, and can serve as a guide on the path towards true “precision control” of sepsis.Author summarySepsis, characterized by the body’s inflammatory response to injury and infection, has a mortality rate of between 28%-50% and affects approximately 1 million patients annually in the United States. Currently, there are no therapies targeting the cellular/molecular processes driving sepsis that have demonstrated the ability to control this disease process. In this work, we utilize a computational model of the human immune response to infectious injury to offer an explanation as to why previously attempted treatment strategies are inadequate and why the current approach to drug/therapy-development is inadequate. We then use evolutionary computation algorithms to explore drug-intervention space using this same computational model. This allows us to characterize the scale and scope of interventions needed to successfully control sepsis, as well as the types of data needed to derive these interventions. We demonstrate that multi-point and time-dependent varying controls are necessary and able to control the cytokine network dynamics of the immune system.

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Importance of IL-10 Modulation by Probiotic Microorganisms in Gastrointestinal Inflammatory Diseases

ISRN Gastroenterology ◽

10.5402/2011/892971 ◽

2011 ◽

Vol 2011 ◽

pp. 1-11 ◽

Cited By ~ 42

Author(s):

Alejandra de Moreno de LeBlanc ◽

Silvina del Carmen ◽

Meritxell Zurita-Turk ◽

Clarissa Santos Rocha ◽

Maarten van de Guchte ◽

...

Keyword(s):

Immune Response ◽

Inflammatory Cytokine ◽

Inflammatory Diseases ◽

Critical Role ◽

Genetically Engineered ◽

Wide Range ◽

Prevention And Treatment ◽

Therapeutic Properties ◽

Anti Inflammatory Cytokine

Lactic acid bacteria (LAB) represent a heterogeneous group of microorganisms that are naturally present in many foods and possess a wide range of therapeutic properties. The aim of this paper is to present an overview of the current expanding knowledge of one of the mechanisms by which LAB and other probiotic microorganisms participate in the prevention and treatment of gastrointestinal inflammatory disease through their immune-modulating properties. A special emphasis will be placed on the critical role of the anti-inflammatory cytokine IL-10, and a brief overview of the uses of genetically engineered LAB that produce this important immune response mediator will also be discussed. Thus, this paper will demonstrate the critical role that IL-10 plays in gastrointestinal inflammatory diseases and how probiotics could be used in their treatment.

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