Immune Response In Sepsis Research Articles

Therapeutic effects of curcumin on sepsis and mechanisms of action: A systematic review of preclinical studies.

Sepsis is a complex disease that begins with an infectious disorder and causes excessive immune responses. Curcumin is considered as an active component of turmeric that can improve the condition in sepsis due to its anti-inflammatory and antioxidant properties. PubMed, Embase, Google Scholar, Web of Science, and Scopus databases were searched. Searching was not limited to a specific publication period. Only English-language original articles, which had examined the effect of curcumin on sepsis, were included. At first, 1,098 articles were totally found, and 209 articles were selected after excluding duplicated data; 46 articles were remained due to the curcumin effects on sepsis. These included 23 in vitro studies and 23 animal studies. Our results showed that curcumin and various analogs of curcumin can have an inhibitory effect on sepsis-induced complications. Curcumin has the ability to inhibit the inflammatory, oxidative coagulation factors, and regulation of immune responses in sepsis. Despite the promising evidence of the therapeutic effects of curcumin on the sepsis complication, further studies seem necessary to investigate its effect and possible mechanisms of action in human studies.

Neutrophil and monocyte receptor expression in patients with sepsis: implications for diagnosis and prognosis of sepsis.

Understanding the complex immune responses in sepsis is crucial to provide insight into the clinical syndrome. We evaluated the changes in the surface receptors of the cells of innate immunity, neutrophils and monocytes, in patients with sepsis. Since sepsis remains a clinical challenge, we aimed to assess the significance of altered receptor expression in diagnosis and prognosis. Critically ill patients with sepsis (n=31) were investigated for the expression of receptors for IgG heavy chain CD64 and CD16 on neutrophils and CD64 and the lipopolysaccharide receptor CD14 on monocytes by flow cytometry and compared to 23 patients with no sepsis. Patients with sepsis had increased expression of neutrophil CD64. Neutrophil CD64 was specific for discriminating patients with sepsis but showed weak sensitivity. When integrated in a scoring system, neutrophil CD64 in combination with C-reactive protein (CRP) and SOFA score showed a diagnostic accuracy of 0.93 for sepsis and significantly predicted increased mortality risk. While neutrophil CD16 did not discriminate for sepsis, decreased expression was associated with increased mortality risk. In contrast, monocyte CD64 and CD14 expression was unaltered in sepsis and was not associated with mortality risk. Our study demonstrates that unlike monocytes, neutrophil receptor expression is altered in patients with sepsis receiving intensive care. It is promising to apply a combination approach to diagnose sepsis especially in time-limited conditions.

Host-Derived Delta-Like Canonical Notch Ligand 1 as a Novel Diagnostic Biomarker for Bacterial Sepsis-Results From a Combinational Secondary Analysis.

Background: Sepsis is a life-threatening syndrome, resulting from a dysbalanced host response to infection. However, especially the early, pro-inflammatory immune response in sepsis is similar to other inflammatory conditions without infectious cause, e.g., trauma or surgery. This aspect challenges the value of current biomarkers for diagnosis, as these are often broadly induced. We earlier identified Delta-like Protein 1 (DLL1), a canonical Notch ligand, to be released from monocytes upon bacterial stimulation. Considering the importance of monocytes in the pathophysiology of sepsis, we hypothesized that this mechanism might occur also in the clinical setting and DLL1 might serve as a biomarker of life-threatening bacterial infection.Methods: We combined samples from three different studies, including subgroups of patients with sepsis (n = 80), surgical patients (n = 50), trauma patients (n = 36), as well as healthy controls (n = 50). We assessed plasma concentrations of DLL1 using ELISA. We performed Area-under-receiver-operator-curve (AUROC) analysis to evaluate the diagnostic performance of DLL1 compared to leucocytes, C-reactive protein (CRP), and procalcitonin (PCT).Results: Plasma concentrations of DLL1 were strongly elevated already at sepsis onset and maintained elevated until day 7. In contrast, neither surgical patients nor patients after severe trauma presented with elevated levels, while conventional biomarkers of inflammation (e.g., leucocytes and CRP), responded. AUROC analysis revealed a cut-off of 30 ng/ml associated with the best diagnostic performance, yielding a superior accuracy of 91% for DLL1, compared to 75, 79, and 81% for CRP, leucocytes, and PCT.Conclusion: DLL1 is a novel host-derived biomarker for the diagnosis of sepsis with a better performance compared to established ones, most likely due to its high robustness in non-infectious inflammatory responses.Clinical Trial Registration: POCSEP-Trial DRKS00008090; MIRSI DRKS00005463; SPRINT DRKS00010991.

Differential Roles of Dendritic Cells in Expanding CD4 T Cells in Sepsis.

Sepsis is a systemically dysregulated inflammatory syndrome, in which dendritic cells (DCs) play a critical role in coordinating aberrant immunity. The aim of this study is to shed light on the differential roles played by systemic versus mucosal DCs in regulating immune responses in sepsis. We identified a differential impact of the systemic and mucosal DCs on proliferating allogenic CD4 T cells in a mouse model of sepsis. Despite the fact that the frequency of CD4 T cells was reduced in septic mice, septic mesenteric lymph node (MLN) DCs proved superior to septic spleen (SP) DCs in expanding allogeneic CD4 T cells. Moreover, septic MLN DCs markedly augmented the surface expression of MHC class II and CD40, as well as the messaging of interleukin-1β (IL-1β). Interestingly, IL-1β-treated CD4 T cells expanded in a dose-dependent manner, suggesting that this cytokine acts as a key mediator of MLN DCs in promoting septic inflammation. Thus, mucosal and systemic DCs were found to be functionally different in the way CD4 T cells respond during sepsis. Our study provides a molecular basis for DC activity, which can be differential in nature depending on location, whereby it induces septic inflammation or immune-paralysis.

The Fluctuations of Leukocytes and Circulating Cytokines in Septic Humanized Mice Vary With Outcome.

Sepsis remains a major challenge in translational research given its heterogeneous pathophysiology and the lack of specific therapeutics. The use of humanized mouse chimeras with transplanted human hematopoietic cells may improve the clinical relevance of pre-clinical studies. However, knowledge of the human immuno-inflammatory response during sepsis in humanized mice is scarce; it is unclear how similar or divergent mouse and human-origin immuno-inflammatory responses in sepsis are. In this study, we evaluated the early outcome-dependent immuno-inflammatory response in humanized mice generated in the NSG strain after cecal ligation and puncture (CLP) sepsis. Mice were observed for 32 h post-CLP and were assigned to either predicted-to-die (P-DIE) or predicted-to-survive (P-SUR) groups for retrospective comparisons. Blood samples were collected at baseline, 6 and 24 h, whereas the bone marrow and spleen were collected between 24 and 32 h post-CLP. In comparison to P-SUR, P-DIE humanized mice had a 3-fold higher frequency of human splenic monocytes and their CD80 expression was reduced by 1.3-fold; there was no difference in the HLA-DR expression. Similarly, the expression of CD80 on the bone marrow monocytes from P-DIE mice was decreased by 32% (p < 0.05). Sepsis induced a generalized up-regulation of both human and murine plasma cytokines (TNFα, IL-6, IL-10, IL-8/KC, MCP-1); it was additionally aggravated in P-DIE vs. P-SUR. Human cytokines were strongly overridden by the murine ones (approx. ratio 1:9) but human TNFα was 7-fold higher than mouse TNFα. Interestingly, transplantation of human cells did not influence murine cytokine response in NSG mice, but humanized NSG mice were more susceptible to sepsis in comparison with NSG mice (79 vs. 33% mortality; p < 0.05). In conclusion, our results show that humanized mice reflect selected aspects of human immune responses in sepsis and therefore may be a feasible alternative in preclinical immunotherapy modeling.

Reduced Mannose-Binding Lectin-Associated Serine Protease (MASP)-1 is Associated with Disturbed Coagulation in Septic Shock.

Activation of the complement system is part of the dysregulated immune response in sepsis. The mannose-binding lectin-associated serine proteases (MASP)-1 and -2 activate the lectin pathway of the complement system. Besides, these proteins can activate coagulation in vitro. However, the role of the lectin pathway proteins in the development of sepsis-related disseminated intravascular coagulation (DIC) is only sparsely investigated. This article investigates the association between lectin pathway proteins and coagulation disturbances in septic shock patients. We included 36 septic shock patients from the intensive care unit, Aarhus University Hospital, Denmark. Blood samples were obtained within 24 hours after admission (day 1), and subsequently on day 2 and day 3. Plasma concentrations of mannose-binding lectin (MBL), H-ficolin, M-ficolin, CL-L1, CL-K1, MASP-1, -2 and -3, MBL-associated proteins of 19 and 44 kDa as well as complement factor C3dg were assessed. Standard coagulation parameters, thrombin generation, thrombin-anti-thrombin (TAT) complex and pro-thrombin fragment 1 + 2 were measured. Sequential Organ Failure Assessment (SOFA) score, DIC score and 30-day mortality were assessed. Reduced MASP-1 plasma concentration was associated with DIC score ≥5 (p = 0.02), impaired thrombin generation (p = 0.03) and lower plasma TAT complex levels (p = 0.03). No association was found between lectin pathway proteins and SOFA score or 30-day mortality. Reduced MASP-1 concentrations were associated with impaired coagulation in septic shock patients. This indicates that increased MASP-1 activation and consumption is associated with the more severe coagulation disturbances in sepsis and points to a possible role for MASP-1 in sepsis-related DIC.

SNASP inhibits TLR signaling to regulate immune response in sepsis.

Many Toll-like receptors (TLRs) signal through TNF receptor-associated factor 6 (TRAF6) to activate innate immune responses. Here, we show that somatic nuclear autoantigenic sperm protein (sNASP) binds to TRAF6 to prevent TRAF6 autoubiquitination in unstimulated macrophages. Following LPS stimulation, a complex consisting of sNASP, TRAF6, IRAK4, and casein kinase 2 (CK2) is formed. CK2 phosphorylates sNASP at serine 158, allowing sNASP to dissociate from TRAF6. Free TRAF6 is then autoubiquitinated, followed by activation of downstream signaling pathways. In sNasp S158A knockin (S158A-KI) mice, LPS-treated macrophages could not phosphorylate sNASP, which remained bound to TRAF6. S158A-KI mice were more susceptible to sepsis due to a marked reduction in IL-1β, TNF-α, and IFN-γ production accompanied by an inability to clear bacteria and recruit leukocytes. Furthermore, phosphorylation-regulated release of sNASP from TRAF6 is observed following activation of TLR-1, -2, -4, -5, and -6. Thus, sNASP is a negative regulator of TLR signaling to modulate the innate immune response.

Ketamine Improves Sepsis-induced Immunosuppression by Attenuating Intracellular Calcium Elevation in Rat Peripheral Mononuclear Cells

Immune response in sepsis divided into two phases, hyper-inflammation (cytokine storm) and hypo-inflammation (immunosuppression). The mechanism of immunosuppression appears to involve apoptosis of immune cells, particularly mononuclear cells and it predisposes to secondary infection that is believed as the predominant driving force for mortality. We aimed to determine the effect of ketamine on mononuclear cells count related to intracellular calcium contained within these cells during the immunosuppression phase of sepsis. This in vivo study was performed in Rattus Novergicus with Fecal Induced Perionitis (FIP) procedure to induce polymicrobial sepsis. Rats were treated with each respective dose of ketamine (2.5, 5, and 10 mg/kg) 1 hour after sepsis induction. Murine Sepsis Score was measured at 1 and 24 hours post-FIP. After 24 hours, animals were sacrificed, and the percentage of intracellular calcium inside CD4, and CD8 T cells, B cells and monocytes, along with these cells counts were determined with flowcytometry. There are significant elevation of intracellular calcium in CD4 T-cells, B-cells and monocytes after FIP-induction and ketamine treatment suppressed this FIP-induced elevation. Measurement of mononuclear cells count showed a relevant result, in which FIP induced mononuclear cells massive loss and ketamine could inhibit the loss. MSS data showed ketamine 5 mg/kg could improve 24 hours MSS with 100% survivability. These findings suggest that ketamine have an inhibitory effect in mononuclear-cells apoptosis mechanism through attenuating intracellular calcium elevation in polymicrobial sepsis. These inhibitory effects of ketamine might correlate with a better survival and clinical outcome.

Epigenetics : Important aspects for anesthesiologists, pain and intensive care physicians

Epigenetics, i.e. an altered reading of the genome without altering the genes themselves is agrowing scientific field. A distinction is made between changes in the DNA by modification of the histones and non-coding RNA that alter the messenger (m)RNAs. Epigenetic modifications can be triggered by personal circumstances or other external factors and therefore influence the occurrence of diseases. Epigenetics are therefore of particular interest to anesthesiologists, pain specialists and intensive care physicians, as anesthetic drugs may have along-term influence on protein transcription leading for example to alterations in neurocognition after anesthesia, chronification of postoperative pain and immune response in sepsis. Non-coding microRNAs known to be altered in avariety of perioperatively relevant diseases e. g. heart infarct, might serve as prognostic factors of perioperative outcome. Moreover, there are ways to influence epigenetic changes through life style and certain medications. In this review article, examples of anesthesia, intensive care and pain medicine-relevant diseases and the influence of epigenetics on them are presented.

Swiprosin-1 deficiency impairs macrophage immune response of septic mice.

Despite the fact that many therapeutic strategies have been adopted to delay the development of sepsis, sepsis remains one of the leading causes of death in noncoronary intensive care units. Recently, sepsis-3 was defined as life-threatening organ dysfunction due to a dysregulated host response to infection. Here, we report that swiprosin-1 (also known as EFhd2) plays an important role in the macrophage immune response to LPS-induced or cecal ligation and puncture-induced (CLP-induced) sepsis in mice. Swiprosin-1 depletion causes higher mortality, more severe organ dysfunction, restrained macrophage recruitment in the lung and kidney, and attenuated inflammatory cytokine production (including IL-1β, IL-6, TNF-α, IL-10, and IFN-γ). The immunosuppression caused by swiprosin-1 deficiency is manifested by impaired bactericidal capacity and decreased HLA-DR expression in macrophages. Swiprosin-1 affects the activation of the JAK2/STAT1/STAT3 pathway by regulating the expression of IFN-γ receptors in macrophages. Our findings provide a potential target for the regulation of the macrophage immune response in sepsis.

IL-7 and Its Beneficial Role in Sepsis-Induced T Lymphocyte Dysfunction.

Sepsis, defined as life-threatening organ dysfunction caused by dysregulated host response to infection, has recently been acknowledged as a worldwide health priority. Sepsis remains the leading cause of mortality in intensive care units and accounts for 6 million deaths every year. Few therapeutic options targeting host immune response in sepsis have demonstrated their efficacy so far. Increasing evidence suggests that a profound immune suppression develops following sepsis, affecting innate and adaptive immune response, of which intensity and duration is associated with increased risk of death and nosocomial infection. Immunostimulant treatments are thus now evaluated in sepsis, and recombinant human IL-7 (rhIL-7) represents a promising candidate. rhIL-7 has been evaluated in several clinical trials in patients with altered lymphocytic responses (HIV infection, hematopoietic stem cell transplantation, and cancer). Recent studies in animal models and in patients' samples ex vivo demonstrated its efficacy in improving sepsis-induced T cell alterations. Finally, the first clinical trial evaluating rhIL-7 in septic shock patients has just been published. This review will discuss the use of rhIL-7 to treat sepsis-induced T cell dysfunction by introducing the pathophysiology of sepsis and sepsis-related lymphocyte alterations before focusing on rhIL-7 and its potential use of as a therapeutic intervention in patients.

Alteration of sphingolipid metabolism as a putative mechanism underlying LPS-induced BBB disruption.

Septic encephalopathy with confusion and agitation occurs early during sepsis and contributes to the severity of the disease. A decrease in the sphingosine-1-phosphate (S1P) blood levels has been shown in patients and in animal models of sepsis. The lipid mediator S1P is known to be involved in endothelial barrier function in a context-dependent manner. We utilized lipopolysaccharide (LPS)-injected mice as a model for septic encephalopathy and first performed tracer permeability assays to assess the blood-brain barrier (BBB) breakdown invivo. At time points corresponding to the BBB breakdown post LPS injection, we aimed to characterize the regulation of the sphingolipid signaling pathway at the BBB during sepsis. We measured sphingolipid concentrations in blood, in mouse brain microvessels (MBMVs), and brain tissue. We also analyzed the expression of S1P receptors, transporters, and metabolizing enzymes in MBMVs and brain tissue. Primary mouse brain microvascular endothelial cells (MBMECs) were isolated to evaluate the effects of LPS on transendothelial electrical resistance (TEER) as a measure of permeability invitro. We observed a relevant decrease in S1P levels after LPS injection in all three compartments (blood, MBMVs, brain tissue) that was accompanied by an increased expression of the S1P receptor type 1 and of sphingosine kinase 1 on one hand and of the S1P degrading enzymes lipid phosphate phosphatase 1 (LPP1) and S1P phosphatase 1 on the other hand, as well as a down-regulation of sphingosine kinase 2. Application of LPS to a monolayer of primary MBMECs did not alter TEER, but serum from LPS-treated mice lead to a breakdown of the barrier compared to serum from vehicle-treated mice. We observed profound alterations of the sphingolipid metabolism at the BBB after LPS injection that point toward a therapeutic potential of drugs interfering with this pathway as novel approach for the detrimental overwhelming immune response in sepsis. Read the Editorial Highlight for this article on page 115. Cover Image for this Issue: doi. 10.1111/jnc.14161.

Circulating miRNAs in sepsis-A network under attack: An in-silico prediction of the potential existence of miRNA sponges in sepsis.

Biomarkers based on the molecular mechanism of sepsis are important for timely diagnosis and treatment. A large panel of small non-coding microRNAs was reported to modulate the immune response in sepsis but have not been tested in clinical practice. Large-scale identification of microRNA networks in sepsis might reveal a new biological mechanism that can be also targeted by gene therapy. Therefore, the main objective of this study is to perform a comparison of the miRNA network between septic patients and healthy controls. We used the previously measured levels of expression of 16 different circulating human and viral microRNAs in plasma from 99 septic patients and 53 healthy controls. We used three different computational methods to find correlations between the expressions of microRNAs and to build microRNA networks for the two categories, septic patients and healthy controls. We found that the microRNA network of the septic patients is significantly less connected when compared to miRNA network of the healthy controls (21 edges vs 52 edges, P < 0.0001). We hypothesize that several microRNAs (miR-16, miR-29a, miR-146, miR-155, and miR-182) are being sponged in sepsis explaining the loss of connection in the septic patient miRNA network. This was specific for sepsis, as it did not occur in other conditions characterized by an increased inflammatory response such as in post-surgery patients. Using several target prediction instruments, we predicted potential common sponges for the miRNA network in sepsis from several signaling pathways. Understanding the dynamics of miRNA network in sepsis is useful to explain the molecular pathophysiology of sepsis and for designing therapeutic strategies that target essential components of the immune response pathways.

Human leucocyte antigen (HLA-DR) gene expression is reduced in sepsis and correlates with impaired TNFα response: A diagnostic tool for immunosuppression?

BackgroundSepsis is defined as a dysregulated immune response to infection. Impaired immune response in sepsis, often described as endotoxin tolerance, is characterized by unresponsiveness of monocytes on lipopolysaccharide (LPS) stimulation to release tumor necrosis factor α (TNFα). Furthermore, decreased monocyte surface protein expression of human leucocyte antigen DR (HLA-DR) is a marker for changes of the innate immune response during sepsis. Quantitative polymerase chain reaction (qPCR) and flow-cytometry (FACS) have been used to measure protein or gene expression of HLA-DR. We aimed to determine whether changes in mRNA expression of HLA-DR are associated with impaired TNFα response in human sepsis.MethodsSurface protein together with mRNA expression of HLA-DR were measured by FACS and qPCR in a cohort of 9 sepsis patients and compared to 10 pre-operative control patients in a prospective study. In addition, 20 patients with post-surgical inflammation, 20 patients with sepsis or septic shock were included and TNFα was determined following ex vivo stimulation of whole blood with 500 pg/mL LPS. Total RNA was prepared from whole blood and subjected to qPCR analysis for expression analysis of HLA-DR alpha (HLA-DRA) to correlate TNFα response with HLA-DRA expression.ResultsPatients with sepsis presented higher numbers of monocytes in peripheral blood (P<0.001) but decreased surface protein and mRNA HLA-DR levels when compared to controls. In all patients mRNA expression of HLA-DRA was decreased by approximately 70% compared to controls (P<0.01) and was lowest in patients with sepsis or septic shock (P<0.01). TNFα response to LPS was decreased in all patients (median 319 pg/mL versus controls 1256 pg/mL; P<0.01) and lowest in patients with sepsis or septic shock (median 128 pg/mL; P<0.01). HLA-DRA correlated positively with TNFα response in all study participants (r +0.60, P<0.001) and within patients (r +0.67, P<0.001). The TNFα:HLA-DRA ratio correlated negatively with severity and the Sequential Organ Failure Assessment (SOFA) score (Spearman’s rho -0.59, P<0.001)ConclusionIn this study, HLA-DRA expression was associated with a functional assay of the innate immune response. Future interventional studies aimed at the immune response during sepsis could make use of these methods for optimizing target groups based on biological plausibility and intervention effectiveness.

Pulmonary innate type 2 inflammatory responses protect against Staphylococcus aureus-induced sepsis

Abstract Sepsis is defined as life-threatening organ dysfunction caused by the body’s response to infection. Sepsis is associated with overwhelming type 1 or type 17 immunologic inflammation, but the role of type 2 immune responses in sepsis remains unknown. To test the role of type 2 immune responses in sepsis, we treated mice with intratracheal IL-33 to induce an innate pulmonary type 2 response, followed by intravenous infection with S. aureus to induce sepsis. Surprisingly, type 2 responses were beneficial during acute infection, as IL-33 treatment protected mice from S. aureus-induced death. An increase in the ratio of lung eosinophils to neutrophils was revealed in IL-33 treated, S. aureus infected mice, suggesting that type 2 responses suppress lung neutrophilia. Further, no difference was found in splenic granulocytes or lymphocytes, indicating that activation of pulmonary immune responses alone was sufficient for protection. Infection of PLZF null mice, which have defective NKT and ILC2 cells normally required for type 2 innate responses after IL-33 treatment, resulted in accelerated mortality compared with wild type littermate controls. Moreover, IL-33 did not rescue PLZF null mice from death. However, infection of CD1d null mice, which lack only NKT cells but have intact ILC2s, demonstrated no difference in mortality. Thus, pulmonary type 2 innate immunity provided by ILC2s is critical for protection against S. aureus-mediated death.

Pediatric Sepsis Markers: Interleukins and Others

AbstractCytokines are a very important part in the regulation of immune response in sepsis. They are cellular signaling proteins whose production is a result of activation of specific receptors. Variations in the genes encoding cytokines have a significant role in interindividual susceptibility to sepsis and its severity, and their function may be modulated by age, gender, and some environmental factors. Cytokines are classified into the subsets of proinflammatory, anti-inflammatory, and multiple function cytokines. Regulated balance between proinflammatory cytokines, anti-inflammatory cytokines, and soluble inhibitors of proinflammatory cytokines is important for eliminating pathogens and reducing inflammation. High levels of some cytokines, such as tumor necrosis factor-α, interleukin (IL)-1, and IL-6, determine the course of disease and outcome in sepsis. Likewise, numerous other biomarkers may be potential indicators of sepsis, but none has been routinely used. The best approach to the diagnosis of sepsis is the combination of different biomarkers.

Regulation of Cellular Immune Responses in Sepsis by Histone Modifications.

Severe sepsis, septic shock, and related inflammatory syndromes are driven by the aberrant expression of proinflammatory mediators by immune cells. During the acute phase of sepsis, overexpression of chemokines and cytokines drives physiological stress leading to organ failure and mortality. Following recovery from sepsis, the immune system exhibits profound immunosuppression, evidenced by an inability to produce the same proinflammatory mediators that are required for normal responses to infectious microorganisms. Gene expression in inflammatory responses is influenced by the transcriptional accessibility of the chromatin, with histone posttranslational modifications determining whether inflammatory gene loci are set to transcriptionally active, repressed, or poised states. Experimental evidence indicates that histone modifications play a central role in governing the cytokine storm of severe sepsis, and that aberrant chromatin modifications induced during the acute phase of sepsis may mediate chronic immunosuppression in sepsis survivors. This review will focus on the role of histone modifications in governing immune responses in severe sepsis, with an emphasis on specific leukocyte subsets and the histone modifications observed in these cells during chronic stages of sepsis. Additionally, the expression and function of chromatin-modifying enzymes (CMEs) will be discussed in the context of severe sepsis, as potential mediators of epigenetic regulation of gene expression in sepsis responses. In summary, this review will argue for the use of chromatin modifications and CME expression in leukocytes as potential biomarkers of immunosuppression in patients with severe sepsis.

CB2 and GPR55 Receptors as Therapeutic Targets for Systemic Immune Dysregulation.

The endocannabinoid system (ECS) is involved in many physiological processes and has been suggested to play a critical role in the immune response and the central nervous system (CNS). Therefore, ECS modulation has potential therapeutic effects on immune dysfunctional disorders, such as sepsis and CNS injury-induced immunodeficiency syndrome (CIDS). In sepsis, excessive release of pro- and anti-inflammatory mediators results in multi-organ dysfunction, failure, and death. In CIDS, an acute CNS injury dysregulates a normally well-balanced interplay between CNS and the immune system, leading to increased patients’ susceptibility to infections. In this review, we will discuss potential therapeutic modulation of the immune response in sepsis and CNS injury by manipulation of the ECS representing a novel target for immunotherapy.

Evaluating the effect of infliximab on the healing of left colonic anastomosis in the presence of intra-abdominal sepsis

Background and study aimsInfliximab (IFX) is a chimeric anti-TNF-α body which is effectively used in the treatment of inflammatory bowel diseases and a variety of autoimmune diseases. The effect of IFX on the healing of intestinal anastomosis has been evaluated in several studies, however with conflicting results. Furthermore, the effect of IFX on colonic anastomosis in sepsis has not been evaluated to date. In this study, we aimed to investigate whether IFX has an adverse effect on the healing process of colonic anastomosis either under normal or septic condition. Material and methodThe efficiency of IFX was assessed with respect to anastomotic bursting pressure (ABP), tissue hydroxyproline levels (THL) and histopathological examination of left colonic anastomosis in 40 male rats. The rats were randomly allocated into four groups of 10 rats each as control (C), septic control (SC), control IFX (C-IFX) and septic IFX (S-IFX). ResultsThe anastomotic bursting pressure was measured at 182±19.1, 158±15.4, 161±26.8 and 100±10.3mm/Hg, in C, SC, C-IFX and S-IFX; respectively. IFX administration did not influence the anastomotic strength under normal condition whereas in sepsis significantly induced the reduction of APB. The mean THL was almost similar in both control groups (p=0.87), whilst IFX reduced the level of TH in sepsis comparing with control groups (p=0.01). IFX significantly impaired immune response in sepsis resulting in poor anastomotic healing in S-IFX group. ConclusionOur study demonstrated that IFX had no detrimental effect on the healing of colonic anastomosis under normal condition whilst significantly impaired the healing process in sepsis.

Therapeutic iron restriction in sepsis

Sepsis represents the systemic immune response to an infection. Mortality of sepsis slightly decreased over the past years, but due to the growing incidence, the absolute number of deaths still increases and belongs to the three most frequent causes of death worldwide. To date, there is no specific treatment for sepsis available yet. Iron is essential to both human beings and microbes and of great significance in many physiological and biochemical processes. Since iron is involved in the bacterial proliferation and immune dysregulation, we hypothesize that restricting host iron levels by application of iron chelators attenuates bacterial growth and improves the detrimental dysregulation of the systemic immune response in sepsis.