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Background: Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is the rescue treatment proposed to patients with refractory cardiogenic shock. The VA-ECMO implantation promotes inflammation and ischemia-reperfusion injuries through the VA-ECMO flow, causing digestive mucosa barrier disrupture and inducing translocation of bacterial wall components—Lipopolysaccharides (LPS) with further inflammation and circulatory impairment. LPS is a well-studied surrogate indicator of bacterial translocation. Oxiris membrane is a promising and well-tolerated device that can specifically remove LPS. The main study aim is to compare the LPS elimination capacity of Oxiris membrane vs. a non-absorbant classical renal replacement (RRT) membrane in patients with cardiogenic shock requiring VA-ECMO.Methods: ECMORIX is a randomized, prospective, single-center, single-blind, parallel-group, controlled study. It compares the treatment with Oxiris membrane vs. the standard continuous renal replacement therapy care in patients with cardiogenic shock support by peripheral VA-ECMO. Forty patients will be enrolled in both treatment groups. The primary endpoint is the value of LPS serum levels after 24 h of treatment. LPS serum levels will be monitored during the first 72 h of treatment, as clinical and cardiac ultrasound parameters, biological markers of inflammation and 30-day mortality.Discussion: Oxiris membrane appears to be beneficial in controlling the VA-ECMO-induced ischemia-reperfusion inflammation by LPS removal. ECMORIX results will be of major importance in the management of severe cases requiring VA-ECMO and will bring pathophysiological insights about the LPS role in this context.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT04886180.

The objective of the present study was to identify biological signatures of severe coronavirus disease 2019 (COVID-19) predictive of admission in the intensive care unit (ICU). Over 170 immunological markers were investigated in a ‘discovery’ cohort (n = 98 patients) of the Lausanne University Hospital (LUH-1). Here we report that 13 out of 49 cytokines were significantly associated with ICU admission in the three cohorts (P, Infection with SARS CoV2 results in the induction of multiple cytokine and inflammatory pathways. Here the authors demonstrate the association of HGF and CXCL13 production with increased severity and mortality in COVID-19 patients.

ObjectiveCoronavirus disease (COVID-19) has been associated with a large variety of neurologic disorders. However, the mechanisms underlying these neurologic complications remain elusive. In this study, we aimed at determining whether neurologic symptoms were caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) direct infection or by either systemic or local proinflammatory mediators.MethodsIn this cross-sectional study, we checked for SARS-CoV-2 RNA by quantitative reverse transcription PCR, SARS-CoV-2–specific antibodies, and 49 cytokines/chemokines/growth factors (by Luminex) in the CSF +/− sera of a cohort of 22 COVID-19 patients with neurologic presentation and 55 neurologic control patients (inflammatory neurologic disorder [IND], noninflammatory neurologic disorder, and MS).ResultsWe detected anti–SARS-CoV-2 immunoglobulin G in patients with severe COVID-19 with signs of intrathecal synthesis for some of them. Of the 4 categories of tested patients, the CSF of IND exhibited the highest level of cytokines, chemokines, and growth factors. By contrast, patients with COVID-19 did not present overall upregulation of inflammatory mediators in the CSF. However, patients with severe COVID-19 (intensive care unit patients) exhibited higher concentrations of CCL2, CXCL8, and vascular endothelium growth factor A (VEGF-A) in the CSF than patients with a milder form of COVID-19. In addition, we could show that intrathecal CXCL8 synthesis was linked to an elevated albumin ratio and correlated with the increase of peripheral inflammation (serum hepatocyte growth factor [HGF] and CXCL10).ConclusionsOur results do not indicate active replication of SARS-CoV-2 in the CSF or signs of massive inflammation in the CSF compartment but highlight a specific impairment of the neurovascular unit linked to intrathecal production of CXCL8.

SARS-CoV-2 is the trigger of MIS-C, which suggests that other viruses may trigger different forms of Kawasaki disease. The discovery of inborn errors of immunity underlying MIS-C would facilitate that of inborn errors of immunity to viruses underlying Kawasaki disease., Multisystem inflammatory syndrome in children (MIS-C) emerged in April 2020 in communities with high COVID-19 rates. This new condition is heterogenous but resembles Kawasaki disease (KD), a well-known but poorly understood and clinically heterogenous pediatric inflammatory condition for which weak associations have been found with a myriad of viral illnesses. Epidemiological data clearly indicate that SARS-CoV-2 is the trigger for MIS-C, which typically occurs about 1 mo after infection. These findings support the hypothesis of viral triggers for the various forms of classic KD. We further suggest that rare inborn errors of immunity (IEIs) altering the immune response to SARS-CoV-2 may underlie the pathogenesis of MIS-C in some children. The discovery of monogenic IEIs underlying MIS-C would shed light on its pathogenesis, paving the way for a new genetic approach to classic KD, revisited as a heterogeneous collection of IEIs to viruses.

BACKGROUND: Ex vivo whole blood stimulation assays (WBSA) have been used to characterize the cytokine response to diet in cats. The present study aimed to use this assay to determine the cytokine response to diets being fed at the time of diagnosis to dogs with chronic enteropathy (CE) and to compare this to a control group of dogs presented for non-gastrointestinal (GI) causes.RESULTS: Dogs with chronic GI signs and dogs presented for non-GI causes were prospectively recruited. For each case, residual blood following diagnostic sampling was placed into heparin. WBSAs were performed using crude extracts of the diet currently being fed and provided by the owner. Supernatants were collected and analyzed for tumor necrosis factor (TNF)-alpha, interleukin (IL)-10 and IL-4 using an enzyme-linked immunosorbent assay. The case group consisted of 22 dogs with CE diagnosed on histopathology of GI biopsy and 9 with suspected CE. The non-GI group consisted of 18 dogs. Of the diets being fed at or prior to diagnosis, hydrolyzed protein diets elicited significantly lower IL-10 and TNF-alpha concentrations compared to commercial intact protein diets in dogs with confirmed or suspected CE (P-value 0.004 and CONCLUSIONS: Hydrolyzed protein diets elicited a significantly reduced cytokine response when incubated with patient whole blood ex vivo compared to commercial intact protein diets in dogs with CE. The IL-4 to IL-10 ratio as a marker of dietary responsiveness warrants further investigation, together with assessment of the cytokine response to diet at the intestinal mucosal surface.

Early response to first-line antipsychotic treatments is strongly associated with positive long-term symptomatic and functional outcome in psychosis. Unfortunately, attempts to identify reliable predictors of treatment response in first-episode psychosis (FEP) patients have not yet been successful. One reason for this could be that FEP patients are highly heterogeneous in terms of symptom expression and underlying disease biological mechanisms, thereby impeding the identification of one-size-fits-all predictors of treatment response. We have used a clustering approach to stratify 325 FEP patients into four clinical subtypes, termed C1A, C1B, C2A and C2B, based on their symptoms assessed using the Positive and Negative Syndrome Scale (PANSS) scale. Compared to C1B, C2A and C2B patients, those from the C1A subtype exhibited the most severe symptoms and were the most at risk of being non-remitters when treated with the second-generation antipsychotic drug amisulpride. Before treatment, C1A patients exhibited higher serum levels of several pro-inflammatory cytokines and inflammation-associated biomarkers therefore validating our stratification approach on external biological measures. Most importantly, in the C1A subtype, but not others, lower serum levels of interleukin (IL)-15, higher serum levels of C-X-C motif chemokine 12 (CXCL12), previous exposure to cytomegalovirus (CMV), use of recreational drugs and being younger were all associated with higher odds of being non-remitters 4 weeks after treatment. The predictive value of this model was good (mean area under the curve (AUC) = 0.73 ± 0.10), and its specificity and sensitivity were 45 ± 0.09% and 83 ± 0.03%, respectively. Further validation and replication of these results in clinical trials would pave the way for the development of a blood-based assisted clinical decision support system in psychosis. ispartof: Translational Psychiatry vol:9 issue:1 pages:1-20 ispartof: location:United States status: published

Compared to adults, children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have predominantly mild or asymptomatic infections, but the underlying immunological differences remain unclear. Here, we describe clinical features, virology, longitudinal cellular, and cytokine immune profile, SARS-CoV-2-specific serology and salivary antibody responses in a family of two parents with PCR-confirmed symptomatic SARS-CoV-2 infection and their three children, who tested repeatedly SARS-CoV-2 PCR negative. Cellular immune profiles and cytokine responses of all children are similar to their parents at all timepoints. All family members have salivary anti-SARS-CoV-2 antibodies detected, predominantly IgA, that coincide with symptom resolution in 3 of 4 symptomatic members. Plasma from both parents and one child have IgG antibody against the S1 protein and virus-neutralizing activity detected. Using a systems serology approach, we demonstrate higher levels of SARS-CoV-2-specific antibody features of these family members compared to healthy controls. These data indicate that children can mount an immune response to SARS-CoV-2 without virological confirmation of infection, raising the possibility that immunity in children can prevent the establishment of SARS-CoV-2 infection. Relying on routine virological and serological testing may not identify exposed children, with implications for epidemiological and clinical studies across the life-span., Children with SARS-CoV-2 infection are more likely to have mild symptoms and may be asymptomatic, but underlying reasons remain unclear. Here, the authors show cellular, cytokine and antibody response to SARS-CoV-2 infection in three children who repeatedly tested negative for the virus by PCR, despite high exposure in the household.

In the present study, we have quantified the effects of transport, relocation and acclimate/adapt to their new surroundings on female squirrel monkey. These responses are measured in blood samples obtained from squirrel monkeys, at different time points relative to their relocation from their old home to their new home. A group of squirrel monkeys we transported, by truck, for approximately 10 hours. Peripheral blood mononuclear cells (PBMCs) were assayed in order to evaluate the phenotype of lymphocyte subsets by flow, mitogen-specific immune responses of PBMCs in vitro, and levels of cytokines at various time points including immediately before transport, immediately upon arrival, and after approximately 150 days of acclimation. We observed significant changes in T cells and subsets, NK and B cells (CD4+, CD8+, CD4+/CD8+, CD16+, and CD20+). Mitogen specific (e.g. PHA, PWM and LPS) proliferation responses, IFN-γ by ELISPOT assay, and cytokines (IL-2, IL-4 and VEGF) significant changes were observed. Changes seen in the serum chemistry measurements mostly complement those seen in the hematology data. The specific goal was to empirically assess the effects of relocation stress in squirrel monkeys in terms of changes in the numbers and functions of various leukocyte subsets in the blood and the amount of time required for acclimating to their new environment. Such data will help to determine when newly arrived animals become available for use in research studies.

AIM: To investigate markers of systemic inflammation in pre- and postmenopausal women and identify possible predictors of systemic inflammation with menopause.METHODS: Cross-sectional study of 69 healthy women between 45- and 60 years. Blood samples were collected to assess leukocyte subsets and plasma cytokines. MRI and DXA scans were performed to assess body composition. Through uni- and multivariate analyses, follicle-stimulating hormone (FSH), visceral fat mass and age were evaluated as predictors of systemic inflammation in relation to menopause.RESULTS: Postmenopausal women tended to have higher leukocyte counts (5.4 x109 vs. 4.9 x109 cells/l, p = 0.05) reflected in increased total lymphocytes (1.8 x109 vs. 1.6 x109 cells/l, p = 0.01) and monocytes (0.5 x109 vs. 0.4 x109 cells/l, p = 0.02), compared to premenopausal women. Increased visceral fat mass was a strong predictor of high leukocyte subsets. Postmenopausal women had higher plasma TNF-α (2.24 vs. 1.91 pg/ml, p = 0.01) and IL-6 (0.45 vs. 0.33 pg/ml, p = 0.004) compared to premenopausal women and high FSH was a significant predictor of increased plasma TNF-α, IL-1β and IL-6. Menopause was further associated with increased T-cells (1,336 vs. 1,128 cells/μl, p = 0.04) reflected in significantly higher counts of exhausted-, senescent-, and memory CD4+ T-cell subsets.CONCLUSIONS: Menopause is associated with increased systemic inflammation as well as exhausted- and senescent T-cells. We suggest, that both increased visceral fat mass and declining sex hormone levels might contribute to postmenopausal systemic inflammation and calls for further large-scale studies to confirm these findings.

Several studies have shown increased in vitro cytokine responses to non-related pathogens after Bacillus Calmette-Guérin (BCG) vaccination. A total of 158 infants (80 BCG administered within 7 days of birth; 78 controls) were bled 4 days post-randomization, and at age 3 and 13 months. Geometric mean concentrations of IL-1β, TNF-α, IL-6 (24 h stimulation) and IFN-γ, IL-10, IL-17, IL-22 (96 h stimulation) in response to in vitro stimulation with RPMI, LPS, PHA, Escherichia coli, Streptococcus pneumoniae, Candida albicans and BCG were compared among BCG vaccinated children and controls. BCG vaccination did not affect in vitro cytokine production, except IFN-γ and IL-22 response to BCG. Stratifying for 'age at randomization' we found a potentiating effect of BCG on cytokine production (TNF-α, IL-6, IL-10) in the 4 days post randomization stimulations, among children who were vaccinated at age 2-7 days versus age 0-1 days. BCG vaccination did not potentiate cytokine production to non-BCG antigens. At 4 days post randomization, BCG was associated with higher cytokine production in the later randomized children.

It would be desirable to be able to distinguish fever as a result of febrile non-haemolytic transfusion reactions (FNHTR) from other febrile conditions. To further characterize the inflammatory feature of FNHTR, we measured a large panel of inflammatory markers in pre- and posttransfusion plasma samples from patients with and without FNHTR following the transfusion of leucoreduced red blood cells. As FNHTR patients only displayed a significant increase in IL-6, we conclude that changes in plasma cytokine levels during FNHTR are unlikely to be used diagnostically. An incidental finding of a distinct cytokine pattern in pretransfusion samples from FNHTR patients warrants further investigations, as it might be used to characterize the nature of FNHTR and to predict the risk of these adverse events.

International audience; Until recently, hematopoietic stem cell transplantation was the only curative option for Wiskott-Aldrich syndrome (WAS). The first attempts at gene therapy for WAS using a Upsilon-retroviral vector improved immunological parameters substantially but were complicated by acute leukemia as a result of insertional mutagenesis in a high proportion of patients. More recently, treatment of children with a state-of-the-art self-inactivating lentiviral vector (LV-w1.6 WASp) has resulted in significant clinical benefit without inducing selection of clones harboring integrations near oncogenes. Here, we describe a case of a presplenectomized 30-year-old patient with severe WAS manifesting as cutaneous vasculitis, inflammatory arthropathy, intermittent polyclonal lymphoproliferation, and significant chronic kidney disease and requiring long-term immunosuppressive treatment. Following reduced-intensity conditioning, there was rapid engraftment and expansion of a polyclonal pool of transgene-positive functional T cells and sustained gene marking in myeloid and B-cell lineages up to 20 months of observation. The patient was able to discontinue immunosuppression and exogenous immunoglobulin support, with improvement in vasculitic disease and proinflammatory markers. Autologous gene therapy using a lentiviral vector is a viable strategy for adult WAS patients with severe chronic disease complications and for whom an allogeneic procedure could present an unacceptable risk. This trial was registered at www.clinicaltrials.gov as #NCT01347242.

Historically, connexin hemichannels have been considered as structural precursors of gap junctions. However, accumulating evidence points to independent roles for connexin hemichannels in cellular signaling by connecting the intracellular compartment with the extracellular environment. Unlike gap junctions, connexin hemichannels seem to be mainly activated in pathological processes. The present study was set up to test the potential involvement of hemichannels composed of connexin32 and connexin43 in acute hepatotoxicity induced by acetaminophen. Prior to this, in vitro testing was performed to confirm the specificity and efficiency of TAT-Gap24 and TAT-Gap19 in blocking connexin32 and connexin43 hemichannels, respectively. Subsequently, mice were overdosed with acetaminophen followed by treatment with TAT-Gap24 or TAT-Gap19 or a combination of both after 1.5 hour. Sampling was performed 3, 6, 24 and 48 hours following acetaminophen administration. Evaluation of the effects of connexin hemichannel inhibition was based on a series of clinically relevant read-outs, measurement of inflammatory cytokines and oxidative stress. Subsequent treatment of acetaminophen-overdosed mice with TAT-Gap19 only marginally affected liver injury. In contrast, a significant reduction in serum alanine aminotransferase activity was found upon administration of TAT-Gap24 to intoxicated animals. Furthermore, co-treatment of acetaminophen-overdosed mice with both peptides revealed an additive effect as even lower serum alanine aminotransferase activity was observed. Blocking of connexin32 or connexin43 hemichannels individually was found to decrease serum quantities of pro-inflammatory cytokines, while no effects were observed on the occurrence of hepatic oxidative stress. This study shows for the first time a role for connexin hemichannels in acetaminophen-induced acute liver failure.

Non-alcoholic steatohepatitis is a highly prevalent liver pathology featured by hepatocellular fat deposition and inflammation. Connexin32, which is the major building block of hepatocellular gap junctions, has a protective role in hepatocarcinogenesis and is downregulated in chronic liver diseases. However, the role of connexin32 in non-alcoholic steatohepatitis remains unclear. Connexin32 −/− mice and their wild-type littermates were fed a choline-deficient high-fat diet. The manifestation of non-alcoholic steatohepatitis was evaluated based on a battery of clinically relevant read-outs, including histopathological examination, diverse indicators of inflammation and liver damage, in-depth lipid analysis, assessment of oxidative stress, insulin and glucose tolerance, liver regeneration and lipid-related biomarkers. Overall, more pronounced liver damage, inflammation and oxidative stress were observed in connexin32 −/− mice compared to wild-type animals. No differences were found in insulin and glucose tolerance measurements and liver regeneration. However, two lipid-related genes, srebf1 and fabp3, were upregulated in Cx32 −/− mice in comparison with wild-type animals. These findings suggest that connexin32-based signalling is not directly involved in steatosis as such, but rather in the sequelae of this process, which underlie progression of non-alcoholic steatohepatitis.

Systems biology can unravel complex biology but has not been extensively applied to human newborns, a group highly vulnerable to a wide range of diseases. We optimized methods to extract transcriptomic, proteomic, metabolomic, cytokine/chemokine, and single cell immune phenotyping data from, SCOPUS: ar.j, info:eu-repo/semantics/published

Solid organ transplantation (SOT) is a well-established and life-saving treatment for patients with end-stage organ failure. Organ rejection and infections are among the main complications to SOT and largely determines the clinical outcome. The correct level of immunosuppression is of major importance to prevent these complications. However, it is a consistent observation that in recipients on the same immunosuppressive regimens the clinical outcome varies, and no reliable marker exists to monitor immune function. In a prospective, observational study, we plan to enroll 630 adult patients with a planned organ transplantation at Rigshospitalet, University of Copenhagen, Denmark. Prior to and on different time points up to two years after transplantation we will perform a complete immunological profile on the recipients. This profile will consist of classical descriptive immune phenotyping (flow cytometry and circulating biomarkers) and the functional assay TruCulture®. In TruCulture® whole blood is incubated ex vivo with stimulants imitating bacterial, viral and fungal infections, where after a panel of selected cytokines is quantified. Clinical data from electronic health records will be obtained from the PERSIMUNE (Centre of Excellence for Personalized Medicine of Infections Complications in Immune Deficiency at Rigshospitalet, Copenhagen) data repository, a warehouse of data generated as part of routine care including vital signs, biochemistry, microbiology, pathology as well as medication, demographics, diagnoses, hospital contacts, surgical procedures and mortality. This will be the first large scale study to determine several aspects of immune function and perform a complete immunological profiling in SOT recipients. It is expected that knowledge generated will provide information to generate prediction models identifying patients at increased risk of infection and/or rejection. If the study is successful, we will subsequently use the generated prediction models to propose personalized immunosuppressive regimens to be tested in future randomized controlled trials. This study has been approved by the Regional ethical committee (H-17024315), the Danish Data Protection Agency (RH-2016-47, RH-2015-04, I-Suite 03605) and the Danish National board of Health (3–3013-1060/1). The trial is retrospectively registered at clinicaltrials.gov ( NCT03847285 ) the 20th February 2019.

Recent evidence suggests that certain vaccines, including Bacillus-Calmette Guérin (BCG), can induce changes in the innate immune system with non-specific memory characteristics, termed ‘trained immunity’. Here we present the results of a randomised, controlled phase 1 clinical trial in 20 healthy male and female volunteers to evaluate the induction of immunity and protective efficacy of the anti-tuberculosis BCG vaccine against a controlled human malaria infection. After malaria challenge infection, BCG vaccinated volunteers present with earlier and more severe clinical adverse events, and have significantly earlier expression of NK cell activation markers and a trend towards earlier phenotypic monocyte activation. Furthermore, parasitemia in BCG vaccinated volunteers is inversely correlated with increased phenotypic NK cell and monocyte activation. The combined data demonstrate that BCG vaccination alters the clinical and immunological response to malaria, and form an impetus to further explore its potential in strategies for clinical malaria vaccine development., Immune activation induces long-term alterations of setpoints, impacting responses to subsequent unrelated stimuli. Here the authors show that volunteers vaccinated with BCG respond to controlled human malaria infection with increased clinical symptoms and an inverse correlation between immune activation markers and parasitemia.

Background and aimsHepatitis C virus (HCV) infection is associated with insulin resistance, which may lead to type 2 diabetes and its complications. Although HCV infects mainly hepatocytes, it may impair insulin sensitivity at the level of uninfected extrahepatic tissues (muscles and adipose tissue). The aim of this study was to assess whether an interferon-free, antiviral therapy may improve HCV-associated hepatic vs. peripheral insulin sensitivity.MethodsIn a single-arm exploratory trial, 17 non-diabetic, lean chronic hepatitis C patients without significant fibrosis were enrolled, and 12 completed the study. Patients were treated with a combination of sofosbuvir/ledipasvir and ribavirin for 12 weeks, and were submitted to a 2-step euglycemic hyperinsulinemic clamp with tracers, together with indirect calorimetry measurement, to measure insulin sensitivity before and after 6 weeks of antivirals. A panel of 27 metabolically active cytokines was analyzed at baseline and after therapy-induced viral suppression.ResultsClamp analysis performed in 12 patients who achieved complete viral suppression after 6 weeks of therapy showed a significant improvement of the peripheral insulin sensitivity (13.1% [4.6-36.7], p = 0.003), whereas no difference was observed neither in the endogenous glucose production, in lipolysis suppression nor in substrate oxidation. A distinct subset of hepatokines, potentially involved in liver-to-periphery crosstalk, was modified by the antiviral therapy.ConclusionPharmacological inhibition of HCV improves peripheral (but not hepatic) insulin sensitivity in non-diabetic, lean individuals with chronic hepatitis C without significant fibrosis.

Background Although trough levels of immunosuppressive drugs are largely used to monitor immunosuppressive therapy after solid organ transplantation, there is still no established tool that allows for a validated assessment of functional degree of immunosuppression or the identification of clinically relevant over- or under-immunosuppression, depending on graft homeostasis. Reliable non-invasive markers to predict biopsy proven acute rejection (BPAR) do not exist. Literature data suggest that longitudinal measurements of immune markers might be predictive of BPAR, but data in children are scarce. We therefore propose an observational prospective cohort study focusing on immune monitoring in children after liver transplantation. We aim to describe immune function in a cohort of children before and during the first year after liver transplantation and plan to investigate how the immune function profile is associated with clinical and laboratory findings. Methods In an international multicenter prospective approach, children with end-stage liver disease who undergo liver transplantation are enrolled to the study and receive extensive immune monitoring before and at 1, 2, 3, 4 weeks and 3, 6, 12 months after transplantation, and whenever a clinically indicated liver biopsy is scheduled. Blood samples are analyzed for immune cell numbers and circulating levels of cytokines, chemokines and factors of angiogenesis reflecting immune cell activation. Statistical analysis will focus on the identification of trajectorial patterns of immune reactivity predictive for systemic non-inflammatory states, infectious complications or BPAR using joint modelling approaches. Discussion The ChilSFree study will help to understand the immune response after pLTx in different states of infection or rejection. It may provide insight into response mechanisms eventually facilitating immune tolerance towards the graft. Our analysis may yield an applicable immune panel for non-invasive early detection of acute cellular rejection, with the prospect of individually tailoring immunosuppressive therapy. The international collaborative set-up of this study allows for an appropriate sample size which is otherwise difficult to achieve in the field of pediatric liver transplantation.

Background Discriminating between autoimmune pancreatitis (AIP), chronic pancreatitis (CP), and pancreatic ductal adenocarcinoma (PDAC) can be challenging. In this retrospective study, levels of serum and tissue cytokines were analyzed as part of the clinical strategy for the preoperative differentiation between AIP and PDAC. The identification of differential cytokine profiles may help to prevent unnecessary surgical resection and allow optimal treatment of these pathologies. Methods To compare the cytokine profiles of AIP, CP, and PDAC patients, serum and pancreatic tissue homogenates were subjected to multiplex analysis of 17 inflammatory mediators. In total, serum from 73 patients, composed of 29 AIP (14 AIP-1 and 15 AIP-2), 17 CP, and 27 PDAC, and pancreatic tissue from 36 patients, including 12 AIP (six AIP-1 and six AIP-2), 12 CP, and 12 PDAC, were analyzed. Results Comparing AIP and PDAC patients’ serum, significantly higher concentrations were found in AIP for interleukins IL-1β, IL-7, IL-13, and granulocyte colony-stimulating factor (G-CSF). G-CSF also allowed discrimination of AIP from CP. Furthermore, once AIP was divided into subtypes, significantly higher serum levels for IL-7 and G-CSF were measured in both subtypes of AIP and in AIP-2 for IL-1β when compared to PDAC. G-CSF and TNF-α were also significantly differentially expressed in tissue homogenates between AIP-2 and PDAC. Conclusions The cytokines IL-1β, IL-7, and G-CSF can be routinely measured in patients’ serum, providing an elegant and non-invasive approach for differential diagnosis. G-CSF is a good candidate to supplement the currently known serum markers in predictive tests for AIP and represents a basis for a combined blood test to differentiate AIP and particularly AIP-2 from PDAC, enhancing the possibility of appropriate treatment. Electronic supplementary material The online version of this article (doi:10.1186/s12967-017-1227-3) contains supplementary material, which is available to authorized users.

Inflammatory cytokines are potential modulators of infarct progression in acute ischaemic stroke, and are therefore possible targets for future treatment strategies. Cytokine studies in animal models of surgically induced stroke may, however, be influenced by the fact that the surgical intervention itself contributes towards the cytokine response. Community-dwelling domestic dogs suffer from spontaneous ischaemic stroke, and therefore, offer the opportunity to study the cytokine response in a noninvasive set-up. The aims of this study were to investigate cytokine concentrations in plasma and cerebrospinal fluid (CSF) in dogs with acute ischaemic stroke and to search for correlations between infarct volume and cytokine concentrations. Blood and CSF were collected from dogs less than 72 h after a spontaneous ischaemic stroke. Infarct volumes were estimated on MRIs. Interleukin (IL)-2, IL-6, IL-8, IL-10 and tumour necrosis factor in the plasma, CSF and brain homogenates were measured using a canine-specific multiplex immunoassay. IL-6 was significantly increased in plasma (P = 0.04) and CSF (P = 0.04) in stroke dogs compared with healthy controls. The concentrations of other cytokines, such as tumour necrosis factor and IL-2, were unchanged. Plasma IL-8 levels correlated significantly with infarct volume (Spearman's r = 0.8, P = 0.013). The findings showed increased concentrations of IL-6 in the plasma and CSF of dogs with acute ischaemic stroke comparable to humans. We believe that dogs with spontaneous stroke offer a unique, noninvasive means of studying the inflammatory processes that accompany stroke while reducing confounds that are unavoidable in experimental models.

BACKGROUND: Despite advances in medicine in head trauma management, traumatic brain injury (TBI) still remains a serious health concern, affecting people regardless of age. It is a leading cause of morbidity and mortality particularly in children and young adults. Therefore, studies are being carried out to try to establish reliable biomarkers to improve the accuracy of TBI diagnosis and associated secondary pathologies.METHODS: Implementation of valid TBI biomarkers could possibly reduce the necessity to use computed cranial tomography (CCT), especially in patients suffering from mild TBI to rule out intracranial bleeding.AIM: This review provides a critical assessment of biomarkers currently under investigation and their clinical value for the diagnosis, treatment and outcome prediction of TBI.

BACKGROUND: Despite advances in medicine in head trauma management, traumatic brain injury (TBI) still remains a serious health concern, affecting people regardless of age. It is a leading cause of morbidity and mortality particularly in children and young adults. Therefore, studies are being carried out to try to establish reliable biomarkers to improve the accuracy of TBI diagnosis and associated secondary pathologies. METHODS: Implementation of valid TBI biomarkers could possibly reduce the necessity to use computed cranial tomography (CCT), especially in patients suffering from mild TBI to rule out intracranial bleeding. AIM: This review provides a critical assessment of biomarkers currently under investigation and their clinical value for the diagnosis, treatment and outcome prediction of TBI.

BACKGROUND: Multiple trauma can lead to posttraumatic complications such as systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), and sepsis. Currently, these complications are monitored using clinical and organ-specific parameters. The immune system is activated by trauma. Cytokines, which are the messenger molecules of this system, can be determined in serum. Furthermore, they are associated with the intensity of the inflammatory and anti-inflammatory reactions. AIM: This review describes clinical studies that measured cytokines such as TNF-α, IL-1β, IL-6, IL-8, and IL-10 to prognosticate posttraumatic complications. On the other hand, IL-6 can be helpful in deciding which primary operation to perform, i.e., external fixator or intramedullary nail. Moreover, IL-6 indicates the strength of the immune reaction. Thereby, it may help in determining the optimal time for secondary surgery.

BACKGROUND: Multiple trauma can lead to posttraumatic complications such as systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), and sepsis. Currently, these complications are monitored using clinical and organ-specific parameters. The immune system is activated by trauma. Cytokines, which are the messenger molecules of this system, can be determined in serum. Furthermore, they are associated with the intensity of the inflammatory and anti-inflammatory reactions.AIM: This review describes clinical studies that measured cytokines such as TNF-α, IL-1β, IL-6, IL-8, and IL-10 to prognosticate posttraumatic complications. On the other hand, IL-6 can be helpful in deciding which primary operation to perform, i.e., external fixator or intramedullary nail. Moreover, IL-6 indicates the strength of the immune reaction. Thereby, it may help in determining the optimal time for secondary surgery.

© 2016, Springer-Verlag Berlin Heidelberg. Pannexins constitute a relatively new family of transmembrane proteins that form channels linking the cytoplasmic compartment with the extracellular environment. The presence of pannexin1 in the liver has been documented previously, where it underlies inflammatory responses, such as those occurring upon ischemia–reperfusion injury. In the present study, we investigated whether pannexin1 plays a role in acute drug-induced liver toxicity. Hepatic expression of pannexin1 was characterized in a mouse model of acetaminophen-induced hepatotoxicity. Subsequently, mice were overdosed with acetaminophen followed by treatment with the pannexin1 channel inhibitor 10Panx1. Sampling was performed 1, 3, 6, 24 and 48 h after acetaminophen administration. Evaluation of the effects of pannexin1 channel inhibition was based on a number of clinically relevant readouts, including protein adduct formation, measurement of aminotransferase activity and histopathological examination of liver tissue as well as on a series of markers of inflammation, oxidative stress and regeneration. Although no significant differences were found in histopathological analysis, pannexin1 channel inhibition reduced serum levels of alanine and aspartate aminotransferase. This was paralleled by a reduced amount of neutrophils recruited to the liver. Furthermore, alterations in the oxidized status were noticed with upregulation of glutathione levels upon suppression of pannexin1 channel opening. Concomitant promotion of regenerative activity was detected as judged on increased proliferating cell nuclear antigen protein quantities in 10Panx1-treated mice. Pannexin1 channels are important actors in liver injury triggered by acetaminophen. Inhibition of pannexin1 channel opening could represent a novel approach for the treatment of drug-induced hepatotoxicity.

Omentin is an adipokine that reportedly protects against cardiometabolic risk. We investigated the relationships between omentin concentrations and subclinical cardiovascular disease in rheumatoid arthritis (RA). Omentin concentrations were measured in 213 (104 black; 109 white) RA patients. Relationships of omentin levels with those of endothelial activation markers, ultrasound determined carotid intima-media thickness and plaque, and matrix metalloproteinase (MMP)-2, -3 and -9 that mediate altered plaque stability, were identified in confounder adjusted multivariate regression models. Omentin concentrations were inversely associated with MMP-3 levels [β = -364 (0.113), p = 0.002]. This relationship was influenced by population origin, RA activity and the erythrocyte sedimentation rate and joint deformity count (interaction p value = 0.009, 0.04, 0.04 and 0.007, respectively). Accordingly, the omentin-MMP-3 concentration relationship was reproduced in white [β (SE) = -0.450 (0.153), p = 0.0004)] but not black patients [β (SE) = -0.099 (0.195), p = 0.6)], in participants with disease remission or mild disease activity [β (SE) = -0.411 (0.139), p = 0.004] but not with moderate or severe RA activity [β (SE) = -0.286 (0.202), p = 0.2], and in those with a small [β (SE) = -0.534 (0.161), p = 0.001] but not large erythrocyte sedimentation rate [-0.212 (0.168), p = 0.2] and without [β (SE) = -0.554 (0.165), p = 0.0001] but not with large joint deformity counts [-0.110 (0.173), p = 0.5]. Omentin levels were unrelated to endothelial activation and atherosclerosis. Among patients with RA, a lack of plaque stabilizing effects by omentin may contribute to the reported link between severe disease and increased cardiovascular risk. The association between concentrations of omentin and MMP-3 is population specific in RA.

Background Malaria and dengue are two of the most common vector-borne diseases in the world, but co-infection is rarely described, and immunologic comparisons of co-infection with mono-infection are lacking. Methodology and Principal Findings We collected symptom histories and blood specimens from subjects in a febrile illness surveillance study conducted in Iquitos and Puerto Maldonado, Peru, between 2002–2011. Nineteen symptoms and 18 immune markers at presentation were compared among those with co-infection with Plasmodium/dengue virus (DENV), Plasmodium mono-infection, and DENV mono-infection. Seventeen subjects were identified as having Plasmodium/DENV co-infection and were retrospectively matched with 51 DENV mono-infected and 44 Plasmodium mono-infected subjects. Those with Plasmodium mono-infection had higher levels of IL-4, IL-6, IL-10, IL-12, IL-13, IL-17A, IFN-γ, and MIP1-α/CCL3 compared with DENV mono-infection or co-infection; those with Plasmodium mono-infection had more cough than those with DENV mono-infection. Subjects with DENV mono-infection had higher levels of TGF-β1 and more myalgia than those with Plasmodium mono-infection. No symptom was more common and no immune marker level was higher in the co-infected group, which had similar findings to the DENV mono-infected subjects. Conclusions/Significance Compared with mono-infection with either pathogen, Plasmodium/DENV co-infection was not associated with worse disease and resembled DENV mono-infection in both symptom frequency and immune marker level., Author Summary Dengue and malaria are two of the most important diseases spread by mosquitoes. Clinical manifestations of both febrile diseases overlap considerably, and either can be fatal. In addition, they are co-endemic in many places throughout the world. Despite this, only a handful of reports of co-infection with dengue virus and Plasmodium species are reported in the literature. Through our febrile surveillance program in the Peruvian Amazon, we were able to retrospectively identify 17 cases of co-infection with dengue virus and Plasmodium. Our study aimed to assess whether co-infection was associated with more symptoms or a different immune response compared with mono-infection alone. To answer this question, we utilized data and blood specimens collected during the acute presentation of these 17 subjects and compared them to a matched group of subjects with either dengue virus mono-infection or Plasmodium mono-infection. Our findings indicate co-infection with both pathogens was not associated with more symptoms and the immune profile of co-infection resembled dengue virus mono-infection more than Plasmodium mono-infection.

Sézary syndrome (SS), an aggressive form of erythrodermic pruritic cutaneous T cell lymphoma (CTCL), from an immunological perspective characterized by increased Th2 cytokine levels, elevated serum IgE and impaired cellular immunity. Not only the clinical appearance but also the hallmark immunological characteristics of SS often share striking similarities with acute flares of atopic dermatitis (AD), a common benign chronic inflammatory skin disease. Given the overlap of several immunological features, the application of similar or even identical therapeutic approaches in certain stages of both diseases may come into consideration. The aim of this review is to compare currently accepted immunological aspects and possible therapeutic targets in AD and SS.

Adipose tissue may release mediators that induce a chronic inflammatory state and alterations in coagulation, which contribute to insulin resistance, atherosclerosis, and thrombosis. We investigated whether inflammatory and/or prothrombotic states exist in obese children and assessed their interrelationship. Sixty-one subjects were recruited, aged between 6 and 16 years, to participate in a cross-sectional study at Children's University Hospital of Geneva. Selected pro/anti-inflammatory cytokines/chemokines and hemostasis parameters were measured in obese children and lean controls. Cardiovascular risk factors in the family were indexed. Fasting glucose level, insulin, prothrombin time (PT), fibrinogen, activated partial thromboplastin time (aPTT), D-dimer, endogenous thrombin potential (ETP), C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-10 (IL-10), interferon-γ-inducible-protein (IP-10), monocyte chemoattractant protein 1 (MCP-1), and interleukin-1 receptor antagonist (IL-1Ra) were measured. We estimated insulin resistance by homeostatic model assessment (HOMA). Anti- (IL-1Ra) and proinflammatory cytokines (MCP-1, IL-6) were significantly increased in obese children in comparison to the control group, even before puberty. Hemostasis was also altered in obese children with a significantly increased fibrinogen level, increased D-dimer, a shortened PT, as well as an increased ETP. No correlation was found between cytokine levels and hemostasis parameters, except for IL-6 and fibrinogen. Obese children present with inflammatory and prothrombotic states as early as 6 years of age and these states are similar in prepubertal and pubertal obese children. The cytokines IL-1Ra and MCP-1 were most significantly increased in obese children. Further investigation is necessary to determine if these cytokines, together with ETP, can reliably predict the development of diabetes and atherosclerosis.

International audience; Sleep disorders are associated with inflammation and sympathetic activation, which are suspected to induce endothelial dysfunction, a key factor in the increased risk of cardiovascular disease. Less is known about the early effects of acute sleep deprivation on vascular function. We evaluated microvascular reactivity and biological markers of endothelial activation during continuous 40 h of total sleep deprivation (TSD) in 12 healthy men (29 +/- 3 yr). The days before [day 1 (D1)] and during TSD (D3), at 1200 and 1800, endothelium-dependent and -independent cutaneous vascular conductance was assessed by iontophoresis of acetylcholine and sodium nitroprusside, respectively, coupled to laser-Doppler flowmetry. At 0900, 1200, 1500, and 1800, heart rate (HR) and instantaneous blood pressure (BP) were recorded in the supine position. At D1, D3, and the day after one night of sleep recovery (D4), markers of vascular endothelial cell activation, including soluble intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, and interleukin-6 were measured from blood samples at 0800. Compared with D1, plasma levels of E-selectin were raised at D3, whereas intercellular adhesion molecule-1 and interleukin-6 were raised at D4 (P < 0.05). The endothelium-dependent and -independent CVC were significantly decreased after 29 h of TSD (P < 0.05). By contrast, HR, systolic BP, and the normalized low-frequency component of HR variability (0.04-0.15 Hz), a marker of the sympathetic activity, increased significantly within 32 h of TSD (P < 0.05). In conclusion, acute exposure to 40 h of TSD appears to cause vascular dysfunction before the increase in sympathetic activity and systolic BP.

Cardiotrophin-1 is a cytokine that induces hypertrophy and dysfunction in cardiomyocytes and has been shown to be increased in hypertensive patients. The objective of this study was to evaluate the association of cardiotrophin-1 with heart failure (HF) in hypertensive patients and its usefulness as a biomarker of stage C heart failure. Hypertensive patients without cardiac abnormalities (stage A, n = 64), with left ventricular hypertrophy (LVH) (stage B, n = 58), and with left ventricular hypertrophy and clinical manifestations of chronic heart failure (stage C, n = 39) were studied. Plasma cardiotrophin-1 was measured by an enzyme-linked inmunosorbent assay. Plasma cardiotrophin-1 progressively increased (P < 0.001), along with progression of heart failure stages, in hypertensive patients. Plasma cardiotrophin-1 was directly (r = 0.416, P < 0.001) and inversely (r = 0.263, P < 0.01) correlated with left ventricular (LV) mass index and ejection fraction, respectively, in all hypertensive patients. These associations were independent of a number of potential confounding factors. Receiver operating characteristic curves showed that a cut-off of 48.72 fmol/ml for cardiotrophin-1 provided higher sensitivity for diagnosing stage C heart failure than a cut-off of 375.54 pg/ml for amino-terminal probrain natriuretic peptide (NT-proBNP) (80% vs. 72%). Sixty-four percent of stage C hypertensive patients with NT-proBNP values below 375.54 pg/ml value exhibited cardiotrophin-1 values above 49.16 fmol/ml. These findings indicate that plasma cardiotrophin-1 is associated with progression of heart failure in hypertensive patients. Cardiotrophin-1 measurement may provide additional information to that afforded by NT-proBNP to diagnose stage C heart failure in these patients.

Liver failure is the major cause of death in alcoholic steatohepatitis (ASH). In experimental hepatitis, granulocyte-colony stimulating factor (G-CSF) mobilizes hematopoietic stem cells, induces liver regeneration, and improves survival. We studied the short-term effects of G-CSF on CD34+ stem cell mobilization, liver cell proliferation, and liver function in patients with ASH. Twenty-four patients (mean age 54 years) with alcoholic cirrhosis [Child-Turcotte-Pugh score 10 (7-12)] and concomitant biopsy-proven ASH [Maddrey score 36 (21-60)] were randomized to standard care associated with 5 days of G-CSF (10 microg/kg/day, group A, n = 13) or standard care alone (group B, n = 11). Serial measurement of CD34+ cells, liver tests, cytokines [hepatocyte growth factor (HGF); tumor necrosis factor alpha; tumor necrosis factor-R1; interleukin-6; alfa-fetoprotein], and (13)C-aminopyrine breath tests were performed. Proliferating hepatic progenitor cells [HPC; double immunostaining (Ki67/cytokeratin 7)], histology, and neutrophils were assessed on baseline and day 7 biopsies. Abstinent alcoholic patients with cirrhosis served as controls for immunohistochemistry. G-CSF was well tolerated. At day 7, both CD34+ cells (+747% versus -6%, P < 0.003), and HGF (+212% versus -7%, P < 0.03) increased in group A but not in group B. Cytokines and aminopyrine breath test changes were similar between groups. On repeat biopsy, a >50% increase in proliferating HPC was more frequent in group A than in group B (11 versus 2, P < 0.003). Changes in Ki67+/cytokeratin 7+ cells correlated with changes in CD34+ cells (r = 0.65, P < 0.03). Neutrophils and histological changes were similar in both groups. CONCLUSION: G-CSF mobilizes CD34+ cells, increases HGF, and induces HPC to proliferate within 7 days of administration. Larger trials would be required to determine whether these changes translate into improved liver function.

Accumulating evidence suggests that periodontal infections may have an impact on systemic health. In patients with untreated periodontitis, very high values for several inflammatory markers in serum are expressed simultaneously. We investigated to what extent these peak values change after nonsurgical and surgical periodontal treatment, with adjunctive antibiotics administered during the first or the second treatment phase. In a single-center, randomized, placebo-controlled, and double-masked clinical trial, 80 patients with chronic or aggressive periodontitis were randomized into 2 treatment groups: group A, receiving systemic amoxicillin and metronidazole during the first, nonsurgical phase of periodontal therapy (phase 1), and group B, receiving the antibiotics during the second, surgical phase (phase 2). Serum samples were obtained at baseline (BL), 3 mo after phase 1 (M3), and 6 and 12 mo after phase 2 (M6, M12). Samples were evaluated for 15 cytokines and 9 acute-phase proteins using the Bio-Plex bead array multianalyte detection system. For each analyte, peak values were defined as greater than mean +2 SD of measurements found in 40 periodontally healthy persons. Sixty-six patients showed a peak value of at least 1 analyte at BL. At M12, the number of these patients was only 36 ( P = 0.0002). This decrease was stronger in group A (BL: 35, M12: 19, P = 0.0009) than in group B (BL: 31, M12: 17, P = 0.14). Twenty patients displayed peak values of at least 4 biomarkers at BL. The nonsurgical therapy delivered in the first phase reduced most of these peaks (group A, BL: 9, M3: 4, P = 0.17; group B, BL: 11, M3: 2, P = 0.01), irrespective of adjunctive antibiotics. The reductions obtained at M3 were maintained until M12 in both groups. Initial, nonsurgical periodontal therapy reduced the incidence of peak levels of inflammatory markers. Antibiotics and further surgical therapy did not enhance the effect ( Clinicaltrials.gov NCT02197260).

Background Interferon (IFN)-β exerts anti-inflammatory effects, coupled to remarkable neurological improvements in multiple sclerosis, a neuroinflammatory condition of the central nervous system. Analogously, it has been hypothesized that IFN-β, by limiting inflammation, decreases neuronal death and promotes functional recovery after stroke. However, the core actions of endogenous IFN-β signaling in stroke are unclear. Methods To address this question, we used two clinically relevant models of focal cerebral ischemia, transient and permanent middle cerebral artery occlusion, and two genetically modified mouse lines, lacking either IFN-β or its receptor, the IFN-α/β receptor. Subsets of inflammatory and immune cells isolated from the brain, blood, and spleen were studied using flow cytometry. Sensorimotor deficits were assessed by a modified composite neuroscore, the rotating pole and grip strength tests, and cerebral infarct volumes were given by lack of neuronal nuclei immunoreactivity. Results Here, we report alterations in local and systemic inflammation in IFN-β knockout (IFN-βKO) mice over 8 days after induction of focal cerebral ischemia. Notably, IFN-βKO mice showed a higher number of infiltrating leukocytes in the brain 2 days after stroke. Concomitantly, in the blood of IFN-βKO mice, we found a higher percentage of total B cells but a similar percentage of mature and activated B cells, collectively indicating a higher proliferation rate. The additional differential regulation of circulating cytokines and splenic immune cell populations in wild-type and IFN-βKO mice further supports an important immunoregulatory function of IFN-β in stroke. Moreover, we observed a significant weight loss 2–3 days and a reduction in grip strength 2 days after stroke in the IFN-βKO group, while endogenous IFN-β signaling did not affect the infarct volume. Conclusions We conclude that endogenous IFN-β signaling attenuates local inflammation, regulates peripheral immune cells, and, thereby, may contribute positively to stroke outcome. Electronic supplementary material The online version of this article (doi:10.1186/s12974-015-0427-0) contains supplementary material, which is available to authorized users.

Objective— We previously demonstrated that subjects with functional ATP-binding cassette ( ABC ) A1 mutations have increased atherosclerosis, which has been attributed to the role of ABCA1 in reverse cholesterol transport. More recently, a proinflammatory effect of Abca1 deficiency was shown in mice, potentially contributing to atherogenesis. In this study, we investigated whether ABCA1 deficiency was associated with proinflammatory changes in humans. Approach and Results— Thirty-one heterozygous, 5 homozygous ABCA1 mutation carriers, and 21 matched controls were studied. 18 Fluorodeoxyglucose positron emission tomography with computed tomographic scanning was performed in a subset of carriers and controls to assess arterial wall inflammation (target:background ratio). Heterozygous ABCA1 mutation carriers had a 20% higher target:background ratio than in controls (target:background ratio; P =0.008). In carriers using statins (n=7), target:background ratio was 21% reduced than in nonstatin users (n=7; P =0.03). We then measured plasma cytokine levels. Tumor necrosis factor α, monocyte chemoattractant protein-1, and interleukin-6 levels were increased in heterozygous and homozygous ABCA1 mutation carriers. We isolated monocytes from carriers and controls and measured inflammatory gene expression. Only TNFα mRNA was increased in monocytes from heterozygous ABCA1 mutation carriers. Additional studies in THP-1 macrophages showed that both ABCA1 deficiency and lipoprotein-deficient plasma from ABCA1 mutation carriers increased inflammatory gene expression. Conclusions— Our data suggest a proinflammatory state in ABCA1 mutation carriers as reflected by an increased positron emission tomography–MRI signal in nonstatin using subjects, and increased circulating cytokines. The increased inflammation in ABCA1 mutation carriers seems to be attenuated by statins.

Soft tissue infections (STIs) occur as a result of the colonization of pathogenic bacteria upon the destruction of normal skin microbial flora and the skin integrity. Streptococci and staphylococci are the most frequent causes of bacterial STIs. Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen are often used in STIs because of their analgesic and antipyretic effects. However, evidence suggests that these drugs might delay both epithelization and angiogenesis in the early phases of wound healing because of an antiproliferative effect. The aim of this study was to investigate the effect of ibuprofen on the wound healing in STIs caused by Staphylococcus aureus in immunosuppressed mice. A total of 120 female Balb/c mice were used in the study and the mice were assigned to four test groups and two control groups. The test groups were defined as follows; B (Bacteria group, n= 23), BI (Bacteria + Ibuprofen group, n= 23), BA (Bacteria + Ampicillin group, n= 23), BIA (Bacteria + Ampicillin + Ibuprofen group, n= 21); and the control groups were defined as follows; S1B2 (only immunosuppressed controls, n= 15) and S2B2 (Sham group). Immunosupression was induced with cyclophosphamide and the experimental infection was generated by subcutaneous inoculation of bacterial suspension (2 x 10(8) cfu/ml) of methicillin-sensitive S.aureus ATCC 25923 to the right hind leg. Ibuprofen was given to the mice by gastric gavage (50 mg/kg/day), and ampicillin (100 mg/kg/day) by intramuscular injection. Wound sizes that appear in the animals were measured on a daily basis. Serum and tissue (epithelial tissue, connective tissue, sebaceous glands, sweat glands) samples were obtained on the first, third and seventh days. The tissue samples were examined histopathologically by hematoxylin-eosin (HE) staining method and IL-1, IL-6, TNF-α and VEGF (Vascular Endothelial Growth Factor) levels were determined in serum samples by ELISA method. The tissue cytokine reactions were also evaluated by immunohistochemical (immunoperoxidase staining) method in tissue samples. In our study, no significant change was detected in the wound sizes of B and BI groups from the second day to the end of study period (p> 0.05). On the other hand the wound dimensions of BA and BIA groups gradually decreased and remained superficial. The average serum levels of TNF-α and IL-1 was detected low in all groups. The mean value of serum IL-6 on the first day in group B was determined to be higher compared to other groups, and when this difference was compared to groups BI and BA, and the control group, it was found statistically significant (p< 0.05). In addition, the VEGF levels which were detected low in all groups in the third day of infection increased significantly at the seventh day. The results of histopathologic and immunohistochemical studies have supported the results of ELISA and yielded similar results with serum cytokine patterns. In conclusion, our data indicated that ibuprofen has no negative effect on the wound healing in soft-tissue infections caused by S.aureus.