Transient Systemic Inflammation Research Articles

Human scent as a first-line defense against disease

Individuals may have a different body odor, when they are sick compared to healthy. In the non-human animal literature, olfactory cues have been shown to predict avoidance of sick individuals. We tested whether the mere experimental activation of the innate immune system in healthy human individuals can make an individuals’ body odor be perceived as more aversive (intense, unpleasant, and disgusting). Following an endotoxin injection (lipopolysaccharide; 0.6 ng/kg) that creates a transient systemic inflammation, individuals smelled more unpleasant compared to a placebo group (saline injection). Behavioral and chemical analyses of the body odor samples suggest that the volatile components of samples from “sick” individuals changed qualitatively rather than quantitatively. Our findings support the hypothesis that odor cues of inflammation in axillary sweat are detectable just a few hours after experimental activation of the innate immune system. As such, they may trigger behavioral avoidance, hence constituting a first line of defense against pathogens of infected conspecifics.

Cognitive Impairments in Patients with Bronchial Asthma.

The course of bronchial asthma can be accompanied by cognitive impairments. However, the relationship between cognitive dysfunction and asthma has not been fully revealed, nor has it been fully established what causes cognitive impairments in patients with asthma. There is an opinion that transient hypoxia and persistent systemic inflammation with insufficient control of bronchial asthma can be accompanied by neurotoxicity in relation to the hippocampus and indirectly lead to deterioration of cognitive functions. Comorbid conditions, such as obesity, allergic rhinitis, and depressive states can increase cognitive dysfunction in asthmatics. The review considers the pathophysiology of cognitive dysfunction in patients with bronchial asthma, as well as the impact of comorbid conditions on the cognitive status. This information will allow systematizing the available knowledge about the state of cognitive functions in asthma for timely detection and correction of their impairments and, ultimately, optimization of the management of these patients.

A Transient Inflammatory Response Induced by Lipopolysaccharide Infusion Lowers Markers of Endogenous Cholesterol and Bile Acid Synthesis in Healthy Normocholesterolemic Young Men.

Inflammation is associated with changes in plasma lipids, lipoproteins, and cholesterol efflux capacity (CEC). It is unknown if the changes in lipids and lipoproteins during inflammation are related to changes in cholesterol absorption, synthesis, and bile acid synthesis. We, therefore, examined the effects of acute lipopolysaccharide (LPS)-induced transient systemic inflammation on lipids, lipoproteins, CEC, and markers of cholesterol metabolism. We also evaluated whether markers for cholesterol metabolism at baseline predict the intensity of the inflammatory response. Eight healthy young subjects received LPS infusion, and blood was sampled for the following 24 h. In addition to lipids, lipoproteins, and CEC, we also measured markers for cholesterol absorption and synthesis, bile acid synthesis, and inflammation. Compared with baseline, plasma total cholesterol, low-density lipoprotein cholesterol, and CEC decreased, while triglycerides increased in the 24 h following LPS infusion. TC-standardized levels of cholesterol synthesis markers (lathosterol, lanosterol, and desmosterol) and a bile acid synthesis marker (7α-OH-cholesterol) also decreased, with no changes in cholesterol absorption markers (campesterol, sitosterol, and cholestanol). Baseline TC-standardized levels of desmosterol and 7α-OH-cholesterol were positively correlated with concentrations of various inflammatory markers. Changes in TC-standardized desmosterol and 7α-OH-cholesterol were negatively correlated with concentrations of inflammatory markers. LPS infusion reduced endogenous cholesterol synthesis and bile acid synthesis in healthy young men.

Abstract 517: Tebentafusp induces transient systemic inflammation and modifies the micro-environment to sensitize uveal melanoma tumors to cytotoxic CD8 cells

Abstract Background: Tebentafusp is a unique investigational TCR-anti-CD3 bispecific fusion protein that targets melanoma-expressed gp100 antigen and has shown monotherapy activity in advanced metastatic melanoma [1, 2, 3]. In a phase I/II trial (NCT02570308) that enrolled late stage metastatic uveal melanoma patients, we explored the effects of tebentafusp on serum cytokines and on the tumor and its micro-environment. Methods: NCT02570308 was conducted in HLA-A*02:01+ patients with advanced uveal melanoma: This analysis focuses on patients who went through weekly dosing at Cycle 1, Day1 (C1D1, 20mcg) and C1D8 (30mcg), followed by a dose of 68mcg administered weekly at C1D15 onwards. Serum samples and tumor biopsies were taken pre-treatment and at multiple time points post-treatment, and were profiled as follows: a multiplex panel of 11 immune markers (Luminex) in sera from 124 patients; immunohistochemistry (IHC) and genome-wide transcriptional RNAseq analysis of up to 57 paired baseline and on-treatment biopsies at C1D16. Whole slide digital image analysis was used to calculate positive IHC cells per mm2 in the tumor. Results: Tebentafusp caused transient immune activation as evidenced by significant increases in serum levels of IFNγ and IFNγ-inducible chemokines including CXCL9/10/11 reaching maximal changes at 8-24 hours after dosing (fold change FC: 8-10). Induction of the T cell cytokines IL-2 and IL-10 was accompanied by transient increases in the inflammatory cytokines IL-6, TNFα and the chemokine CCL2 (FC: 5-14).After 3 doses of tebentafusp, a significant increase in CD3 positive immune cells in the tumor was seen (p<0.001; FC=3), particularly cytotoxic CD8+ cells, (p=0.002; FC=2). RNAseq analysis revealed significant induction of IFNα (FC=2) and IFNγ (FC=2) signatures. mRNAs known to be induced by IFNγ and implicated in response to anti-PD1/L1 were significantly increased: CXCL9/10/11, GZMB (FC=3-5). Expression of antigen presentation genes including HLA class 1, TAP1, 2 and PSMB8 was significantly induced (FC=2-3). Homeostasis mechanisms characterized by IDO1 and PD-L1 were induced (FC=4 and 2 respectively); however, low baseline FOXP3 expression levels were unchanged. These immune responses were accompanied by significant reductions in expression levels of tumor-specific melanoma markers gp100 and TYRP1 (30-40% reduction) and tumor proliferation genes including MKI67, BIRC5, CDK2 (20-30% reduction). Conclusions: Tebentafusp caused transient increases in inflammatory cytokines and chemokines in serum and modified the micro-environment of metastatic uveal melanoma tumors to sensitize to cytotoxic CD8+ cells.[1] NCT01211262; ASCO 2019 [2] Clinical Cancer Research; 2020.[3] #195; ESMO IO; 2020 Citation Format: Marcus O. Butler, Sarah Stanhope, Revashnee Naidoo, Emma Leach, Sarnjeet Kaur, Laura Collins, Shaad Abdullah, Koustubh Ranade, Alexander N. Shoushtari. Tebentafusp induces transient systemic inflammation and modifies the micro-environment to sensitize uveal melanoma tumors to cytotoxic CD8 cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 517.

Inhibition of early plasmin activation following thermal injury attenuates systemic inflammatory markers and inflammation within injured muscle

Introduction Burn injuries drive systemic inflammation, increasing the risk of organ dysfunction, and impeding the repair of injured tissues. Traumatic injuries provoke excess activation of plasmin, the protease responsible for degrading fibrin clots, causing bleeding complications. Although burn injuries rarely carry bleeding risks, excess plasmin activity can drive inflammatory signaling and vascular permeability, suggesting plasmin contributes to burn-induced inflammation. Therefore, we hypothesized that excess plasmin activation provoked by burn injury exacerbates inflammation at the site of tissue injury and systemically. Methods A validated, murine burn model in combination with muscle injury was employed to assess the study hypothesis. Sham animals received only calf muscle injuries. Mice expressing an NF-κB-inducible luciferase reporter were used to quantify inflammatory signaling by bioluminescence in tissues. To inhibit plasmin activity, mice received plasminogen antisense oligonucleotide (Plg ASO, IONIS Pharmaceuticals) before injury, or antifibrinolytic drug tranexamic acid (TXA) administered for 12 hours post-burn. Controls received control (Ctl) ASO or saline. Plasmin activation was measured by circulating complexes of plasmin and its inhibitor α2-antiplasmin (PAP). Inflammation was measured serially by plasma interleukin-6 (IL-6), neutrophil to lymphocyte ratio (NLR), and NF-κB activity in the injured muscle. Results Burn injury resulted in a 3-5 fold increase in plasmin activity measured by PAP(P<0.05) compared with sham animals and provoked a significant increase in plasma IL-6(P<0.005) and NLR(P<0.05) within 6-12 hours post-injury, at levels consistent with transient systemic inflammation. In mice without burns, muscle injury alone provoked NF-κB activity from 1-3 days post-injury with resolution by 5 days. With the addition of the burn injury, NF-κB activity within the injured calf muscle was significantly elevated between 1-3 days post-injury (P<0.01) and prolonged in the injured muscle (Figure 1). When plasmin was reduced with Plg ASO and TXA treatments, plasma IL-6 and NLR levels were reduced within 24 hours post-burn (P<0.05), and NF-κB activity within muscle was significantly reduced between 1-3 days post-burn (P<0.05)(Figure 1). Conclusion Burns provoke systemic and augment local inflammation in a muscle injury remote to the burn site. Inhibition of early plasmin activation after burn reduces systemic inflammatory markers and local inflammation within injured tissues. Significance Burn injuries incite significant global inflammation, increasing the risk of life-threatening complications, and chronic comorbidities. Because plasma drives inflammation after acute injury, it may be a therapeutic target to reduce tissue inflammation. However, plasmin is essential for fibrinolysis and tissue repair, and the beneficial effects of inhibiting plasmin following burn are likely time-dependent.

Transient systemic inflammation in adult male mice results in underweight progeny.

While the testes represent an immune-privileged organ, there is evidence that systemic inflammation is accompanied by local inflammatory responses. We therefore examined whether transient systemic inflammation caused any inflammatory and functional consequences in murine testes. Using a single systemic administration of Toll-like receptor (TLR) agonists [lipopolysaccharide (LPS) or peptidoglycan (PG) or polyinosinic-polycytidylic acid (polyIC)] in young adult male mice, we assessed testicular immune-inflammatory landscape and reproductive functionality. Our findings demonstrated a significant induction of testicular TNF-α, IL-1β and IL-6 transcripts within 24h of TLR agonist injection. By day 6, these cytokine levels returned to baseline. While there was no change in caudal sperm counts at early time points, eight weeks later, twofold decrease in sperm count and reduced testicular testosterone levels were evident. When these mice were subjected to mating studies, no differences in mating efficiencies or litter sizes were observed compared with controls. Nonetheless, the neonatal weights of progeny from LPS/PG/polyIC-treated sires were significantly lower than controls. Postnatal weight gain up to three weeks was also slower in the progeny of LPS/polyIC-treated sires. Placental weights at 17.5days post-coitum were significantly lower in females mated to LPS- and polyIC-treated males. Given this likelihood of an epigenetic effect, we found lower testicular levels of histone methyltransferase enzyme, mixed-lineage leukaemia-1, in mice given LPS/PG/polyIC 8weeks earlier. Exposure to transient systemic inflammation leads to transient local inflammation in the testes, with persistent sperm-mediated consequences for foetal development.

Improved oral hygiene care is associated with decreased risk of occurrence for atrial fibrillation and heart failure: A nationwide population-based cohort study.

Poor oral hygiene can provoke transient bacteremia and systemic inflammation, a mediator of atrial fibrillation and heart failure. This study aims to investigate association of oral hygiene indicators with atrial fibrillation and heart failure risk in Korea. We included 161,286 subjects from the National Health Insurance System-Health Screening Cohort who had no missing data for demographics, past history, or laboratory findings. They had no history of atrial fibrillation, heart failure, or cardiac valvular diseases. For oral hygiene indicators, presence of periodontal disease, number of tooth brushings, any reasons of dental visit, professional dental cleaning, and number of missing teeth were investigated. During median follow-up of 10.5 years, 4911 (3.0%) cases of atrial fibrillation and 7971 (4.9%) cases of heart failure occurred. In multivariate analysis after adjusting age, sex, socioeconomic status, regular exercise, alcohol consumption, body mass index, hypertension, diabetes, dyslipidemia, current smoking, renal disease, history of cancer, systolic blood pressure, blood and urine laboratory findings, frequent tooth brushing (≥3 times/day) was significantly associated with attenuated risk of atrial fibrillation (hazard ratio: 0.90, 95% confidence interval (0.83-0.98)) and heart failure (0.88, (0.82-0.94)). Professional dental cleaning was negatively (0.93, (0.88-0.99)), while number of missing teeth ≥22 was positively (1.32, (1.11-1.56)) associated with risk of heart failure. Improved oral hygiene care was associated with decreased risk of atrial fibrillation and heart failure. Healthier oral hygiene by frequent tooth brushing and professional dental cleaning may reduce risk of atrial fibrillation and heart failure.

Evidence of a wide gap between COVID-19 in humans and animal models: a systematic review

BackgroundAnimal models of COVID-19 have been rapidly reported after the start of the pandemic. We aimed to assess whether the newly created models reproduce the full spectrum of human COVID-19.MethodsWe searched the MEDLINE, as well as BioRxiv and MedRxiv preprint servers for original research published in English from January 1 to May 20, 2020. We used the search terms (COVID-19) OR (SARS-CoV-2) AND (animal models), (hamsters), (nonhuman primates), (macaques), (rodent), (mice), (rats), (ferrets), (rabbits), (cats), and (dogs). Inclusion criteria were the establishment of animal models of COVID-19 as an endpoint. Other inclusion criteria were assessment of prophylaxis, therapies, or vaccines, using animal models of COVID-19.ResultThirteen peer-reviewed studies and 14 preprints met the inclusion criteria. The animals used were nonhuman primates (n = 13), mice (n = 7), ferrets (n = 4), hamsters (n = 4), and cats (n = 1). All animals supported high viral replication in the upper and lower respiratory tract associated with mild clinical manifestations, lung pathology, and full recovery. Older animals displayed relatively more severe illness than the younger ones. No animal models developed hypoxemic respiratory failure, multiple organ dysfunction, culminating in death. All species elicited a specific IgG antibodies response to the spike proteins, which were protective against a second exposure. Transient systemic inflammation was observed occasionally in nonhuman primates, hamsters, and mice. Notably, none of the animals unveiled a cytokine storm or coagulopathy.ConclusionsMost of the animal models of COVID-19 recapitulated mild pattern of human COVID-19 with full recovery phenotype. No severe illness associated with mortality was observed, suggesting a wide gap between COVID-19 in humans and animal models.

Improved oral hygiene is associated with decreased risk of new-onset diabetes: a nationwide population-based cohort study.

Inflammation plays an important role in the development of diabetes, a major global health problem. Periodontal disease is also common in the general population. Because periodontal disease and poor oral hygiene can provoke transient bacteraemia and systemic inflammation, we hypothesised that periodontal disease and oral hygiene indicators would be associated with the occurrence of new-onset diabetes. In this study we analysed data collected between 2003 and 2006 on 188,013 subjects from the National Health Insurance System-Health Screening Cohort (NHIS-HEALS) in Korea who had no missing data for demographics, past medical history, oral hygiene indicators or laboratory findings. The presence of periodontal disease was defined on the basis of a modified version of ICD-10 codes (Korean Classification of Disease, sixth edition), if claims for treatment for acute periodontitis (K052), chronic periodontitis (K053) and periodontosis (K054) were made more than two times by a dentist, or if, according to medical records, subjects received treatment by a dentist for periodontal disease with ICD-10 codes K052, K053 or K054. Oral hygiene behaviours (number of tooth brushings, a dental visit for any reason and professional dental cleaning) were collected as self-reported data of dental health check-ups. Number of missing teeth was ascertained by dentists during oral health examination. The incidence of new-onset diabetes was defined according to ICD-10 codes E10-E14. The criterial included at least one claim per year for both visiting an outpatient clinic and admission accompanying prescription records for any glucose-lowering agent, or was based on a fasting plasma glucose ≥7mmol/l from NHIS-HEALS. Of the included subjects, 17.5% had periodontal disease. After a median follow-up of 10.0years, diabetes developed in 31,545 (event rate: 16.1%, 95% CI 15.9%, 16.3%) subjects. In multivariable models, after adjusting for demographics, regular exercise, alcohol consumption, smoking status, vascular risk factors, history of malignancy and laboratory findings, the presence of periodontal disease (HR 1.09, 95% CI 1.07, 1.12, p < 0.001) and number of missing teeth (≥15 teeth) remained positively associated with occurrence of new-onset diabetes (HR 1.21, 95% CI 1.09, 1.33, p < 0.001, p for trend <0.001). Frequent tooth brushing (≥3 times/day) was negatively associated with occurrence of new-onset diabetes (HR 0.92, 95% CI 0.89, 0.95, p < 0.001, p for trend <0.001). Frequent tooth brushing may be an attenuating factor and the presence of periodontal disease and an increased number of missing teeth may be augmenting factors for the occurrence of new-onset diabetes. Improving oral hygiene may be associated with a decreased risk of occurrence of new-onset diabetes.

Safety, toxicity and immunogenicity of a malaria vaccine based on the circumsporozoite protein (FMP013) with the adjuvant army liposome formulation containing QS21 (ALFQ)

Antibodies to Circumsporozoite protein (CSP) confer protection against controlled human malaria infection (CHMI) caused by the parasite Plasmodium falciparum. Although CSP is highly immunogenic, it does not induce long lasting protection and efforts to improve CSP-specific immunological memory and duration of protection are underway. We have previously reported that the clinical grade CSP vaccine FMP013 was immunogenic and protective against malaria challenge in mice when combined with the Army Liposomal Formulation adjuvant containing immune modulators 3D-PHAD™ and QS21 (ALFQ). To move forward with clinical evaluation, we now report the safety, toxicity and immunogenicity of clinical grade FMP013 and ALFQ in Rhesus macaques. Three groups of Rhesus (n = 6) received half or full human dose of FMP013 + ALFQ on a 0-1-2 month schedule, which showed mild local site reactions with no hematologic derangements in red blood cell homeostasis, liver function or kidney function. Immunization induced a transient systemic inflammatory response, including elevated white blood cell counts, mild fever, and a few incidences of elevated creatine kinase, receding to normal range by day 7 post vaccination. Optimal immunogenicity in Rhesus was observed using a 1 mL ALFQ + 20 µg FMP013 dose. Doubling the FMP013 antigen dose to 40 µg had no effect while halving the ALFQ adjuvant dose to 0.5 mL lowered immunogenicity. Similar to data generated in mice, FMP013 + ALFQ induced serum antibodies that reacted to all regions of the CSP molecule and a Th1-biased cytokine response in Rhesus. Rhesus antibody response to FMP013 + ALFQ was found to be non-inferior to historical benchmarks including that of RTS,S + AS01 in humans. A four-dose GLP toxicity study in rabbits confirmed no local site reactions and transient systemic inflammation associated with ALFQ adjuvant administration. These safety and immunogenicity data support the clinical progression and testing of FMP013 + ALFQ in a CHMI trial in the near future.

Abstract P2-01-01: Early relapses in breast cancer can be prevented by a perioperative NSAID, which would be a solution to a 2000 year old problem

Abstract A bimodal pattern of hazard of relapse among early stage breast cancer patients has been identified in multiple databases from US, Europe and Asia. We have been studying these data to determine if this can lead to new ideas on how to prevent relapse in breast cancer. Using computer simulation and access to a very high quality database from Milan for patients treated with mastectomy only, we proposed that relapses within 3 years of surgery are stimulated somehow by the surgical procedure. During the week post surgery, metastatic development is enhanced 100 fold according to the simulation. Most relapses in breast cancer are in this early category. Retrospective data from a Brussels anesthesiology group suggested a plausible mechanism. Use of ketorolac, a common NSAID analgesic used in surgery was associated with far superior disease-free survival in the first 5 years after surgery. The expected prominent early relapse events in months 9-18 are reduced 5-fold. Transient systemic inflammation accompanying surgery (identified by IL-6 in serum) could facilitate angiogenesis of dormant micrometastases, proliferation of dormant single cells, and seeding of circulating cancer stem cells resulting in early relapse and could have been effectively blocked by the perioperative anti-inflammatory agent. If this observation holds up to further scrutiny, it could mean that the simple use of this safe, inexpensive and effective anti-inflammatory agent at surgery might eliminate early relapses. Similar bimodal patterns have been identified in other cancers suggesting a general effect. Based on the writings of Galen and Celsus, metastatic development after breast tumors were removed was known to them 2000 years ago. This effect has been demonstrated recently in a mouse model by Krall et al Science Translational Medicine and reviewed in NEJM by Komaroff. In a series of experiments in 273 mice, aggressive mouse breast cancer cells were implanted in various locations. Initially, the tumor cells grew but then became dormant. This dormancy occurred only in mice with intact immunity, which suggests that the immune system can contain certain dormant metastases. Surgery of any type (including resection of a primary tumor) led to aggressive growth of metastases in 60% of animals, compared with 10% of control animals that did not undergo surgery. Surgical procedures caused systemic inflammatory responses. Activated monocytes from the marrow traveled to the sites of the dormant metastases and became tumor associated macrophages. These macrophages suppressed the immune system near the tumor, awakening the metastases from their dormancy. Treating the animals with NSAIDs before and immediately following surgery greatly attenuated growth of these metastases. Since this effect has by now been shown in two Belgian retrospective studies as well as a mouse model we suggest this be tested in one or more clinical trials. We also note that the bleeding potential from using NSAIDs before surgery can apparently be reduced with the use of Tranexamic Acid – currently being tested in a clinical trial for mastectomy. Citation Format: Retsky MW, Baum M, Vaidya JS, Rogers RA, Hrushesky WJ, Demicheli R, Forget P. Early relapses in breast cancer can be prevented by a perioperative NSAID, which would be a solution to a 2000 year old problem [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-01-01.

Does Human Experimental Endotoxemia Impact Negative Cognitions Related to the Self?

A role of inflammatory processes in the pathophysiology of depression is increasingly recognized. Experimental endotoxemia offers an established model to induce transient systemic inflammation in healthy humans, and has been proposed as an experimental paradigm of depression. Indeed, different symptoms of depression can be observed during experimental endotoxemia, including negative mood or dysthymia as key symptoms of depression. Hopelessness and low self-esteem constitute common cognitive symptoms in depression, but have not been specifically assessed during endotoxemia. Thus, we pooled data from healthy volunteers who received low-dose endotoxin (i.e., 0.4 or 0.8 ng/kg lipopolysaccharide, LPS) or placebo in three randomized, controlled studies to investigate the effects of LPS on cognitive schemata related to depression. Validated questionnaires were used to assess self-esteem, hopelessness and the vulnerability factor intolerance of uncertainty after intravenous injection of LPS or placebo. Plasma tumor necrosis factor (TNF)-α and interleukin (IL)-6 were repeatedly assessed, along with self-reported mood. Because not all questionnaires were available from primary studies, data were analyzed in two separate data sets: In data set 1, self-esteem and intolerance of uncertainty were assessed in N = 87 healthy volunteers, who randomly received either 0.4 or 0.8 ng/kg LPS or placebo. In data set 2, hopelessness was measured in N = 59 volunteers who randomly received either LPS (0.8 ng/kg) or placebo. In both data sets, LPS-application led to significant increases in TNF-α and IL-6, reflecting systemic inflammation. Positive mood was significantly decreased in response to LPS, in line with inflammation-induced mood impairment. General self-esteem, intolerance of uncertainty and hopelessness did not differ between LPS- and placebo groups, suggesting that these negative cognitive schemata are not responsive to acute LPS-induced systemic inflammation. Interestingly, LPS-treated volunteers reported significantly lower body-related self-esteem, which was associated with increased TNF-α concentration. Thus, certain aspects of self-esteem related to physical attractiveness and sportiness were reduced. It is conceivable that this effect is primarily related to physical sickness symptoms and reduced physical ability during experimental endotoxemia. With respect to cognitive symptoms of depression, it is conceivable that LPS affects cognitive processes, but not negative cognitive schemata, which are rather based on learning and repeated experiences.

Inflammatory Response 24 h Post-Exercise in Youth with Juvenile Idiopathic Arthritis.

The aim of this study was to measure the impact, at 24 h post-exercise, of a single exercise bout on plasma inflammatory markers such as calprotectin, IL-6, sIL-6 R, sgp130 and the hypothalamic-pituitary-adrenal (HPA) axis in children with juvenile idiopathic arthritis (JIA).Twelve children with JIA attended the laboratory on three consecutive days (control day, exercise day and 24 h post-exercise), including a 20-min exercise bout on a cycle-ergometer at 70% of max. HR at 8:30 a.m. on day 2. Plasma concentrations of calprotectin, IL-6, sIL-6 R, sgp130, cortisol, ACTH and DHEA were measured on venous blood samples taken every day.at rest and at 8:30, 8:50, 9:30, 10:30 a.m. and 12:00, 3:00, 5:30 p.m.A single exercise bout increased plasma calprotectin 1.7-fold (p<0.001) but did not increase IL-6 and soluble IL-6 receptors in short-term post-exercise recovery. However, at 24 h post-exercise, calprotectin, IL-6 and its receptors had decreased compared to control-day levels. There was a transient 2-fold increase in post-exercise self-evaluated pain (p=0.03) that disappeared in the evening without repercussions the following day.Physical activity in children with JIA results in a slight transient systemic inflammation but seems to be followed by counter-regulation at 24 h post-exercise with a decrease in proinflammatory markers.

Inflammation in the developing rat modulates astroglial reactivity to seizures in the mature brain.

Astrocytes participate in neuronal development and excitability, and produce factors enhancing or suppressing inflammatory processes occurring due to neurodegenerative diseases, such as epilepsy. Seizures, in turn, trigger the release of inflammatory mediators, causing structural and functional changes in the brain. Therefore, it appears reasonable to determine whether generalized inflammation at developmental periods can affect astrocyte reactivity to epileptic seizures occurring in the adult brain. Lipopolysaccharide (LPS) was injected in 6- or 30-day-old rats (P6 or P30, respectively). At the age of 2months, seizures were induced, and pilocarpine and morphological changes of astrocytes located within the hippocampal formation were assessed. Additionally, expression of glial fibrillary acidic protein (GFAP), glutamine synthetase (GS), aquaporin 4 (AQP4), and inwardly rectifying potassium channel Kir 4.1 (Kir4.1) was determined using Western blots. The animal group given LPS on P6 displayed maximal susceptibility to pilocarpine-induced seizures, significantly higher than the group that received LPS on P30. In the immunohistologically examined hippocampal formation, the GFAP-immunoreactive area was not affected by LPS alone. However, it was reduced following seizures in naïve controls but not in LPS-pretreated rats. Increases in the ramification of astrocytic processes were detected only in adult rats given LPS on P30, not on P6. Seizures abolished the effects. Following seizures, the process ramification showed no significant change in the two LPS-treated rat groups, whereas it was significantly reduced in the dentate gyrus of LPS-untreated controls. Glial fibrillary acidic protein (GFAP) expression showed no changes induced with LPS alone and rose slightly after seizures. AQP4 content was lower in rats given LPS on P6 and was seizure-resistant in the two LPS-treated groups, contrary to a decrease in untreated controls. GS expression was not affected by LPS treatments and was reduced after seizures without an intergroup difference. Kir4.1 underwent highly significant increases in all groups experiencing seizures, but LPS alone had no effect. It can be concluded that the generalized inflammatory status led to some important changes in astrocytes reflected, in part at least by permanent modifications of their morphology and molecular profile. Moreover, the previously experienced inflammation prevented the cells from much stronger changes in response to seizures observed in adult untreated controls. The obtained results point to a link between the activation of astrocytes by transient systemic inflammation occurring during the developmental period and their subsequent reactivity to seizures, which may play an important role in the functional features of the brain, including its susceptibility to seizures.

Perioperative use of NSAID might prevent early relapses in breast and other cancers: An upstream approach

A bimodal pattern of hazard of relapse among early stage breast cancer patients has been identified in multiple databases from US, Europe and Asia. We are studying these data to determine if this can lead to new ideas on how to prevent relapse in breast cancer. Using computer simulation and access to a very high quality database from Milan for patients treated with mastectomy only, we proposed that relapses within 3 years of surgery are stimulated somehow by the surgical procedure. Most relapses in breast cancer are in this early category. Retrospective data from a Brussels anesthesiology group suggests a plausible mechanism. Use of ketorolac, a common NSAID analgesic used in surgery was associated with far superior disease-free survival in the first five years after surgery. The expected prominent early relapse events in months 9-18 are reduced 5-fold. Transient systemic inflammation accompanying surgery (identified by IL-6 in serum) could facilitate angiogenesis of dormant micro metastases, proliferation of dormant single cells, and seeding of circulating cancer stem cells (perhaps in part released from bone marrow) resulting in early relapse and could have been effectively blocked by the perioperative anti-inflammatory agent. If this observation holds up to further scrutiny, it could mean that the simple use of this safe, inexpensive and effective anti-inflammatory agent at surgery might eliminate early relapses. We suggest this would be most effective for triple negative breast cancer and be especially valuable in low and middle income countries. Similar bimodal patterns have been identified in other cancers suggesting a general effect.

Can exercise affect the course of inflammatory bowel disease? Experimental and clinical evidence.

The inflammatory bowel disease (IBD) consisting of Crohn's disease (CD) and ulcerative colitis (UC) are defined as idiopathic, chronic and relapsing intestinal disorders occurring in genetically predisposed individuals exposed to environmental risk factors such as diet and microbiome changes. Since conventional drug therapy is expensive and not fully efficient, there is a need for alternative remedies that can improve the outcome in patients suffering from IBD. Whether exercise, which has been proposed as adjunct therapy in IBD, can be beneficial in patients with IBD remains an intriguing question. In this review, we provide an overview of the effects of exercise on human IBD and experimental colitis in animal models that mimic human disease, although the information on exercise in human IBD are sparse and poorly understood. Moderate exercise can exert a beneficial ameliorating effect on IBD and improve the healing of experimental animal colitis due to the activity of protective myokines such as irisin released from working skeletal muscles. CD patients with higher levels of exercise were significantly less likely to develop active disease at six months. Moreover, voluntary exercise has been shown to exert a positive effect on IBD patients' mood, weight maintenance and osteoporosis. On the other hand, depending on its intensity and duration, exercise can evoke transient mild systemic inflammation and enhances pro-inflammatory cytokine release, thereby exacerbating the gastrointestinal symptoms. We discuss recent advances in the mechanism of voluntary and strenuous exercise affecting the outcome of IBD in patients and experimental animal models.

Human experimental endotoxemia in modeling the pathophysiology, genomics, and therapeutics of innate immunity in complex cardiometabolic diseases.

Inflammation is a fundamental feature of several complex cardiometabolic diseases. Indeed, obesity, insulin resistance, metabolic dyslipidemia, and atherosclerosis are all closely linked inflammatory states. Increasing evidence suggests that the infectious, biome-related, or endogenous activation of the innate immune system may contribute to the development of metabolic syndrome and cardiovascular disease. Here, we describe the human experimental endotoxemia model for the specific study of innate immunity in understanding further the pathogenesis of cardiometabolic disease. In a controlled, experimental setting, administration of an intravenous bolus of purified Escherichia coli endotoxin activates innate immunity in healthy human volunteers. During endotoxemia, changes emerge in glucose metabolism, lipoprotein composition, and lipoprotein functions that closely resemble those observed chronically in inflammatory cardiovascular disease risk states. In this review, we describe the transient systemic inflammation and specific metabolic consequences that develop during human endotoxemia. Such a model provides a controlled induction of systemic inflammation, eliminates confounding, undermines reverse causation, and possesses unique potential as a starting point for genomic screening and testing of novel therapeutics for treatment of the inflammatory underpinning of cardiometabolic disease.

Transient systemic inflammation does not alter the induction of tolerance to gastric autoantigens by migratory dendritic cells.

It has been proposed that activation of dendritic cells (DCs) presenting self-antigens during inflammation may lead to activation of autoreactive T cells and the development of autoimmunity. To test this hypothesis, we examined the presentation of the autoantigen recognized in autoimmune gastritis, gastric H(+)/K(+) ATPase, which is naturally expressed in the stomach and is constitutively presented in the stomach-draining lymph nodes. Systemic administration to mice of the TLR9 agonist CpG DNA, agonist anti-CD40 Ab, or TLR4 agonist LPS all failed to abrogate the process of peripheral clonal deletion of H(+)/K(+) ATPase-specific CD4 T cells or promote the development of autoimmune gastritis. We demonstrated that migratory DCs from the stomach-draining lymph nodes are the only DC subset capable of constitutively presenting the endogenous gastric H(+)/K(+) ATPase autoantigen in its normal physiological context. Analysis of costimulatory molecules indicated that, relative to resident DCs, migratory DCs displayed a partially activated phenotype in the steady state. Furthermore, migratory DCs were refractory to stimulation by transient exposure to TLR agonists, as they failed to upregulate costimulatory molecules, secrete significant amounts of inflammatory cytokines, or induce differentiation of effector T cells. Together, these data show that transient systemic inflammation failed to break tolerance to the gastric autoantigen, as migratory DCs presenting the gastric autoantigen remain tolerogenic under such conditions, demonstrating the robust nature of peripheral tolerance.

Endotoxin-induced experimental systemic inflammation in humans: A model to disentangle immune-to-brain communication

Systemic inflammation is among the most prominent and most frequently observed responses of the immune system. Over the past decades, it has become clear that inflammatory cytokines not only affect immune and metabolic functions but also cause a wide range of behavioral and mood changes. Based on experimental findings in animals and observations in clinical populations it has been hypothesized that inflammation-induced neurocognitive changes contribute to the pathophysiology of neuropsychiatric diseases. However, since certain aspects of human behavior cannot be modeled in laboratory animals, there is a need for human models of systemic inflammation. In this review, we summarize recent studies employing administration of endotoxin as a model to induce transient systemic inflammation in healthy human subjects.

Reduction of breast cancer relapses with perioperative non-steroidal anti-inflammatory drugs: new findings and a review.

To explain a bimodal pattern of hazard of relapse among early stage breast cancer patients identified in multiple databases, we proposed that late relapses result from steady stochastic progressions from single dormant malignant cells to avascular micrometastases and then on to growing deposits. However in order to explain early relapses, we had to postulate that something happens at about the time of surgery to provoke sudden exits from dormant phases to active growth and then to detection. Most relapses in breast cancer are in the early category. Recent data from Forget et al. suggest an unexpected mechanism. They retrospectively studied results from 327 consecutive breast cancer patients comparing various perioperative analgesics and anesthetics in one Belgian hospital and one surgeon. Patients were treated with mastectomy and conventional adjuvant therapy. Relapse hazard updated Sept 2011 are presented. A common Non-Steroidal Anti-Inflammatory Drug (NSAID) analgesic used in surgery produced far superior disease-free survival in the first 5 years after surgery. The expected prominent early relapse events in months 9-18 are reduced 5-fold. If this observation holds up to further scrutiny, it could mean that the simple use of this safe, inexpensive and effective anti-inflammatory agent at surgery might eliminate early relapses. Transient systemic inflammation accompanying surgery could facilitate angiogenesis of dormant micrometastases, proliferation of dormant single cells, and seeding of circulating cancer stem cells (perhaps in part released from bone marrow) resulting in early relapse and could have been effectively blocked by the perioperative anti-inflammatory agent.