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The epidemiology of low-grade chronic systemic inflammation and type 2 diabetes.

The fattening of the human species and the accompanying emergence of the metabolic syndrome and of type 2 diabetes as remarkably frequent clinical entities are among the major epidemiologic events of our time. Control of the diabetes epidemic requires a greater understanding of the pathophysiologic processes underlying these phenomena. Many epidemiologic studies have now shown associations between inflammation markers and diabetes, with the most consistent being for leukocytes and the strongest being for C-reactive protein. Consistent protective associations have also been reported for adiponectin, an adipocyte secretory protein with antiinflammatory actions. Although great variability is seen between reported associations, as a whole these studies suggest a role for inflammation linked to obesity. The variability reported is in part due to differences in model adjustment, in how diabetes was ascertained, and in the different means used to operationalize the concept of low-grade chronic systemic inflammation. It is also due, in part, to sample characterization, as findings are heterogeneous across some subgroups, such as those defined by smoking. Consistent with their association with type 2 diabetes, inflammation markers have also be shown to predict conditions present in the prediabetes state such as weight gain, hypertension, gestational diabetes, and decline in insulin sensitivity.

Chronic Disease↗

The two faces of IKK and NF-kappaB inhibition: prevention of systemic inflammation but increased local injury following intestinal ischemia-reperfusion.

We studied the role of NF-kappaB in acute inflammation caused by gut ischemia-reperfusion through selective ablation of IkappaB kinase (IKK)-beta, the catalytic subunit of IKK that is essential for NF-kappaB activation. Ablation of IKK-beta in enterocytes prevented the systemic inflammatory response, which culminates in multiple organ dysfunction syndrome (MODS) that is normally triggered by gut ischemia-reperfusion. IKK-beta removal from enterocytes, however, also resulted in severe apoptotic damage to the reperfused intestinal mucosa. These results show the dual function of the NF-kappaB system, which is responsible for both tissue protection and systemic inflammation, and underscore the caution that should be exerted in using NF-kappaB and IKK inhibitors.

Animals↗

Acute systemic inflammation transiently synchronizes clock gene expression in equine peripheral blood.

Peripheral clocks receive timing signals from the master mammalian pacemaker in the suprachiasmatic nucleus (SCN) and function to adaptively anticipate daily changes that influence local physiology. Evidence suggests that peripheral immune activation may act as a resetting signal for circadian clocks in peripheral tissues. We wished to investigate whether acute systemic inflammation could synchronize clock gene expression in equine peripheral blood, a tissue that does not normally oscillate in this species. We report that in vivo administration of lipopolysaccharide (LPS) results in significant upregulation of the core clock genes Per2 and Bmal1 in equine blood, in association with an acute rise in tumor necrosis factor (TNF) alpha and core body temperature compared to vehicle-treated control animals. Furthermore, co-administration of LPS and phenylbutazone, a non-steroidal anti-inflammatory drug (NSAID) known to inhibit prostaglandin (PG) E(2) synthesis in the horse, prevents both the febrile response and the synchronized increase in clock gene expression. However, the rise in Per2 and Bmal1 expression cannot be replicated in equine peripheral blood mononuclear cells (PBMCs) ex vivo by treatment with PGE(2), LPS or a heat shock mimicking the in vivo febrile response. These results may suggest an indirect communication pathway between immune modulators and the molecular machinery of cell clocks in peripheral blood. This potential immune feedback regulation of an equine peripheral clock implies a role for the circadian system in contributing to innate immune reactions and maintaining homeostasis in a tissue that acts as the first line of defense during an infectious challenge.

ARNTL Transcription Factors↗

Helicobacter pylori heat shock protein 60 and risk of coronary heart disease: a case control study with focus on markers of systemic inflammation and lipids.

AIM: it has been suggested that antibodies against heat shock proteins seem to be involved in the pathogenesis of coronary heart disease (CHD). We conducted a case-control study to investigate whether antibodies against Helicobacter pylori heat shock protein 60 (hsp60) are associated with CHD, and focused specifically on markers of systemic inflammation and lipids. METHODS: all patients of German nationality aged 40-68 years who underwent coronary angiography at the University of Ulm between October 1996 and November 1997 and who had at least one coronary stenosis greater than 50% were included in the study. Controls were sampled from voluntary blood donors and were matched for sex and age. H. pylori hsp60 was assessed by Western blot (H. pylori Westernblot, AID Co., Strassberg, Germany). In addition, C-reactive protein, fibrinogen, plasma viscosity, leukocytes, HDL-cholesterol and Lp(a) were determined. RESULTS: overall, 312 patients and 479 controls were enrolled in the study (response in patients 78%, in controls 84%). Whereas 25.0 and 22.4% of the cases showed a hsp60 extinction of 100 or 20-99% (according to the reference blot), respectively, only 21.3 and 14.8% of the controls did so (P=0.004). The age and sex adjusted odds ratio (OR) for CHD was 1.53 (95% confidence interval (CI) 1.14-2.06) given an extinction of 20-100% compared with an extinction of 0-19%. The OR for CHD decreased to 1.28 (95% CI 0.90-1.81) after further adjustment for other covariates. With exception of HDL-cholesterol (lowest in subjects with the highest hsp60 extinction) none of the investigated inflammatory markers was associated with the hsp60 distribution. CONCLUSION: a high H. pylori hsp60 extinction seems not to be an independent risk factor for CHD in this population.

Adult↗

Infection with Helicobacter pylori, coronary heart disease, cardiovascular risk factors, and systemic inflammation: the Third National Health and Nutrition Examination Survey.

BACKGROUND: Few data have been published on the association of variables of the metabolic syndrome and infection with Helicobacter pylori, a putative risk factor for cardiovascular morbidity, in large, representative samples of total populations. The null hypothesis was no association of prevalent infection with H. pylori with prevalent coronary heart disease (CHD), systemic inflammation, and variables associated with the metabolic syndrome in American men. DESIGN: Cross-sectional survey of a large national sample, the Third National Health and Nutrition Examination Survey. METHODS: Among men aged 40-74 years, the survey measured history of CHD, glycated hemoglobin percent, and concentrations of fasting serum glucose, insulin, triglycerides, HDL cholesterol, and C-reactive protein (CRP). RESULTS: Prevalence of infection with H. pylori increased with age. H. pylori infection was not correlated with serum CRP, prevalence of diagnosed diabetes mellitus, glycated hemoglobin percent, or other risk factors other than age. In diabetic men but not in all men, seropositivity was significantly associated with CHD prevalence. CONCLUSIONS: No consistent associations of H. pylon infection with diabetes prevalence or variables of the insulin resistance syndrome were found in American men aged 40-74 years. In diabetic men, H. pylori infection was associated with CHD prevalence.

Adult↗

Toll-like receptor-4 signaling mediates hepatic injury and systemic inflammation in hemorrhagic shock.

BACKGROUND: Hemorrhagic shock and resuscitation (HS/R) activates inflammatory pathways leading to organ injury after trauma. Toll-like receptors (TLRs), such as TLR4, are required for activation of proinflammatory cellular signaling pathways in response to microbial products, but can also recognize endogenous molecules released from damaged tissues. Using mouse strains deficient in TLR4 protein or signaling, we hypothesized that TLR4 would be important for development of systemic inflammation and hepatic injury after HS/R. We sought to determine the role of lipolysaccharide through use of CD14-/- mice. STUDY DESIGN: TLR4-mutant (C[3H]/HeJ), TLR4-deficient (TLR4-/-), CD14-/-, TLR2-/- mice and wild-type (WT) controls were subjected to HS/R or sham procedure (Sham). At 6.5 hours, mice were euthanized for determination of serum interleukin (IL)-6, IL-10, and alanine aminotransferase concentrations. Hepatic nuclear factor-kappaB DNA-binding (electrophoretic mobility shift assay) and tumor necrosis factor, IL-10, and inducible nitric oxide synthase mRNA expression (semiquantitative reverse transcriptase-polymerase chain reaction) were determined. RESULTS: Relative to sham, TLR4-competent (C[3H]/HeOuJ) mice exhibited a significant increase in serum alanine aminotransferase, IL-6, and IL-10 after HS/R (p < 0.05). TLR4-mutant (C[3H]/HeJ) mice were protected from HS/R-induced hepatocellular injury and had lower circulating IL-6 and IL-10 levels than WT (p < 0.05). Similarly, TLR4-/- mice had lower circulating IL-6 and IL-10 levels than WT after HS/R (p < 0.05). Hepatic nuclear factor-kappaB activation and tumor necrosis factor, IL-10, and inducible nitric oxide synthase mRNA expression were lower in TLR4-mutant compared with TLR4-competent mice after HS/R. In contrast, serum ALT concentrations were comparable between CD14-/- and TLR2-/- mice and their WT counterparts after HS/R. CONCLUSIONS: These results suggest that TLR4, but not TLR2, signaling is required for initiation of the systemic inflammatory response and development of hepatocellular injury after HS/R. Lack of involvement of CD14 argues for a lipolysaccharide-independent role for TLR4 in this process.

Alanine Transaminase↗

Why are patients with chronic obstructive pulmonary disease at increased risk of cardiovascular diseases? The potential role of systemic inflammation in chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) increases the risk of cardiovascular disease 2- to 3-fold. The factors responsible for this association remain largely unknown. METHODS AND RESULTS: We analyzed data from participants, > or =50 years of age, of the Third National Health and Nutrition Examination Survey (n=6629) to determine whether C-reactive protein (CRP) and other systemic inflammatory markers are present in participants with chronic airflow obstruction and are associated with cardiac injury. Participants with severe airflow obstruction had circulating leukocyte, platelet, and fibrinogen levels that were 460/ microL (95% confidence interval [CI], 30 to 890/ microL), 39 510/ microL (95% CI, 21 730 to 57 290/ microL), and 41.63 mg/dL (95% CI, 19.87 to 63.39 mg/dL) higher, respectively, than in those without airflow obstruction. They were also 2.18 times (95% CI, 1.46 to 3.27) more likely to have an elevated circulating CRP level. Moderate airflow obstruction was associated with smaller but still significant increases in these levels. Moderate and severe airflow obstruction was associated with increased occurrence of ischemic changes on electrocardiograms of participants. In the presence of both highly elevated CRP and moderate or severe airflow obstruction, the Cardiac Infarction Injury Score was 2.68 and 5.88 U higher, respectively, than in those without airflow obstruction and with low CRP, which suggests an additive effect of CRP and COPD on the risk of cardiac injury. CONCLUSION: Low-grade systemic inflammation was present in participants with moderate to severe airflow obstruction and was associated with increased risk of cardiac injury. This may in part explain the high rates of cardiovascular complications in COPD.

Aged↗

Associations of dietary flavonoids with risk of type 2 diabetes, and markers of insulin resistance and systemic inflammation in women: a prospective study and cross-sectional analysis.

OBJECTIVE: Flavonoids, as antioxidants, may prevent the progressive impairment of pancreatic beta-cell function due to oxidative stress and may thus reduce the occurrence of type 2 diabetes. The aim of the present study was to examine the association of dietary flavonol and flavone intake with type 2 diabetes, and biomarkers of insulin resistance and systemic inflammation. METHODS: In 38,018 women aged > or =45 y and free of cardiovascular disease, cancer and diabetes with an average 8.8 y of follow-up, we calculated relative risks (RRs) of incident type 2 diabetes (1,614 events) according to dietary intake of total or individual flavonols and flavones and flavonoid-rich foods. We also measured and examined plasma concentrations of insulin, HbA(1C), CRP, and IL-6 in relation to total flavonol and flavone intake among 344 nondiabetic women. RESULTS: During 332,905 person-years of follow-up, none of total flavonols and flavones, quercetin, kaempferol, myricetin, apigenin, and luteolin was significantly associated with risk of type 2 diabetes. Among flavonoid-rich foods, apple and tea consumption was associated with diabetes risk. Women consuming > or =1 apple/d showed a significant 28% reduced risk of type 2 diabetes compared with those who consumed no apples (the multivariate-adjusted RR = 0.72, 95% CI: 0.56, 0.92; p = 0.006 for trend). Tea consumption was also inversely associated with diabetes risk but with a borderline significant trend (> or =4 cups/d vs. none: RR 0.73, 95% CI: 0.52-1.01; p for trend = 0.06). In 344 nondiabetic women, total intake of flavonols and flavones was not significantly related to plasma concentrations of fasting insulin, HbA(1C), CRP, or IL-6. CONCLUSIONS: These results do not support the hypothesis that high intake of flavonols and flavones reduces the development of type 2 diabetes, although we cannot rule out a modest inverse association with intake of apples and tea.

Biomarkers↗

Point of care measurement of lepirudin and heparin anticoagulation during systemic inflammation.

BACKGROUND: The number of indications for recombinant human hirudin lepirudin therapy has increased in recent years, and now includes acute coronary syndromes and heparin-induced thrombocytopenia. Hence, point of care monitoring appears desirable for therapy with lepirudin. As CoaguChek Plus (CCP) provides a rapid bedside test to monitor therapy with other anticoagulants, we aimed to determine its suitability for lepirudin therapy. METHODS: Forty-four healthy volunteers received a 2 ng/kg endotoxin infusion (to induce coagulation) together with clinically relevant doses of lepirudin or heparin in a prospective, placebo-controlled, randomised fashion. Measurements of CCP-partial thromboplastin time (aPTT) were compared to laboratory STA-aPTT. RESULTS: As expected, baseline values of CCP-aPTT were shorter than STA-aPTT. Lepirudin increased CCP-aPTT 3-fold, and STA-aPTT 2-fold 1 h after bolus infusion. During lepirudin infusion, the correlation between CCP-aPTT and STA-aPTT was excellent (r=0.86-0.92). Both methods were equally sensitive to over-anticoagulation with heparin. Acute systemic inflammation had little effects on CCP-aPTT. CONCLUSION: CCP-aPTT is suitable for longitudinal point of care monitoring of lepirudin therapy. As baseline values of CCP-aPTT are shorter than STA-aPTT, it is recommended not to indiscriminately change between methods in the follow-up of individual patients.

Adult↗

Dietary n-3 fatty acids differentially affect sickness behavior in mice during local and systemic inflammation.

We tested the hypothesis that increased dietary fish oil levels (via modulation of the production of inflammatory mediators) modulate sickness symptoms (i.e., anorexia, cachexia, fever, lethargy) of systemic and local inflammation. Swiss Webster mice were implanted with biotelemeters to measure body temperature and motor activity and were fed a diet high in n-3 fatty acids (17% wt/wt menhaden oil) or a reference diet (17% wt/wt hydrogenated coconut oil or normal rodent chow) for 6 wk. Local inflammation was induced by subcutaneous injection of turpentine (100 microl/mouse). Systemic inflammation was elicited by intraperitoneal injection of lipopolysaccharide (LPS; 2.5 mg/kg). Fever, lethargy, anorexia, and weight decrease during turpentine abscess were all inhibited (P < 0.05) in mice fed the fish oil diet. Indomethacin, similar to the fish oil diet, attenuated the turpentine-induced symptoms in mice fed a normal diet. Dietary n-3 fatty acids prevented fever and attenuated the decrease in body weight caused by LPS but did not affect the LPS-induced lethargy and anorexia. Within 90 min of LPS injection, the bioactivity of plasma tumor necrosis factor-alpha (TNF-alpha) increased to 98.2 +/- 5.1 ng/ml in mice fed fish oil compared with 32.6 +/- 3.6 ng/ml in those fed the reference diet (P < 0.05). Plasma prostaglandin E2 (PGE2) levels after LPS injection of mice fed the control diet increased within 90 min to 16.4 +/- 5.1 pg/ml. Mice fed the fish oil diet did not show any elevation in plasma PGE2 levels at that time (P < 0.05). We speculate that dietary n-3 fatty acids suppressed PGE2-related responses, including a PGE2-dependent negative feedback on TNF-alpha production, which resulted in differential modulation of sickness behavior depending on the locus of inflammation.

Animals↗

A network-based analysis of systemic inflammation in humans.

Oligonucleotide and complementary DNA microarrays are being used to subclassify histologically similar tumours, monitor disease progress, and individualize treatment regimens. However, extracting new biological insight from high-throughput genomic studies of human diseases is a challenge, limited by difficulties in recognizing and evaluating relevant biological processes from huge quantities of experimental data. Here we present a structured network knowledge-base approach to analyse genome-wide transcriptional responses in the context of known functional interrelationships among proteins, small molecules and phenotypes. This approach was used to analyse changes in blood leukocyte gene expression patterns in human subjects receiving an inflammatory stimulus (bacterial endotoxin). We explore the known genome-wide interaction network to identify significant functional modules perturbed in response to this stimulus. Our analysis reveals that the human blood leukocyte response to acute systemic inflammation includes the transient dysregulation of leukocyte bioenergetics and modulation of translational machinery. These findings provide insight into the regulation of global leukocyte activities as they relate to innate immune system tolerance and increased susceptibility to infection in humans.

Acute Disease↗

Activin A and follistatin in systemic inflammation.

Inflammation is a complex process regulated by a cascade of cytokines and growth factors. This review summarizes the emerging evidence implicating activin A and follistatin in the inflammatory process. Our recent studies have highlighted that activin A is released early in the process as part of the circulatory cytokine cascade during acute systemic inflammation. This release occurs concurrently with tumor necrosis factor (TNF)-alpha and prior to that of interleukin (IL)-6 and follistatin. Although, the cellular source(s) of activin A are yet to be established, circulating blood cells and the vascular endothelium are candidates for this rapid release of activin A into the circulation. The release of activin A and follistatin is also observed in the clinical setting, in particular in sepsis. Furthermore activin A is released into cerebrospinal fluid in a model of meningitis in rabbits. The role of activin A in the inflammatory response is poorly understood, however, in vitro data has highlighted that activin A can have both pro- and anti-inflammatory actions on key mediators of the inflammatory response such as TNF-alpha, IL-1beta and IL-6. Furthermore, emerging data would suggest that activin A induction is restricted to certain types of inflammation and its release is dependant upon the inflammatory setting.

Activins↗

Systemic inflammation increases shear stress-induced platelet plug formation measured by the PFA-100.

The PFA-100 measures platelet plug formation under shear stress and is strongly dependent on von Willebrand Factor (VWF) levels in plasma. We therefore hypothesized that elevated VWF levels, possibly as a result of acute inflammation, adversely influence PFA-100 results. Healthy volunteers received either 2 ng/kg endotoxin or placebo in a randomized controlled trial. Four hours after endotoxin (but not placebo) infusion VWF levels increased by 85%, collagen epinephrine-induced closure time (CT) decreased by 47% and collagen ADP-CT decreased by 38% (P < 0.0001) respectively. In conclusion, systemic inflammation has a major impact on the results obtained by PFA-100 and may confound interpretation of platelet function.

Acute Disease↗

Lipid modulation and systemic inflammation.

N-6 and n-3 PUFAs from the diet are absorbed and reach the cell where they interact with fatty acid binding proteins within cell membranes and cytoplasm. They are processed in the endoplasmic reticulum (desaturation-elongation reactions, lipid synthesis, eicosanoid and epoxide production) and in peroxisomes (beta-oxidation, synthesis, oxidation products). They interact with receptors, ion channels, and nuclear elements; the result is modulation of gene expression. PUFA-induced alterations result in modulation of local and systemic inflammation and inflammatory disease activity.

Dietary Fats, Unsaturated↗

Low-grade systemic inflammation in overweight children: impact of physical fitness.

Obesity as well as low physical fitness and inactivity are associated with an increased incidence of cardiovascular risk factors and coronary artery disease (CAD). Increased inflammation has recently been addressed to play an important role for the relationship between obesity and CAD, as adipose tissue expresses and releases pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). As this relationship is less clear in childhood, we investigated 197 children aged 10-15 years assessing obesity, physical fitness, and a metabolic cardiovascular risk profile including markers of inflammation. Obese children had significantly higher concentrations of inflammatory parameters such as fibrinogen, ferritin, IL-6, and TNF-alpha than non-obese subjects (P<0.01). When dividing the children into groups regarding obesity (BMI < 22.5 kg/mz, BMI > or = 22.5 kglm2) and fitness (< 5 MET, > or = 5 MET), we found that obese, unfit children showed the highest systemic inflammation, whereas fit but obese individuals had as low levels as lean and fit children. These data reveal that even in childhood inflammatory parameters are elevated in obesity and that physical fitness counteracts this association.

Adolescent↗

Extracellular phospholipase A2 inhibitors suppress central nervous system inflammation.

Phospholipase A2 (PLA2) plays a key role in the production of proinflammatory mediators, namely the arachidonic acid-derived eicosanoids, lysophospholipids, and platelet-activating factor, and indirectly influences the generation of cytokines, nitric oxide (NO), and free radicals. Accordingly, regulation of its activity is important in the treatment of inflammation. Since the main site of PLA2 action in inflammatory processes is the cell membrane, we synthesized extracellular PLA2 inhibitors (ExPLIs) composed of N-derivatized phosphatidyl-ethanolamine linked to polymeric carriers. These membrane-anchored lipid conjugates do not penetrate the cell and interfere with vital phospholipid metabolism or cell viability. The ExPLIs markedly inhibited central nervous system inflammation. This was reflected by the suppressed production and secretion of lipopolysaccharide-induced sPLA2, prostaglandin E2, and NO by glial cells and by the amelioration of experimental autoimmune encephalomyelitis in rats and mice.

Animals↗

Tumor necrosis factor receptor regulation of bone marrow cell apoptosis during endotoxin-induced systemic inflammation.

Although inflammation-induced release of cells from the bone marrow (BM) is well established, less is known regarding inflammation-induced modulation of bone marrow cell numbers by apoptosis. The purpose of this study is to assess apoptosis of BM immature and mature myeloid cells and peripheral granulocytes, and to elucidate the role(s) of TNFR-p55 and TNFR-p75 as modulators of apoptosis in these cellular compartments in a mouse model of endotoxin-induced systemic inflammation. Gene knockout (p55(-/-), p75(-/-), and p55(-/-)/p75(-/-)), or wild-type (WT) mice were injected i.p. with saline (Sal) or LPS (4 microg/g) followed by collection of BM cells and peripheral blood after 24 h. Apoptosis was assessed by propidium iodide staining using two-color flow cytometry with differentiated granulocyte-specific Gr1-fluorescein isothiocyanate. Repeated-measures analysis of variance and Neuman-Keuls post hoc test were used for statistical analyses. After i.p. LPS, apoptosis was induced to the higher level in BM Gr1(-) cells than in BM Gr1(+) cells and was not induced in peripheral Gr1(+) cells. Depletion of cell numbers in both BM Gr1(-) and Gr1(+) subpopulations after LPS treatment was consistent with increase of the apoptotic cell percentages in the groups. LPS-induced apoptosis was significantly lower in Gr1(-) cells from the -p55(-/-)/LPS and p55(-/-)/p75(-/-)/LPS mice but not from p75(-/-)/LPS mice as compared with WT/LPS mice, whereas there was no difference in apoptosis of BM Gr1(+) and peripheral Gr1(+) cells among WT groups and knockout groups. Thus, apoptosis of myeloid cells during endotoxemia is minimized because these cells undergo differentiation, which in turn may be because of the attenuation of the proapoptotic effect of TNFR-p55 shown herein to occur with myeloid differentiation. In contrast, TNFR-p75 seems to play a minimal role in apoptosis induction in Gr1(-) myeloid cells during endotoxemia. One explanation for a decrease in BM cell numbers during endotoxemia may be via induction of apoptosis in immature myeloid cells.

Animals↗

Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation.

Sepsis, a potentially fatal clinical syndrome, is mediated by an early (e.g., tumor necrosis factor and IL-1) and late [e.g., high mobility group B-1 (HMGB1)] proinflammatory cytokine response to infection. Specifically targeting early mediators has not been effective clinically, in part because peak mediator activity often has passed before therapy can be initiated. Late-acting downstream effectors, such as HMGB1, that mediate sepsis lethality may be more relevant therapeutic targets. Ethyl pyruvate (EP) recently was identified as an experimental therapeutic that significantly protects against lethal hemorrhagic shock. Here, we report that EP attenuates lethal systemic inflammation caused by either endotoxemia or sepsis even if treatment begins after the early tumor necrosis factor response. Treatment with EP initiated 24 h after cecal puncture significantly increased survival (vehicle survival = 30% vs. EP survival = 88%, P < 0.005). EP treatment significantly reduced circulating levels of HMGB1 in animals with established endotoxemia or sepsis. In macrophage cultures, EP specifically inhibited activation of p38 mitogen-activated protein kinase and NF-kappaB, two signaling pathways that are critical for cytokine release. This report describes a new strategy to pharmacologically inhibit HMGB1 release with a small molecule that is effective at clinically achievable concentrations. EP now warrants further evaluation as an experimental "rescue" therapeutic for sepsis and other potentially fatal systemic inflammatory disorders.

Animals↗