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The effects of recombinant interleukin (IL)-10 and the role of endogenous IL-10 were determined in C57B1/6 mice with pneumonia induced by intranasal inoculation with 10(6) cfu of Streptococcus pneumoniae. Pneumonia induced sustained expression of IL-10 mRNA and protein in lungs, but IL-10 remained undetectable in plasma. Intranasal inoculation of S. pneumoniae in combination with IL-10 (1500 U/mouse) resulted in decreased lung concentrations of tumor necrosis factor-alpha (TNF) and interferon (IFN)-gamma, increased bacterial counts in lungs and blood, and early lethality. Conversely, pretreatment (-2 h) of mice with an anti-IL-10 monoclonal antibody (2 mg/mouse) was associated with increased lung levels of TNF and IFN-gamma, reduced bacterial counts in lungs and plasma 40 h after the inoculation, and prolonged survival. These results indicate that during pneumococcal pneumonia, IL-10 attenuates the proinflammatory cytokine response within the lungs, hampers effective clearance of the infection, and shortens survival. [ABSTRACT FROM AUTHOR]

Venous thrombosis and bacterial infections are common complications of parenteral nutrition. To test the hypothesis that infection facilitates activation of coagulation during parenteral nutrition, healthy subjects were intravenously injected with endotoxin (2 ng/kg) after they had received either 1 week of standard parenteral nutrition (n = 7) or normal enteral feeding (n = 8). Compared with enteral feeding, parenteral nutrition was associated with a selectively enhanced activation of the coagulation system (plasma levels of thrombin-antithrombin III complexes) during endotoxemia. Activation of the fibrinolytic system (plasminogen activator activity, tissue-type plasminogen activator, plasminogen activator inhibitor type 1) proceeded similarly in both study groups. In patients receiving parenteral nutrition, one common complication (bacterial infection) may facilitate the occurrence of another common complication (venous thrombosis) by synergistic stimulation of the coagulation system. [ABSTRACT FROM AUTHOR]

Background: The successful treatment of intraabdominal infection requires a combination of anatomical source control and antibiotics. The appropriate duration of antimicrobial therapy remains unclear., Methods: We randomly assigned 518 patients with complicated intraabdominal infection and adequate source control to receive antibiotics until 2 days after the resolution of fever, leukocytosis, and ileus, with a maximum of 10 days of therapy (control group), or to receive a fixed course of antibiotics (experimental group) for 4±1 calendar days. The primary outcome was a composite of surgical-site infection, recurrent intraabdominal infection, or death within 30 days after the index source-control procedure, according to treatment group. Secondary outcomes included the duration of therapy and rates of subsequent infections., Results: Surgical-site infection, recurrent intraabdominal infection, or death occurred in 56 of 257 patients in the experimental group (21.8%), as compared with 58 of 260 patients in the control group (22.3%) (absolute difference, -0.5 percentage point; 95% confidence interval [CI], -7.0 to 8.0; P=0.92). The median duration of antibiotic therapy was 4.0 days (interquartile range, 4.0 to 5.0) in the experimental group, as compared with 8.0 days (interquartile range, 5.0 to 10.0) in the control group (absolute difference, -4.0 days; 95% CI, -4.7 to -3.3; P<0.001). No significant between-group differences were found in the individual rates of the components of the primary outcome or in other secondary outcomes., Conclusions: In patients with intraabdominal infections who had undergone an adequate source-control procedure, the outcomes after fixed-duration antibiotic therapy (approximately 4 days) were similar to those after a longer course of antibiotics (approximately 8 days) that extended until after the resolution of physiological abnormalities. (Funded by the National Institutes of Health; STOP-IT ClinicalTrials.gov number, NCT00657566.).

Introduction: Human injury or infection induces systemic inflammation with characteristic neuroendocrine responses. Fluctuations in autonomic function during inflammation are reflected by beat-to-beat variation in heart rate, termed heart rate variability (HRV). In the present study, we determine threshold doses of endotoxin needed to induce observable changes in markers of systemic inflammation, investigate whether metrics of HRV exhibit a differing threshold dose from other inflammatory markers, and investigate the size of data sets required for meaningful use of multiscale entropy (MSE) analysis of HRV., Methods: Healthy human volunteers (n = 25) were randomized to receive placebo (normal saline) or endotoxin/lipopolysaccharide (LPS): 0.1, 0.25, 0.5, 1.0, or 2.0 ng/kg administered intravenously. Vital signs were recorded every 30 min for 6 h and then at 9, 12, and 24 h after LPS. Blood samples were drawn at specific time points for cytokine measurements. Heart rate variability analysis was performed using electrocardiogram epochs of 5 min. Multiscale entropy for HRV was calculated for all dose groups to scale factor 40., Results: The lowest significant threshold dose was noted in core temperature at 0.25 ng/kg. Endogenous tumor necrosis factor α and interleukin 6 were significantly responsive at the next dosage level (0.5 ng/kg) along with elevations in circulating leukocytes and heart rate. Responses were exaggerated at higher doses (1 and 2 ng/kg). Time domain and frequency domain HRV metrics similarly suggested a threshold dose, differing from placebo at 1.0 and 2.0 ng/kg, below which no clear pattern in response was evident. By applying repeated-measures analysis of variance across scale factors, a significant decrease in MSE was seen at 1.0 and 2.0 ng/kg by 2 h after exposure to LPS. Although not statistically significant below 1.0 ng/kg, MSE unexpectedly decreased across all groups in an orderly dose-response pattern not seen in the other outcomes., Conclusions: By using repeated-measures analysis of variance across scale factors, MSE can detect autonomic change after LPS challenge in a group of 25 subjects using electrocardiogram epochs of only 5 min and entropy analysis to scale factor of only 40, potentially facilitating MSE's wider use as a research tool or bedside monitor. Traditional markers of inflammation generally exhibit threshold dose behavior. In contrast, MSE's apparent continuous dose-response pattern, although not statistically verifiable in this study, suggests a potential subclinical harbinger of infectious or other insult. The possible derangement of autonomic complexity prior to or independent of the cytokine surge cannot be ruled out. Future investigation should focus on confirmation of overt inflammation following observed decreases in MSE in a clinical setting.

Background: The genetic determinants of the human innate immune response are poorly understood. Apolipoprotein (Apo) E, a lipid-trafficking protein that affects inflammation, has well-described wild-type (ε3) and disease-associated (ε2 and ε4) alleles, but its connection to human innate immunity is undefined., Objective: We sought to define the relationship of APOε4 to the human innate immune response., Methods: We evaluated APOε4 in several functional models of the human innate immune response, including intravenous LPS challenge in human subjects, and assessed APOε4 association to organ injury in patients with severe sepsis, a disease driven by dysregulated innate immunity., Results: Whole blood from healthy APOε3/APOε4 volunteers induced higher cytokine levels on ex vivo stimulation with Toll-like receptor (TLR) 2, TLR4, or TLR5 ligands than blood from APOε3/APOε3 patients, whereas TLR7/8 responses were similar. This was associated with increased lipid rafts in APOε3/APOε4 monocytes. By contrast, APOε3/APOε3 and APOε3/APOε4 serum neutralized LPS equivalently and supported similar LPS responses in Apoe-deficient macrophages, arguing against a differential role for secretory APOE4 protein. After intravenous LPS, APOε3/APOε4 patients had higher hyperthermia and plasma TNF-α levels and earlier plasma IL-6 than APOε3/APOε3 patients. APOE4-targeted replacement mice displayed enhanced hypothermia, plasma cytokines, and hepatic injury and altered splenic lymphocyte apoptosis after systemic LPS compared with APOE3 counterparts. In a cohort of 828 patients with severe sepsis, APOε4 was associated with increased coagulation system failure among European American patients., Conclusions: APOε4 is a determinant of the human innate immune response to multiple TLR ligands and associates with altered patterns of organ injury in human sepsis., (Published by Mosby, Inc.)

Objective: The Toll-like receptor 4 (TLR4) ligand endotoxin triggers robust systemic inflammatory responses in humans at doses equal to or greater than 1 ng/kg. In this study, we tested the hypothesis that evidence of TLR4-induced responses would be detectable in leukocytes challenged with endotoxin doses that are below the threshold needed to trigger a characteristic systemic inflammatory phenotype in humans., Methods: Subjects were challenged with endotoxin at 1, 0.5, or 0.1 ng/kg (n = 5 per dose). Systemic responses were monitored for 24 hours. Blood samples, collected at designated intervals, were used to determine plasma cytokines levels, total and differential leukocyte counts, expression of leukocyte cell surface receptors, and changes in the leukocyte transcriptome. Western blotting was used to determine changes in leukocyte protein expression., Results: We found that in vivo endotoxin at doses below 1.0 ng/kg triggers weak and variable responses in humans. In marked contrast, we show that endotoxin at a concentration as low as 0.1 ng/kg triggers a transient decline in cellular ATP levels in leukocytes. This is associated with the appearance of a unique protein expression signature in leukocytes. The protein expression signature includes 3 prominent features: (i) AMP-activated protein kinase subunit α (AMPKα) degradation, (ii) increased hypoxia inducible factor-1 (HIF-1) α expression, and (iii) autophagy, collectively indicative of a regulated metabolic response. An indistinguishable response phenotype was observed in human leukocytes treated with endotoxin in vitro., Conclusions: These data demonstrate for the first time in humans that a TLR4 ligand concentration that is below the threshold needed to trigger clinically evident systemic inflammatory manifestations initiates a transient decline in ATP levels, AMPKα degradation, HIF-1α expression, and autophagy in leukocytes. This establishes that low-grade TLR4 activation exerts control over leukocyte metabolism in the absence of systemic inflammatory indicators.

A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R(2) between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases.

As cellular variability and circadian rhythmicity play critical roles in immune and inflammatory responses, we present in this study an agent-based model of human endotoxemia to examine the interplay between circadian controls, cellular variability and stochastic dynamics of inflammatory cytokines. The model is qualitatively validated by its ability to reproduce circadian dynamics of inflammatory mediators and critical inflammatory responses after endotoxin administration in vivo. Novel computational concepts are proposed to characterize the cellular variability and synchronization of inflammatory cytokines in a population of heterogeneous leukocytes. Our results suggest that there is a decrease in cell-to-cell variability of inflammatory cytokines while their synchronization is increased after endotoxin challenge. Model parameters that are responsible for IκB production stimulated by NFκB activation and for the production of anti-inflammatory cytokines have large impacts on system behaviors. Additionally, examining time-dependent systemic responses revealed that the system is least vulnerable to endotoxin in the early morning and most vulnerable around midnight. Although much remains to be explored, proposed computational concepts and the model we have pioneered will provide important insights for future investigations and extensions, especially for single-cell studies to discover how cellular variability contributes to clinical implications.

Background and Purpose: Whereas the negative impact of infectious complications (IC) during the index hospitalization after elective surgery is well established, the long-term ramifications of hospital-acquired post-operative infections are not well studied. This analysis evaluated the impact of a hospital-acquired IC after open abdominal vascular surgery on the readmission rate and the mortality rates 30 and 90 days after initial discharge., Methods: Data from all hospitals in the United States that performed elective open abdominal vascular operations in the Medicare population from 2005 to 2007 were extracted from the national Medicare Provider Analysis and Review database. The cohort consisted of all patients undergoing open abdominal vascular operations, including aortic, iliac, and visceral procedures. The ICs evaluated were pneumonia, urinary tract infection (UTI), postoperative sepsis (sepsis), surgical site infection (SSI), and Clostridium difficile infection (CDI). Patients were categorized as either developing an IC during their initial hospitalization (Index+INF) or not developing an IC (No INF). The rates of 30-day readmission, 30-day IC, and 30- and 90-day mortality after the initial discharge were evaluated longitudinally and compared in patients with and without an IC., Results: A total of 29,549 open abdominal vascular procedures were identified, and 4,016 patients (13.6%) developed an IC during their index hospitalization: Pneumonia (5.1% of the total), UTI (2.7%), sepsis (1.6%), SSI (1.4%), and CDI (0.6%). Additionally, 1.13% of patients developed pneumonia, UTI, SSI, or CDI complicated by sepsis. The hospital mortality rate during the initial hospitalization was 13.7% (Index+INF) versus 4.0% (No INF) (p<0.0002). Infectious processes (pneumonia, UTI, SSI, and CDI) complicated by sepsis had an in-hospital mortality rate significantly higher than patients having an IC alone (50.9% vs. 13.7%; p<0.002). The mortality rate 30 and 90 days after the initial discharge was significantly higher for Index+INF than for No INF (4.4% vs. 1.2% and 8.6% vs. 2.6%, respectively; p<0.0002). The highest 30-day mortality rates after discharge were found after CDI+sepsis (30%), pneumonia+sepsis (12.6%), and postoperative sepsis alone (8.6%). The same rank was found for the 90-day mortality rate: 30%, 22.5%, and 13.8%. Overall, readmission was more likely for Index+INF than for No INF (33.7% vs. 21.5%; p<0.0002). Rates of 30-day readmission after an index IC ranged from 32% to 50%., Conclusion: For Medicare beneficiaries undergoing elective open abdominal vascular procedures, the development of any IC significantly increased not only the in-hospital mortality rate but also the mortality rates 30 and 90 days after discharge from the hospital. Index ICs also were associated with a higher 30-day readmission rate. Hospital-acquired infections have a profound late effect on outcomes after discharge. Future programs targeting high-risk patients may improve long-term survival and minimize readmissions.

Enteral (EN) or parenteral (PN) nutrition is used to support critically ill patients until oral feeding resumes. Enteral nutrition is assumed preferable to PN, but the differential influence on immune function is not well defined. Autonomic nervous activity is known to influence innate immune responses, and we hypothesized that EN and PN could influence both autonomic signaling and gene activation in peripheral blood monocytes (PBMs). Ten subjects (aged 18-36 years) received continuous EN or PN for 72 h. Peripheral blood monocytes were isolated from whole blood before and after continuous feeding and were analyzed for gene expression using a microarray platform. Gene expression after feeding was compared from baseline and between groups. To measure autonomic outflow, subjects also underwent heart rate variability (HRV) monitoring during feeding. Time and frequency domain HRV data were compared between groups and five orally fed subjects for changes from baseline and changes over time. During continuous EN and PN, subjects exhibited declines in both time and frequency domain HRV parameters compared with baseline and with PO subjects, indicating a loss of vagal/parasympathetic tone. However, PN feeding had a much greater influence on PBM gene expression compared with baseline than EN, including genes important to innate immunity. Continuous EN and PN are both associated with decreasing vagal tone over time, yet contribute differently to PBM gene expression, in humans. These preliminary findings support assumptions that PN imposes a systemic inflammatory risk but also imply that continuous feeding, independent of route, may impart additional risk through different mechanisms.

Circadian rhythmicity in mammals is primarily driven by the suprachiasmatic nucleus (SCN), often called the central pacemaker, which converts the photic information of light and dark cycles into neuronal and hormonal signals in the periphery of the body. Cells of peripheral tissues respond to these centrally mediated cues by adjusting their molecular function to optimize organism performance. Numerous systemic cues orchestrate peripheral rhythmicity, such as feeding, body temperature, the autonomic nervous system, and hormones. We propose a semimechanistic model for the entrainment of peripheral clock genes by cortisol as a representative entrainer of peripheral cells. This model demonstrates the importance of entrainer's characteristics in terms of the synchronization and entrainment of peripheral clock genes, and predicts the loss of intercellular synchrony when cortisol moves out of its homeostatic amplitude and frequency range, as has been observed clinically in chronic stress and cancer. The model also predicts a dynamic regime of entrainment, when cortisol has a slightly decreased amplitude rhythm, where individual clock genes remain relatively synchronized among themselves but are phase shifted in relation to the entrainer. The model illustrates how the loss of communication between the SCN and peripheral tissues could result in desynchronization of peripheral clocks.

Endogenous glucocorticoids are secreted by the hypothalamic-pituitary-adrenal (HPA) axis in response to a wide range of stressors. Glucocorticoids exert significant downstream effects, including the regulation of many inflammatory genes. The HPA axis functions such that glucocorticoids are released in a pulsatile manner, producing ultradian rhythms in plasma glucocorticoid levels. It is becoming increasingly evident that this ultradian pulsatility is important in maintaining proper homeostatic regulation and responsiveness to stress. This is particularly interesting from a clinical perspective given that pathological dysfunctions of the HPA axis produce altered ultradian patterns. Modeling this system facilitates the understanding of how glucocorticoid pulsatility arises, how it can be lost, and the transcriptional implications of ultradian rhythms. To approach these questions, we developed a mathematical model that integrates the cyclic production of glucocorticoids by the HPA axis and their downstream effects by integrating existing models of the HPA axis and glucocorticoid pharmacodynamics. This combined model allowed us to evaluate the implications of pulsatility in homeostasis as well as in response to acute stress. The presence of ultradian rhythms allows the system to maintain a lower response to homeostatic levels of glucocorticoids, but diminished feedback within the HPA axis leads to a loss of glucocorticoid rhythmicity. Furthermore, the loss of HPA pulsatility in homeostasis correlates with a decrease in the peak output in response to an acute stressor. These results are important in understanding how cyclic glucocorticoid secretion helps maintain the responsiveness of the HPA axis.

Human survival from injury requires an appropriate inflammatory and immune response. We describe the circulating leukocyte transcriptome after severe trauma and burn injury, as well as in healthy subjects receiving low-dose bacterial endotoxin, and show that these severe stresses produce a global reprioritization affecting >80% of the cellular functions and pathways, a truly unexpected "genomic storm." In severe blunt trauma, the early leukocyte genomic response is consistent with simultaneously increased expression of genes involved in the systemic inflammatory, innate immune, and compensatory antiinflammatory responses, as well as in the suppression of genes involved in adaptive immunity. Furthermore, complications like nosocomial infections and organ failure are not associated with any genomic evidence of a second hit and differ only in the magnitude and duration of this genomic reprioritization. The similarities in gene expression patterns between different injuries reveal an apparently fundamental human response to severe inflammatory stress, with genomic signatures that are surprisingly far more common than different. Based on these transcriptional data, we propose a new paradigm for the human immunological response to severe injury.

Glucocorticoids are steroid hormones which, among other functions, exert an antiinflammatory effect. Endogenous glucocorticoids are normally secreted by the adrenal gland in discrete bursts. It is becoming increasingly evident that this pulsatile secretion pattern, leading to ultradian rhythms of plasma glucocorticoid levels, may have important downstream regulatory effects on glucocorticoid-responsive genes. Mathematical modeling of this system can compliment recent experimental data and quantitatively evaluate hypothesized mechanistic underpinnings of differential pulsatile signal transduction. In this paper, we describe an integrated model of pulsatile secretion of glucocorticoids by the hypothalamic-pituitary-adrenal (HPA) axis and the pharmacodynamic effect of glucocorticoids. This model is used to investigate the difference in transcriptional responses to pulsatile and constant glucocorticoid exposure. Nonlinearity in ligand-receptor kinetics leads to the differential expression of glucocorticoid-responsive genes in response to different patterns of glucocorticoid secretion, even when the total amount of glucocorticoid exposure is held constant. Understanding the implications of ultradian rhythms in glucocorticoids is important in studying the dysregulation of HPA axis function leading to altered glucocorticoid secretion patterns in disease.

Heart rate variability (HRV), the quantification of beat-to-beat variability, has been studied as a potential prognostic marker in inflammatory diseases such as sepsis. HRV normally reflects significant levels of variability in homeostasis, which can be lost under stress. Much effort has been placed in interpreting HRV from the perspective of quantitatively understanding how stressors alter HRV dynamics, but the molecular and cellular mechanisms that give rise to both homeostatic HRV and changes in HRV have received less focus. Here, we develop a mathematical model of human endotoxemia that incorporates the oscillatory signals giving rise to HRV and their signal transduction to the heart. Connections between processes at the cellular, molecular, and neural levels are quantitatively linked to HRV. Rhythmic signals representing autonomic oscillations and circadian rhythms converge to modulate the pattern of heartbeats, and the effects of these oscillators are diminished in the acute endotoxemia response. Based on the semimechanistic model developed herein, homeostatic and acute stress responses of HRV are studied in terms of these oscillatory signals. Understanding the loss of HRV in endotoxemia serves as a step toward understanding changes in HRV observed clinically through translational applications of systems biology based on the relationship between biological processes and clinical outcomes.

We discuss a model illustrating how the outcome of repeated endotoxin administration experiments can emerge as a natural consequence of the tightly regulated signaling pathways and also highlight the importance of a dual negative feedback regulation including PI3K/Akt and IRAK-M (IRAK3). We identify the relative time scales of the onset and the magnitude of the stimulus as key determinants of outcome in repeated administration experiments. The results of our simulations involve potentiated response, tolerance, and protective tolerance. Moreover, the knockout of negative regulators shows that IRAK-M is a necessary and sufficient factor for generation of endotoxin tolerance (ET). The effects of the knockout of IRAK-M gene or administration of PI3K inhibitor do yield predictions that have been verified experimentally. Finally, the pretreatment with PI3K inhibitor reveals the interaction between these two negative regulations., (Copyright © 2011. Published by Elsevier Inc.)

Talin is a cytoskeletal protein that binds to integrin β cytoplasmic tails and regulates integrin activation. Talin1 ablation in mice disrupts gastrulation and causes embryonic lethality. However, the role of talin in mammalian epithelial morphogenesis is poorly understood. Here we demonstrate that embryoid bodies (EBs) differentiated from talin1-null embryonic stem cells are defective in integrin adhesion complex assembly, epiblast elongation, and lineage differentiation. These defects are accompanied by a significant reduction in integrin β1 protein levels due to accelerated degradation through an MG-132-sensitive proteasomal pathway. Overexpression of integrin β1 or MG-132 treatment in mutant EBs largely rescues the phenotype. In addition, epiblast cells isolated from talin1-null EBs exhibit impaired cell spreading and focal adhesion formation. Transfection of the mutant cells with green fluorescent protein (GFP)-tagged wild-type but not mutant talin1 that is defective in integrin binding normalizes integrin β1 protein levels and restores focal adhesion formation. Significantly, cell adhesion and spreading are also improved by overexpression of integrin β1. All together, these results suggest that talin1 binding to integrin promotes epiblast adhesion and morphogenesis in part by preventing integrin β1 degradation.

Objective: The goal of this study was to determine the role of Cdc42 in embryonic vasculogenesis and the underlying mechanisms., Methods and Results: By using genetically modified mouse embryonic stem (ES) cells, we demonstrate that ablation of the Rho GTPase Cdc42 blocks vascular network assembly during embryoid body (EB) vasculogenesis without affecting endothelial lineage differentiation. Reexpression of Cdc42 in mutant EBs rescues the mutant phenotype, establishing an essential role for Cdc42 in vasculogenesis. Chimeric analysis revealed that the vascular phenotype is caused by inactivation of Cdc42 in endothelial cells rather than surrounding cells. Endothelial cells isolated from Cdc42-null EBs are defective in directional migration and network assembly. In addition, activation of atypical protein kinase Cι (PKCι) is abolished in Cdc42-null endothelial cells, and PKCι ablation phenocopies the vascular abnormalities of the Cdc42-null EBs. Moreover, the inhibitory phosphorylation of glycogen synthase kinase-3β (GSK-3β) at Ser9 depends on Cdc42 and PKCι, and expression of kinase-dead GSK-3β in Cdc42-null EBs promotes the formation of linear endothelial segments without branches. These results suggest that PKCι and GSK-3β are downstream effectors of Cdc42 during vascular morphogenesis., Conclusions: Cdc42 controls vascular network assembly but not endothelial lineage differentiation by activating PKCι during embryonic vasculogenesis.

Purpose of Review: Myocardial dysfunction in sepsis demonstrates acute reduction in left-ventricular function that is potentially reversible yet also associated with increased mortality. The purpose of this review is to discuss the most recent advances in the current knowledge regarding the pathophysiological mechanisms of septic cardiomyopathy., Recent Findings: There are numerous candidate pathophysiologic mechanisms for the induction of myocardial dysfunction in sepsis. Sarcolemmal and myofibrillar damage to septic rat cardiomyocytes has been observed, and is likely related to oxidative stress. In a septic chimeric murine model, wild-type mice had decreased cardiac function and increased myocardial TNF-α and IL-6 levels whereas TLR-4 knockout mice had attenuated responses to lipopolysaccharide challenge; thus contributing to the increasing evidence for TLR-4's role in the myocardial inflammatory response to lipopolysaccharide. A similar finding regarding endothelial cell NF-κβ signaling inhibition was found using knockout mice., Summary: Septic cardiomyopathy is a significant morbid component of severe sepsis and septic shock. Further research into reducing cardiomyocyte damage via oxidative stress, reducing pro-inflammatory responses induced by TLR-4/NF-κβ signaling, decreasing mitochondrial dysfunction, and improving cellular respiration thereby decreasing apoptosis are examples of areas that may be future therapeutic targets.

Objective: A relationship exists between higher hospital volume and lower mortality, yet the impact of hospital volume on infectious complications after elective abdominal aortic aneurysm (AAA) repair is unknown., Methods: The Medicare database (2005-2007) was utilized. Top 10% for volume were categorized as high-volume (HV) and compared to low-volume (LV) centers for infectious complications and utilization., Results: A total of 42 155 endovascular aneurysm repair (EVAR) and 17 210 open AAA were identified. Mortality in HV was significantly lower than in LV after EVAR and open AAA. After EVAR, HV had lower than LV rates of overall infection (3.10% vs 3.51%; P = .021), PNA (0.94% vs 1.27%, P = .002), and sepsis (0.31% vs 0.45%; P = .03). Length of stay (LOS) and total hospital charges were significantly lower at HV compared to LV after both EVAR and open AAA., Conclusion: For Medicare beneficiaries, undergoing elective AAA repair at hospitals performing higher volume significantly reduced postoperative infectious complications and hospital resource utilization. Further analysis identifying systematic reasons for disparities may offer cost savings and improve outcomes.

The systemic inflammatory response syndrome often accompanies critical illnesses and can be an important cause of morbidity and mortality. Marked abnormalities in cardiovascular function accompany acute illnesses manifested as sustained tachyarrhythmias, which are but one component of systemic dysregulation. The realization that cardiac pacemaker activity is under control of the autonomic nervous system has promoted the analysis of heart rate (HR) variation for assessing autonomic activities. In acute illnesses, autonomic imbalance manifesting in part as parasympathetic attenuation is associated with increased morbidity in patients who manifest systemic inflammatory response syndrome phenotype. Driven by the premise that biological phenotypes emerge as the outcome of the coordinated action of network elements across the host, a multiscale model of human endotoxemia, as a prototype model of systemic inflammation in humans, is developed that quantifies critical aspects of the complex relationship between inflammation and autonomic HR regulation. In the present study, changes in HR response to acute injury, phenotypically expressed as tachycardia, are simulated as a result of autonomic imbalance that reflects sympathetic activity excess and parasympathetic attenuation. The proposed model assesses both the anti-inflammatory and cardiovascular effects of antecedent stresses upon the systemic inflammatory manifestations of human endotoxemia as well as a series of nonlinear inflammatory relevant scenarios. Such a modeling approach provides a comprehensive conceptual framework linking inflammation and physiological complexity via a multiscale model that may advance the translational potential of systems modeling in clinical research.

One of the great challenges in the post-genomic era is to decipher the underlying principles governing the dynamics of biological responses. As modulating gene expression levels is among the key regulatory responses of an organism to changes in its environment, identifying biologically relevant transcriptional regulators and their putative regulatory interactions with target genes is an essential step towards studying the complex dynamics of transcriptional regulation. We present an analysis that integrates various computational and biological aspects to explore the transcriptional regulation of systemic inflammatory responses through a human endotoxemia model. Given a high-dimensional transcriptional profiling dataset from human blood leukocytes, an elementary set of temporal dynamic responses which capture the essence of a pro-inflammatory phase, a counter-regulatory response and a dysregulation in leukocyte bioenergetics has been extracted. Upon identification of these expression patterns, fourteen inflammation-specific gene batteries that represent groups of hypothetically 'coregulated' genes are proposed. Subsequently, statistically significant cis-regulatory modules (CRMs) are identified and decomposed into a list of critical transcription factors (34) that are validated largely on primary literature. Finally, our analysis further allows for the construction of a dynamic representation of the temporal transcriptional regulatory program across the host, deciphering possible combinatorial interactions among factors under which they might be active. Although much remains to be explored, this study has computationally identified key transcription factors and proposed a putative time-dependent transcriptional regulatory program associated with critical transcriptional inflammatory responses. These results provide a solid foundation for future investigations to elucidate the underlying transcriptional regulatory mechanisms under the host inflammatory response. Also, the assumption that coexpressed genes that are functionally relevant are more likely to share some common transcriptional regulatory mechanism seems to be promising, making the proposed framework become essential in unravelling context-specific transcriptional regulatory interactions underlying diverse mammalian biological processes.

Endotoxin is a potent inducer of systemic inflammatory responses in human and rodents. Here, we show that in vivo endotoxin triggers a rapid and transient decline in ATP concentration in human peripheral blood leukocytes and murine peripheral blood leukocytes and liver, which is associated with a brief increase in expression of the autophagy indicator LC3-II. In both of these tissues, the ATP concentration reaches a nadir, and autophagy is induced between 2 and 4 h post-endotoxin infusion, and homeostasis is restored within 12 h. Mouse liver SIRT1 and AMP-activated protein kinase (AMPK) protein expression levels decline precipitously within 10 min and remain below detection levels for up to 12 h post-endotoxin administration. In marked contrast, the expression of HIF-1α is induced within 90 min and remains elevated for up to 12 h. The ATP recovery is delayed, and the increases in both HIF-1α expression and autophagy are prolonged in endotoxin-challenged SIRT1 liver knock-out mice. Resveratrol prevents the decline in ATP concentration and SIRT1 expression, as well as the increase in HIF-1α expression and autophagy in liver of endotoxin-challenged wild type mice but not in SIRT1 liver knock-out mice. These results provide novel insight into the state of both cellular bioenergetics and metabolic networks during the acute phase of systemic inflammation and suggest a role for SIRT1 in acute metabolic decline, as well as the restoration of metabolic homeostasis during an inflammatory challenge.

Exposure of healthy people to lipopolysaccharide (LPS; endotoxin) produces a pro-inflammatory response, subjective symptoms, and decreased heart rate variability (HRV). Given the efficacy of HRV biofeedback (BF) for treating asthma, the large autonomic effects of HRV BF, and the link between vagus nerve activity and inflammation, we hypothesized that HRV BF would dampen the acute manifestations of systemic inflammation induced by LPS challenge. Healthy participants age 18-40 were randomly assigned to four-one-hour training sessions of either HRV BF (n = 6) or a control 15/min paced breathing condition (n = 5) prior to acute experimentally induced LPS exposure. Participants were coached to do the procedures for 10 min each at five hourly time points after LPS injection, and then 2 h later. Subjective symptoms, HRV parameters, and plasma cytokine levels were measured at each time point, 2 h afterward, and the following morning. Participants were able to perform the procedures both during four pre-exposure training sessions and while experiencing LPS-induced symptoms. The HRV BF group showed significant attenuation of the LPS-induced decline in HRV for the 6 h following LPS exposure, suggesting that HRV BF decreased autonomic dysfunction produced by LPS-induced inflammation. HRV BF also reduced symptoms of headache and eye sensitivity to light, but did not affect LPS-induced levels of pro-inflammatory cytokines or symptoms of nausea, muscle aches, or feverishness. Further evaluation of HRV BF appears to be warranted among patients with inflammatory conditions.

Background: Development of infectious complications after high volume elective surgical procedures imposes a significant clinical burden to the United States population. This study evaluated the association of in-hospital delay of elective procedures and the subsequent impact on infectious complications after coronary artery bypass graft (CABG) surgery, colon resection, and lung resection., Study Design: The Nationwide Inpatient Sample was queried between 2003 and 2007, and patients who developed postoperative infectious complications were identified. Time to elective surgery in days from admission was calculated: 0, 1 day, 2 to 5 days, and 6 to 10 days. Infectious complications evaluated included pneumonia, urinary tract infections, postoperative sepsis, and surgical site infections. Chi-square, multivariable logistic regression analyses, analysis of variance, and Cochran-Armitage trend test were used., Results: There were 87,318 CABG procedures, 46,728 colon resections, and 28,960 lung resections evaluated. Total infection rates significantly increased after elective surgery delays: CABG: 0 days, 5.73%;1 day, 6.68%; 2 to 5 days, 9.33%; 6 to 10 days,18.24%; colon resections: 0 days, 8.43 %;1 day, 11.86%; 2 to 5 days,15.79%;6 to 10 days,21.62%; and lung resections: 0 days, 10.17%;1 day, 14.53%; 2 to 5 days, 15.53%; 6 to 10 days, 20.56%, p < 0.0001 for all trends. Trends for increasing infections after delay were significant for pneumonia and sepsis for all procedures (p < 0.0001); urinary tract infections and surgical site infections significantly increased after CABG and colon resection. Age 80 years and older, female gender, black and Hispanic race or ethnicity, and comorbidities including congestive heart failure, chronic pulmonary disease, and renal failure were associated with delay in surgery. Postoperative hospital mortality after delayed procedures was also greater. Mean cost increased after all procedures with delays: CABG, from $25,164 to $42,055 (p < 0.0001); colon resections, from $13,660 to $25,307) (p < 0.0001); and lung resections, from $18,519 to $25,054 (p < 0.0001)., Conclusions: In-hospital delay of elective surgery from the day of admission was associated with a significant increase in infectious complications and mortality. This delay was also associated with a significant increase in hospital cost. Future policy directed toward preventing in-hospital delay of elective surgery may offer significant cost savings and decrease infectious complications after elective surgery., (Copyright © 2010 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate the incidence of postoperative sepsis after elective procedures, to define surgical procedures with the greatest risk for developing sepsis, and to evaluate patient and hospital confounders., Background Data: The development of sepsis after elective surgical procedures imposes a significant clinical and resource utilization burden in the United States. We evaluated the development of sepsis after elective procedures in a nationally representative patient cohort and assessed the effect of sociodemographic and hospital characteristics on the development of postoperative sepsis., Methods: The Nationwide inpatient sample was queried between 2002 and 2006 and patients developing sepsis after elective procedures were identified using the patient safety indicator "Postoperative Sepsis" (PSI-13). Case-mix adjusted rates were calculated by using a multivariate logistic regression model for sepsis risk and an indirect standardization method., Results: A total of 6,512,921 weighted elective surgical cases met the inclusion criteria and 78,669 cases (1.21%) developed postoperative sepsis. Case-mix adjustment for age, race, gender, hospital bed size, hospital location, hospital teaching status, and patient income demonstrated esophageal, pancreatic, and gastric procedures represented the greatest risk for the development of postoperative sepsis. Thoracic, adrenal, and hepatic operations accounted for the greatest mortality rates if sepsis developed. Increasing age, Blacks, Hispanics, and men were more likely to develop sepsis. Decreased median household income, larger hospital bed size, urban hospital location, and nonteaching status were associated with greater rates of postoperative sepsis., Conclusions: The development of postoperative sepsis is multifactorial and procedures, most likely to develop sepsis, did not demonstrate the greatest mortality after sepsis developed. Factors associated with the development of sepsis included race, age, hospital size, hospital location, and patient income. Further evaluation of high-risk procedures, populations, and environments may assist in reducing this costly complication.

During murine peri-implantation development, the egg cylinder forms from a solid cell mass by the apoptotic removal of inner cells that do not contact the basement membrane (BM) and the selective survival of the epiblast epithelium, which does. The signaling pathways that mediate this fundamental biological process are largely unknown. Here we demonstrate that Rac1 ablation in embryonic stem cell-derived embryoid bodies (EBs) leads to massive apoptosis of epiblast cells in contact with the BM. Expression of wild-type Rac1 in the mutant EBs rescues the BM-contacting epiblast, while expression of a constitutively active Rac1 additionally blocks the apoptosis of inner cells and cavitation, indicating that the spatially regulated activation of Rac1 is required for epithelial cyst formation. We further show that Rac1 is activated through integrin-mediated recruitment of the Crk-DOCK180 complex and mediates BM-dependent epiblast survival through activating the phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway. Our results reveal a signaling cascade triggered by cell-BM interactions essential for epithelial morphogenesis.

A wide variety of modeling techniques have been applied towards understanding inflammation. These models have broad potential applications, from optimizing clinical trials to improving clinical care. Models have been developed to study specific systems and diseases, but the effect of circadian rhythms on the inflammatory response has not been modeled. Circadian rhythms are normal biological variations obeying the 24-h light/dark cycle and have been shown to play a critical role in the treatment and progression of many diseases. Several of the key components of the inflammatory response, including cytokines and hormones, have been observed to undergo significant diurnal variations in plasma concentration. It is hypothesized that these diurnal rhythms are entrained by the cyclic production of the hormones cortisol and melatonin, as stimulated by the central clock in the suprachiasmatic nucleus. Based on this hypothesis, a mathematical model of the interplay between inflammation and circadian rhythms is developed. The model is validated by its ability to reproduce diverse sets of experimental data and clinical observations concerning the temporal sensitivity of the inflammatory response., (Copyright (c) 2010. Published by Elsevier Ltd.)

Severe injury and infection are associated with autonomic dysfunction. The realization that a dysregulation in autonomic function may predispose a host to excessive inflammatory processes has renewed interest in understanding the role of central nervous system (CNS) in modulating systemic inflammatory processes. Assessment of heart rate variability (HRV) has been used to evaluate systemic abnormalities and as a predictor of the severity of illness. Dissecting the relevance of neuroimmunomodulation in controlling inflammatory processes requires an understanding of the multiscale interplay between CNS and the immune response. A vital enabler in that respect is the development of a systems-based approach that integrates data across multiple scales, and models the emerging host response as the outcome of interactions of critical modules. Thus, a multiscale model of human endotoxemia, as a prototype model of systemic inflammation in humans, is proposed that integrates processes across the host from the cellular to the systemic host response level. At the cellular level interacting components are associated with elementary signaling pathways that propagate extracellular signals to the transcriptional response level. Further, essential modules associated with the neuroendocrine immune crosstalk are considered. Finally, at the systemic level, phenotypic expressions such as HRV are incorporated to assess systemic decomplexification indicative of the severity of the host response. Thus, the proposed work intends to associate acquired endocrine dysfunction with diminished HRV as a critical enabler for clarifying how cellular inflammatory processes and neural-based pathways mediate the links between patterns of autonomic control (HRV) and clinical outcomes.

Autonomic inputs from the sympathetic and parasympathetic nervous systems, as measured by heart rate variability (HRV), have been reported to correlate to the severity injury and responses to infectious challenge among critically ill patients. In addition, parasympathetic/vagal activity has been shown experimentally to exert anti-inflammatory effects via attenuation of splanchnic tissue TNF-alpha production. We sought to define the influence of gender on HRV responses to in vivo endotoxin challenge in healthy humans and to determine if baseline HRV parameters correlated with endotoxin-mediated circulating cytokine responses. Young (<30 years of age), healthy subjects (n = 30) received endotoxin (2 ng/kg), and HRV and blood samples were obtained serially thereafter. Plasma cytokines were measured by enzyme-linked immunosorbent assay, and HRV parameters were determined by analysis of serial 5-min epochs of heart rate monitoring. In addition, calculation of multiscale entropy deriving from cardiac monitoring data was performed. The influence of factors such as gender, body mass index, and resting heart rate on HRV after endotoxin exposure was assessed. We found that gender, body mass index, or resting heart rate did not significantly alter the HRV response after endotoxin exposure. Using entropy analysis, we observed that females had significantly higher entropy values at 24 h after endotoxin exposure. Using a serially sampling protocol for cytokine determination, we found a significant correlation of several baseline HRV parameters (percentage of interval differences of successive interbeat intervals more than 50 ms, r = 0.42, P < 0.05; high-frequency variability, r = 0.4, P < 0.05; and low-frequency/high-frequency ratio, r = -0.43, P < 0.05) on TNF-alpha release after endotoxin exposure.

Objectives: The intravenous administration of a bolus dose of endotoxin to healthy human subjects triggers acute systemic inflammatory responses that include cytokine production and dynamic changes in gene expression in peripheral blood leukocytes. This study sought to determine the state of clock gene expression in human peripheral blood leukocytes, and leukocyte subpopulations, challenged with in vivo endotoxin at two circadian/diurnal phases of the clock., Design: Clinical and laboratory investigation., Setting: University-based research laboratory and clinical research center., Subjects: Human volunteers., Interventions: Human subjects were administered a standard dose of endotoxin (2 ng/kg) or saline at either 0900 or 2100 hrs. Blood samples were collected at selected time points pre- and postinfusion., Measurements and Main Results: Clock gene expression was determined in human peripheral blood leukocytes, neutrophils, and monocytes by quantitative real-time polymerase chain reaction. The fold change for each gene was determined by use of the 2 method. We show that endotoxin causes profound suppression of circadian clock gene expression, clearly manifested in human peripheral blood leukocytes, neutrophils, and monocytes. Clock, Cry1-2, Per3, CSNK1epsilon, Rora, and Rev-erb gene expression were all reduced by 80% to 90% with the nadir between 3 and 6 hrs postinfusion. Per1 and Per2 reached an expression nadir between 13 and 17 hrs postinfusion. The levels of plasma interleukin-6 and tumor necrosis factor peaked and then returned to baseline within 6 hrs. In contrast, clock gene expression remained suppressed for up to 17 hrs irrespective of the phase of the clock at the time of the endotoxin challenge. Endotoxin did not perturb the melatonin secretory rhythm., Conclusions: Circadian clock gene expression in peripheral blood leukocytes is dramatically altered and possibly uncoupled from the activity of the central clock during periods of acute systemic inflammation. The realignment of the central and peripheral clocks may constitute a previously unappreciated key factor affecting recovery from disease in humans.

Background: Inflammation is a highly complex biological response evoked by many stimuli. A persistent challenge in modeling this dynamic process has been the (nonlinear) nature of the response that precludes the single-variable assumption. Systems-based approaches offer a promising possibility for understanding inflammation in its homeostatic context. In order to study the underlying complexity of the acute inflammatory response, an agent-based framework is developed that models the emerging host response as the outcome of orchestrated interactions associated with intricate signaling cascades and intercellular immune system interactions., Methodology/principal Findings: An agent-based modeling (ABM) framework is proposed to study the nonlinear dynamics of acute human inflammation. The model is implemented using NetLogo software. Interacting agents involve either inflammation-specific molecules or cells essential for the propagation of the inflammatory reaction across the system. Spatial orientation of molecule interactions involved in signaling cascades coupled with the cellular heterogeneity are further taken into account. The proposed in silico model is evaluated through its ability to successfully reproduce a self-limited inflammatory response as well as a series of scenarios indicative of the nonlinear dynamics of the response. Such scenarios involve either a persistent (non)infectious response or innate immune tolerance and potentiation effects followed by perturbations in intracellular signaling molecules and cascades., Conclusions/significance: The ABM framework developed in this study provides insight on the stochastic interactions of the mediators involved in the propagation of endotoxin signaling at the cellular response level. The simulation results are in accordance with our prior research effort associated with the development of deterministic human inflammation models that include transcriptional dynamics, signaling, and physiological components. The hypothetical scenarios explored in this study would potentially improve our understanding of how manipulating the behavior of the molecular species could manifest into emergent behavior of the overall system.

Objective: This study was conducted to evaluate and compare the rates of postoperative infectious complications and death after elective vascular surgery, define vascular procedures with the greatest risk of developing nosocomial infections, and assess the effect of infection on health care resource utilization., Methods: The Nationwide Inpatient Sample (2002-2006) was used to identify major vascular procedures by International Classification of Diseases, 9th Clinical Modification (ICD-9-CM) codes. Infectious complications identified included pneumonia, urinary tract infections (UTI), postoperative sepsis, and surgical site infections (SSI). Case-mix-adjusted rates were calculated using a multivariate logistic regression model for infectious complication or death as an outcome and indirect standardization., Results: A total of 870,778 elective vascular surgical procedures were estimated and evaluated with an overall postoperative infection rate of 3.70%. Open abdominal aortic surgery had the greatest rate of postoperative infections, followed by open thoracic procedures and aorta-iliac-femoral bypass. Thoracic endovascular aneurysm repair (TEVAR) infectious complication rates were two times greater than after EVAR (P < .0001). Pneumonia was the most common infectious complication after open aortic surgery (6.63%). UTI was the most common after TEVAR (2.86%) and EVAR (1.31%). Infectious complications were greater in octogenarians (P < .0002), women (P < .0001), and blacks (P < .0001 vs whites and Hispanics). Nosocomial infections after elective vascular surgery significantly increased hospital length of stay (13.8 +/- 15.4 vs 3.5 +/- 4.2 days; P < .001) and reported total hospital cost ($37,834 +/- $42,905 vs $11,851 +/- $11,816; P < .001)., Conclusions: Elective vascular surgical procedures vary widely in the estimated risk of postoperative infection. Open aortic surgery and endarterectomy of the head and neck vessels have, respectively, the greatest and the lowest reported incidence for postoperative infectious complications. Women, octogenarians, and blacks have the highest risk of infectious complications after elective vascular surgery. Disparities in the development of infectious complications on a systems level were also found in larger hospitals and teaching hospitals. Hospital infectious complications were found to significantly increase health care resource utilization. Strategies that reduce nosocomial complications and target high-risk procedures may offer significant future cost savings., (Copyright 2010 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Introduction: An endotoxin challenge, sepsis, and injury/trauma, trigger significant changes in human peripheral blood leukocytes (PBL) gene expression. In this study, we have sought to test the hypothesis that the Toll-like receptor 4 (TLR4) induced transcription patterns elicited in humans exposed to in vivo endotoxin would parallel gene expression patterns observed in trauma patients with initial non-infectious injury. In addition, we sought to identify functional modules that are commonly affected by these two insults of differing magnitude and duration., Methods: PBL were obtained from seven adult human subject experimental groups. The groups included a group of healthy, hospitalized volunteers (n = 15), that comprised four study groups of subjects challenged with intravenous endotoxin, without or with cortisol, and two serial samplings of trauma patients (n = 5). The PBL were analyzed for gene expression using a 8,793 probe microarray platform (Gene Chip® Focus, Affymetrix). The expression of a subset of genes was determined using qPCR., Results: We describe sequential selection criteria of gene expression data that identifies 445 genes that are significantly differentially expressed (both P ≤ 0.05 and > 1.2 fold-change) in PBL derived from human subjects during the peak of systemic inflammatory responses induced by in vivo endotoxin, as well as in PBL obtained from trauma patients at 1 to 12 days after admission. We identified two functional modules that are commonly represented by this analysis. The first module includes more than 50 suppressed genes that encode ribosomal proteins or translation regulators. The second module includes up-regulated genes encoding key enzymes associated with glycolysis. Finally, we show that several circadian clock genes are also suppressed in PBL of surgical ICU patients., Conclusions: We identified a group of > 400 genes that exhibit similar expression trends in PBL derived from either endotoxin-challenged subjects or trauma patients. The suppressed translational and circadian clock modules, and the upregulated glycolytic module, constitute a robust and long lasting PBL gene expression signature that may provide a tool for monitoring systemic inflammation and injury.

Background: The past 25 years have witnessed immense progress in our understanding of the systemic, tissue-specific, and cellular consequences of severe injury and infection. Despite such insights, considerable controversy remains regarding appropriate biologic and management interventions to prevent or ameliorate the associated adverse outcomes., Methods: A review of several scientific developments arising from studies initiated at Cornell University Medical College during the tenure of Dr. G. Tom Shires. The implications of those and subsequent studies are discussed., Results: An understanding of patient-specific variation and adaptability could direct individualized biologic and management interventions for severe injury and infection., Conclusion: Despite more detailed appreciation of the molecular mechanisms of danger and pathogen recognition and response biology, we have much to learn about the complexity of severe injury and infection. There is a great need to extend our investigation of these mechanisms to experimental and stress-modified clinical scenarios.

Objective: To determine whether the acute anti-inflammatory influence of epinephrine (EPI) extends to changes in heart rate variability (HRV) induced by the prototypical inflammatory stimulus, endotoxin (lipopolysaccharide [LPS])., Summary Background Data: HRV reflects fluctuating cardiac autonomic inputs and is acutely reduced during the systemic inflammation induced by LPS as well as during severe critical illnesses such as sepsis and traumatic injury. While EPI may diminish proinflammatory cytokine release, it is unknown whether this net anti-inflammatory activity extends to HRV., Methods: Healthy volunteers (n = 17) were randomized to either saline + LPS (2 ng/kg) or LPS + antecedent EPI infusion (30 ng/kg/min) from -3 to 6 hours relative to LPS. HRV and blood samples were obtained before EPI and LPS as well as hourly afterward. Plasma cytokines were measured by ELISA. Statistical analysis was by repeated measures analysis of variance. This study was registered at Clinicaltrials.gov and is listed under the following ID number: NCT00753402., Results: LPS acutely influenced all measured parameters of HRV including standard deviation of the average beat to beat intervals over a 5-minute period, percentage of interval differences of successive interbeat intervals greater than 50 milliseconds and square root of the mean squared differences, high frequency (HF), low frequency, low frequency/HF, and very low frequency (all P < 0.01). EPI infusion reduced the inflammatory cytokine response to LPS as measured by decreased TNFalpha, IL-6, and IL-8 (P < 0.01). Relative to the saline + LPS group, antecedent EPI infusion was associated with further reductions in parameters of HRV measuring vagal/parasympathetic activity including, percentage of interval differences of successive interbeat intervals greater than 50 milliseconds, square root of the mean squared differences, and HF (P < 0.05)., Conclusion: Prior EPI exposure exerts anti-inflammatory influences but also may reduce vagus nerve activity. Hence, acute EPI administration may be protective against early inflammatory challenges but diminish vagal nerve responsiveness to subsequent stimuli.