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The immune and endocrine systems collectively control homeostasis in the body. The endocrine system ensures that values of essential factors and nutrients such as glucose, electrolytes and vitamins are maintained within threshold values. The immune system resolves local disruptions in tissue homeostasis, caused by pathogens or malfunctioning cells. The immediate goals of these two systems do not always align. The immune system benefits from optimal access to nutrients for itself and restriction of nutrient availability to all other organs to limit pathogen replication. The endocrine system aims to ensure optimal nutrient access for all organs, limited only by the nutrients stores that the body has available. The actual state of homeostatic parameters such as blood glucose levels represents a careful balance based on regulatory signals from the immune and endocrine systems. This state is not static but continuously adjusted in response to changes in the current metabolic needs of the body, the amount of resources it has available and the level of threats it encounters. This balance is maintained by the ability of the immune and endocrine systems to interact and co-regulate systemic metabolism. In context of metabolic disease, this system is disrupted, which impairs functionality of both systems. The failure of the endocrine system to retain levels of nutrients such as glucose within threshold values impairs functionality of the immune system. In addition, metabolic stress of organs in context of obesity is perceived by the immune system as a disruption in local homeostasis, which it tries to resolve by the excretion of factors which further disrupt normal metabolic control. In this chapter, we will discuss how the immune and endocrine systems interact under homeostatic conditions and during infection with a focus on blood glucose regulation. In addition, we will discuss how this system fails in the context of metabolic disease., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Seasonal changes in day length enhance and suppress immune function in a trait-specific manner. In Siberian hamsters (Phodopus sungorus) winter-like short days (SDs) increase blood leukocyte concentrations and adaptive T cell dependent immune responses, but attenuate innate inflammatory responses to simulated infections. Thyroid hormone (TH) signaling also changes seasonally and has been implicated in modulation of the reproductive axis by day length. Immunologically, TH administration in long days (LD) enhances adaptive immune responses in male Siberian hamsters, mimicking effects of SDs. This experiment tested the hypothesis that T 3 is also sufficient to mimic the effects of SD on innate immune responses. Adult male hamsters housed in LDs were pretreated with triiodothyronine (T 3 ; 1 μg, s.c.) or saline (VEH) daily for 6 weeks; additional positive controls were housed in SD and received VEH, after which cytokine, behavioral, and physiological responses to simulated bacterial infection (lipopolysaccharide; LPS) were evaluated. SD pretreatment inhibited proinflammatory cytokine mRNA expression (i.e. interleukin 1β, nuclear factor kappa-light-chain-enhancer of activated B cells). In addition, the magnitude and persistence of anorexic and cachectic responses to LPS were also lower in SD hamsters, and LPS-induced inhibition of nest building behavior was absent in SD. T 3 treatments failed to affect behavioral (food intake, nest building) or somatic (body mass) responses to LPS in LD hamsters, but one CNS cytokine response to LPS (e.g., hypothalamic TNFα) was augmented by T 3 . Together these data implicate thyroid hormone signaling in select aspects of innate immune responses to seasonal changes in day length., (Copyright © 2019. Published by Elsevier Inc.)

The primary function of platelets is to patrol the vasculature and seal vessel breaches to limit blood loss. However, it is becoming increasingly clear that they also contribute to pathophysiological conditions like thrombosis, atherosclerosis, stroke and infection. Severe sepsis is a devastating disease that claims hundreds of thousands of lives every year in North America and is a major burden to the public health system. Platelet surface receptors like GPIb, αIIbβ3, TLR2 and TLR4 are involved in direct platelet-bacteria interactions. Plasma proteins like fibrinogen and vWF enable indirect interactions. Furthermore, platelet granules contain a plethora of proteins that modulate the immune response as well as microbicidal agents which can directly lyse bacteria. Bacterial toxins are potent platelet activators and can cause intravascular platelet aggregation. Platelets contribute to the antibacterial response of the host involving Kupffer cells, neutrophils and the complement system. In this review we summarize the current knowledge about platelet-bacteria interactions and highlight recent advances in the field., (Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.)

Bioactive lipid mediators play crucial roles in promoting the induction and resolution of inflammation. Eicosanoids and other related unsaturated fatty acids have long been known to induce inflammation. These signaling molecules can modulate the circulatory system and stimulate immune cell infiltration into the site of infection. Recently, DHA- and EPA-derived metabolites have been discovered to promote the resolution of inflammation, an active process. Not only do these molecules stop the further infiltration of immune cells, they prompt non-phlogistic phagocytosis of apoptotic neutrophils, stimulating the tissue to return to homeostasis. After the rapid release of lipid precursors from the plasma membrane upon stimulation, families of enzymes in a complex network metabolize them to produce a large array of lipid metabolites. With current advances in mass spectrometry, the entire lipidome can be accurately quantified to assess the immune response upon microbial infection. In this review, we discuss the various lipid metabolism pathways in the context of the immune response to microbial pathogens, as well as their complex network interactions. With the advancement of mass spectrometry, these approaches have also been used to characterize the lipid mediator response of macrophages and neutrophils upon immune stimulation in vitro. Lastly, we describe the recent efforts to apply systems biology approaches to dissect the role of lipid mediators during bacterial and viral infections in vivo., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Aggressive hepatobiliary pancreatic surgery has been associated with high complication rates. Correlations of Th1/Th2 balance and toll-like receptor (TLR) 2/4 expression with postoperative infection following surgery were prospectively evaluated., Methods: Plasma concentrations of interleukin (IL)-6, IL-10, soluble lymphocyte activation gene (sLAG)-3, and soluble CD30 were determined by enzyme-linked immunosorbent assay, and expression levels of T-bet, GATA-3, TLR2, and TLR4 mRNA in peripheral blood mononuclear cells were assayed by reverse transcription-polymerase chain reaction perioperatively in 56 consecutive patients who underwent hepatobiliary pancreatic surgery., Results: Of the 56 patients, 30 patients had postoperative infection. Postoperative plasma levels of IL-6 and IL-10 were significantly higher in patients with postoperative infection than in those without infection (P < 0.05). Plasma soluble CD30 level and GATA-3 mRNA expression level were significantly higher preoperatively, and remained higher by postoperative d 7 in patients with postoperative infection (P < 0.05). Soluble lymphocyte activation gene levels were not significantly different between the two groups. T-bet mRNA expression level was significantly higher on postoperative d 3, 7, and 14 in patients with postoperative infection (P < 0.05). Preoperative expression levels of GATA-3 mRNA correlated significantly with those of TLR2 and TLR4 mRNA (P < 0.05)., Conclusions: These results suggest that in patients with postoperative infection, Th1/Th2 balance shifts toward Th2 dominance preoperatively.

Recently, a paradigm shift has emerged in T-cell-mediated adaptive immunity. On the heels of the discovery of T cells with immunosuppressive function, so-called regulatory T cells (Tregs), the diversity of effector cells has expanded to include a third helper T cell, termed Th17. The appreciation that Th17 cells are products of a distinct effector pathway depended critically on observations made during investigations of mouse models of autoimmunity, advanced by discovery of the cytokines IL-17 and IL-23. These studies understandably led investigators to highlight the role played by Th17 cells in autoimmunity. Yet while the dysfunctional behavior of this phenotype as a contributor to inflammatory disease remains a central issue, this pathway evolved to meet a need for host protection against potential pathogens. It has become apparent that the Th17 pathway promotes host defense against certain extracellular bacteria and fungi, but more recent studies also implicate a role in protection against some protozoa and viruses. Here we review the experimental history that ultimately uncovered the existence and nature of Th17 cells, and then turn the reader's attention to what is currently known about Th17 cells as a bulwark against pathogens.

Background: Cytokines are thought to play a role in the stimulation of protein synthesis in liver during inflammation and sepsis. We previously showed that administration of tumor necrosis factor-binding protein (TNFbp) prevents the sepsis-induced inhibition of protein synthesis in skeletal muscle. The purpose of the present set of experiments was to investigate the effect of TNFbp on hepatic protein synthesis and its ability to modulate the mechanisms responsible for increased hepatic protein synthesis during chronic (5-day) intraabdominal sepsis., Materials and Methods: We examined the effects of TNFbp on hepatic protein synthesis during sepsis in four groups of rats: control, control + TNFbp, septic, and septic + TNFbp. Saline (1.0 ml) or TNFbp (1 mg/kg, 1.0 ml) was injected daily starting 4 h prior to the induction of sepsis. The effect of sepsis and TNFbp administration on hepatic protein synthesis in vivo was examined 5 days later., Results: Sepsis increased the rate of protein synthesis by 35% relative to controls. Accelerated rates of protein synthesis were accompanied by increased total RNA content, eukaryotic initiation factor (eIF) 2alpha content, and phosphorylation of p70S6 kinase. Injection of TNFbp into septic rats for 5 days did not diminish the sepsis-induced stimulation of hepatic protein synthesis. Compared with controls, septic rats treated with TNFbp also showed elevated total RNA content, elF2alpha content, and phosphorylation of p70S6 kinase. No significant differences in any of the parameters measured were observed between untreated and TNFbp-treated septic rats. Treatment of control animals with TNFbp for 5 days was without effect on any of the parameters examined., Conclusions: TNFbp did not prevent the sepsis-induced stimulation of hepatic protein metabolism or modulate the septic-induced changes in factors regulating protein synthesis. Global rates of protein synthesis in livers from septic rats are accelerated by increases in the abundance or activity of components of translational apparatus., (Copyright 2000 Academic Press.)

Antioxidants are potent radical scavengers that protect against endotoxemia and septic shock in animal models. Using a rat model of peritonitis sepsis induced by cecal incision we studied the effect of the free radical scavenger dimethyl sulfoxide (DMSO) on hepatic nuclear factor kappa B (NF-kappa B) activation, hepatic intercellular adhesion molecule 1 (ICAM-1) gene expression, serum tumor necrosis factor alpha (TNF) formation, and serum glucose concentration. Five groups of rats (N = 5) were treated as follows: (1) untreated control (Untreated), (2) sham operated with laparotomies (Sham), (3) pretreated with 6 ml/kg DMSO followed by sham operation (DMSO/Sham), (4) cecal incision (Sepsis), and (5) pretreated with DMSO followed by cecal incision (DMSO/Sepsis). In the DMSO/Sham group, DMSO did not affect NF-kappa B activation, ICAM-1 gene expression, and TNF formation. At 3 h postcecal incision, DMSO inhibited sepsis-induced hepatic NF-kappa B activation and hepatic ICAM-1 gene expression to control levels and suppressed serum TNF by 75%. In the late (6 h) septic phase, DMSO inhibited NF-kappa B activation (32%), ICAM-1 gene expression (27%), and TNF formation (71%). These findings suggest that the protective mechanism of antioxidants in septic rats may be partly due to the inhibition of NF-kappa B activation and NF-kappa B-mediated events., (Copyright 1999 Academic Press.)

Background: Animal models of stress and sepsis demonstrate increased hypophyseal gene expression of the transcription factor c-fos and the cytokines interleukin-1 and interleukin-6. Chronic central nervous system exposure to interleukin-1 results in hypermetabolism, accelerated nitrogen loss, anorexia, and cachexia. We test the hypothesis that the host response to ovarian carcinoma recapitulates the host response to sepsis regarding the elaboration of the transcription factors and cytokines in the central nervous system, liver, and lung., Materials and Methods: Nude mice were seeded intraperitoneally with either ovarian carcinoma (MA-148) or vehicle. The animal subjects were observed for 5 weeks and sacrificed for brain, pituitary, lung, and liver mRNA. We studied the mRNA accumulation of the transcription factors c-fos, c-jun, and C/EBP alpha and the cytokines interleukin-1 and interleukin-6 using reverse-transcriptase polymerase chain reaction., Results: Compared with the control, ovarian carcinoma in the mouse model resulted in the following: (1) Pituitary c-fos and c-jun mRNA increased 3-fold (P = 0.012) and 6-fold (P < 0.001), respectively; (2) pituitary IL-1 and IL-6 mRNA increased 4-fold (P < 0.001) and 8-fold (P = 0.037), respectively; (3) liver c-fos mRNA increased > 8-fold (P < 0.001); and (4) lung C/EBP alpha mRNA decreased greater than 10-fold (P < 0.001)., Conclusions: We conclude that the host response to ovarian carcinoma in this animal model recapitulates many aspects of the host response to bacterial sepsis especially concerning pituitary gene expression. These data suggest that, as in sepsis, a hypothalamic-hypophyseal-mediated cytokine response in ovarian carcinoma may result in hypermetabolism, accelerated nitrogen loss, anorexia, and cachexia.

In vitro pretreatment of human monocytes (MO) with low-dose lipopolysaccharide (LPSp) inhibits TNF release in response to subsequent LPSa activation. Septic patients are often indistinguishable from patients with systemic inflammatory response syndrome (SIRS). We hypothesized that in vivo exposure to "septic" stimuli impairs subsequent LPSa-stimulated MO TNF production in vitro. Human peripheral MO were obtained after informed consent from controls or patients with sepsis, SIRS, or posttrauma [ACCP/SCCM definitions]. Cells were plated in vitro, incubated 24 hr, and then stimulated with 0-1000 ng/ml LPSa for 4 hr. Parallel control MO were incubated in vitro with 100 ng/ml LPSp for 24 hr and then stimulated with 1000 ng/ml LPSa for 4 hr. Supernatant TNF (mean U/ml +/- SEM) was measured by bioassay. ANOVA was used to determine statistical significance. In vitro LPSp pretreatment markedly inhibited subsequent LPSa-stimulated TNF release. In vitro LPSa-stimulated TNF release was likewise significantly inhibited with MO from septic patients compared to controls. Inhibition was more profound in septic patients with shock (not shown). No impaired TNF release was seen with MO from SIRS or trauma patients. In conclusion, in vivo preexposure to inflammatory stimuli in septic patients alters monocyte regulation in a manner similar to in vitro endotoxin tolerance. Provocative in vitro monocyte LPS stimulation may distinguish patients with sepsis and SIRS.

The aim of this study was to develop a reproducible and sustained sepsis model in rats, lasting 3-4 days and characterized by appropriate metabolic changes, including increased hepatic protein synthesis, consistent with an acute-phase response. The rat cecal ligation and puncture (CLP) model was modified by decreasing the size and number of cecal punctures and increasing fluid resuscitation, which resulted in a 60% survival rate at 96 hr compared to 20% for standard CLP. Cultures of blood and peritoneal fluid 96 hr following induction of sepsis were positive in all septic animals with a mixed aerobic and anaerobic flora but with predominant growth of Escherichia coli. Septic rats demonstrated increased serum lactate levels and leukocytosis, while serum glucose and resting energy expenditure were not different from controls. Hepatic protein synthesis, measured in vivo by flooding dose technique, was increased by 74% in septic animals. Synthesis of the acute-phase proteins alpha 1-acid glycoprotein, complement component C3, and transferrin, measured by incorporation of [14C]leucine into proteins during a 120-min isolated liver perfusion, was increased twofold in septic animals. The present modified CLP model in rats may be useful in studies on the regulation of acute-phase protein synthesis during prolonged sepsis and in experiments aimed at modulating the septic response in liver by different treatments.

The mediators and mechanisms of muscle proteolysis in sepsis are not fully known. We investigated the role of corticosterone in increased muscle proteolysis during sepsis in rats. In one series of experiments, plasma corticosterone and total and myofibrillar protein breakdown rates, determined in incubated extensor digitorum longus muscles as release of tyrosine and 3-methylhistidine, respectively, were measured 16 hr after sham operation (control) or cecal ligation and puncture (sepsis). In other experiments, corticosterone (10 mg/100 g body wt) was injected subcutaneously twice over 16 hr; thereafter, plasma hormone levels and muscle protein breakdown rates were determined. Plasma corticosterone was increased from 14 +/- 1 micrograms/dl in control rats to 38 +/- 8 micrograms/dl in septic rats and total and myofibrillar protein breakdown rates were increased by 99 and 326%, respectively, in muscles from septic rats. When administration of corticosterone resulted in plasma levels similar to those observed in septic rats, total or myofibrillar protein breakdown rates were not altered. The results suggest that corticosterone alone is not responsible for increased muscle proteolysis in septic rats. The data, however, do not rule out the possibility that glucocorticoids may be a cofactor to some other substance or substances in the induction of muscle proteolysis during sepsis.

In the critically ill surgical patient a variety of therapeutic maneuvers is required to maintain a "healthy gut." Provision of adequate amounts of glutamine to the gastrointestinal mucosa appears to be just one of these maneuvers. Other methods utilized to protect the gut from becoming a wound include: (a) minimizing additional systemic insults (such as hypotension, sepsis, multiple operative procedures); (b) aggressive pulmonary care; (c) the judicious use of antibiotics; and (d) aggressive enteral or parenteral feedings. The concept that the gut is an organ of quiescence following surgical stress merits reconsideration. The intestinal tract plays a central role in interorgan glutamine metabolism and is a key regulator of nitrogen handling following surgical stress. Critically ill patients are susceptible to developing gut-origin sepsis, the incidence of which will be diminished by instituting measures and providing treatments which support intestinal structure, function, and metabolism. Provision of glutamine-enriched diets to such patients may be one of these therapies.

Pharmacologic therapy designed to block adrenergic activity or alter hormonal milieu may modulate energy and protein metabolism in stress. The metabolic effects of propranolol (beta adrenergic receptor blocker) in sepsis was investigated in 22 well-nourished rats that underwent superior vena caval cannulation, cecal ligation, and puncture. Animals were randomly assigned to receive either a continuous infusion of 0.7 mg/day of propranolol combined with parenteral nutrition (n = 11) or parenteral nutrition alone (n = 11). Both groups received isocaloric, isonitrogenous, isovolemic, parenteral nutrition post-operatively for 24 hr. Nitrogen balance was better for the propranolol group than for the control group (+743 +/- 84 mg/kg/day versus +300 +/- 63 mg/kg/day, respectively, P less than 0.05). A significant difference between the pharmacologic therapy and control groups was noted for urinary 3-methylhistidine excretion versus control (0.99 +/- 0.08 micrograms/kg/day versus 7.5 +/- 0.37 micrograms/kg/day, respectively, P less than 0.01). Measured energy expenditure was similar for both pharmacologic therapy and control groups (149 +/- 20 kcal/kg/day versus 134 +/- 11 kcal/kg/day, respectively, P = N.S.). No statistically significant difference was demonstrated for 24-hr survival between propranolol and control groups (73 and 64%, respectively). Continuous, low-dose propranolol promotes nitrogen retention and decreases 3-methylhistidine excretion without altering energy expenditure in parenterally fed septic rats.

We have reported that neutrophils from patients with intraabdominal sepsis show suppressed superoxide production in response to soluble chemoattractants. To determine whether this could be a result of altered receptor function, neutrophil function studies and characterization of receptors were performed upon 22 patients recently operated upon for intraabdominal sepsis. Patient cells showed an absence of subagarose migratory response to activation serum (C5) but intact FMLP response. Superoxide production to FMLP was 5.3 +/- 0.1 nmole FcC compared to 11.2 +/- 0.1 nmole for laboratory normals. Addition of cytochalasin B reversed this. Scatchard analyses of patients' cells showed affinity of 55.5 +/- 0.6 as compared to 36.5 +/- 1.8 for controls. The number of receptors of cell was approximately 55,000 for both controls and patients. Internalization studies revealed significant increase in tritiated-FMLP uptake at room temperature. These results support the hypothesis that superoxide suppression is due to enhanced clearance of stimulant by enhanced internalization of the receptor-ligand complex.

The metabolic responses associated with the tumor-bearing state, as compared to states of sepsis and prolonged starvation, were examined. Tumor-bearing rats manifested significant elevation of triglycerides, significant reduction of glucose and insulin levels, significantly increased plasma skeletal muscle proteolysis-inducing activity, and an unchanged hepatic protein synthetic activity compared to control rats. Prolonged starvation produced an adaptation characterized by significant hypoglycemia and hypoinsulinemia, reduced hepatic protein synthesis, and increased peripheral protolysis compared to controls. Septic animals had glucose, insulin, and lipid levels similar to control animals but had increased hepatic protein synthesis. Each state manifested its own unique metabolic response compared to controls. It appears that the metabolic consequences of cancer in this sarcoma rat model is different than septic and prolonged starvation states.

Patients with sepsis often manifest symptoms of encephalopathy similar to those observed in portasystemic encephalopathy. As a causal relationship has been demonstrated between hepatic encephalopathy and a deranged brain neurotransmitter profile, the catecholaminergic and serotoninergic brain neurotransmitter profile in a septic rat model was investigated. Septic animals exhibited lower levels of norepinephrine (NE), 3,4-dihydroxyphenylacetic acid, and homovanillic acid compared to normal controls. Severely septic animals with encephalopathy exhibited significantly lower levels of NE, dopamine, 5-hydroxytryptamine, and 5-hydroxyindoleacetic acid compared to rats only mildly septic with no encephalopathy. The infusion of branched chain amino acids during sepsis had no effect on this deranged brain neurotransmitter profile. Previous results of derangements in the blood-brain barrier transport mechanism combined with the present findings of a deranged brain amino acid and neurotransmitter profile during sepsis may be responsible, at least in part, for the metabolic encephalopathy observed during sepsis and might suggest a common etiology for septic, hepatic, and other metabolic encephalopathies.

The effect of overfeeding on survival from peritoneal infection as well as changes in protein metabolism was evaluated. Rats were randomly divided into two groups and given for 6 days different quantities of a liquid diet containing 18% of the energy supplied as protein and 82% as carbohydrate and lipid via an implanted gastric tube. The control group received 301 +/- 4 kcal/kg/day which was equivalent to their mean voluntary intake and the overfeeding group received 528 +/- 8 kcal/kg/day (P less than 0.001). Following 6 days of enteral feeding, all rats received a jugular vein cannulation and cecal ligation with enterotomies. The overfeeding group showed a significantly (P less than 0.05) higher mortality rate to experimental peritonitis, a 24% lower leucine incorporation into whole body protein (P less than 0.05), and a 28% lower fractional synthetic rate of serum albumin (P less than 0.05). Although overfeeding in the rat increased body weight gain and was associated with significantly (P less than 0.001) greater nitrogen balance before infection, it can be concluded that such diets increase mortality to peritonitis and reduce whole body protein and serum albumin synthesis in response to such infections.

The concept of early selective mitochondrial injury has been proposed to explain the global metabolic dysfunction observed in the septic state. A two phase study was undertaken to test the validity of this hypothesis. In the initial phase, an endotoxin shock model was employed in the rat to delineate the function of skeletal muscle mitochondria. Mitochondrial function was determined polarimetrically, comparing state three and state four rates, respiratory control index (RCI) and ADP:O ratios. No significant alteration in these parameters was observed in the endotoxic state. Phase II of the study was designed to investigate mitochondrial function in a bacterial peritonitis rat model. Both liver and skeletal muscle mitochondrial function were determined to control for possible alterations in liver metabolism. Neither muscle nor liver mitochondria exhibited functional impairment during sepsis. We conclude from this study that neither endotoxemia nor peritonitis selectively "kills" mitochondria as previously suggested.

Protein turnover in cardiac and skeletal muscle is affected by the provision of amino acids, particularly the branched chain amino acids (BCAA). The effect of each of the BCAA, valine, leucine, and isoleucine, on the systolic function of isolated normal or septic rat heart perfused as a Langendorff preparation was examined. Thirty normal control and 28 septic rats (cecal ligation and puncture) were perfused with either Krebs + 8.5 mM glucose or Krebs + 5.0 mM glucose and 3.5 mM valine, leucine, or isoleucine. Septic hearts perfused with Krebs + 8.5 mM glucose exhibited developed force (DF) and force velocity (dF/dt) levels which were reduced to an average of 45 and 50%, respectively, compared to normal controls, and improved by 35% during 60 min perfusion over measurements made at time zero. In normal hearts DF and dF/dt decreased significantly during perfusion with leucine (27%) and isoleucine (20%). In sepsis, perfusion with leucine and isoleucine resulted in a mild improvement in systolic function. However, valine was far less effective than leucine and isoleucine in maintaining systolic function in sepsis, due apparently to valine being a less efficient energy substrate for the cardiac muscle in a state of severe energy deficit. Thus, valine, leucine, and isoleucine seem to exert different effects on the systolic function of normal and septic isolated rat hearts.