Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In recent years many efforts have been undertaken to elucidate the complex interactions between mediators of the endocrine system and the immune system. The main effector of growth hormone (GH) is insulin-like growth factor-1 (IGF-1), an endocrine mediator of growth and development under physiological conditions. Besides this important function, IGF-1 also plays a prominent role in the regulation of immunity and inflammation. This article will address the involvement of IGF-1 in innate as well as acquired immunity and host-defense. We also discuss the role of IGF-1 in the course of inflammatory disorders, including sepsis and sepsis-induced catabolism as well as degenerative arthritis. Based on recent insights, we finally examine the pathophysiological background, potential pitfalls and perspectives of IGF-1 suppletion therapy in these conditions.
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PMID:Insulin-like growth factor-1 (IGF-1) and growth hormone (GH) in immunity and inflammation. 1037 8

Both starvation and sepsis are characterized by growth hormone (GH) insensitivity, which leads to a reduction in circulating insulin-like growth factor (IGF)-I. Because of the anabolic properties of this growth factor, its decline may contribute to the growth arrest and the catabolic reaction observed in starvation and sepsis. This review focuses on the mechanisms responsible for the reduction in circulating IGF-I and impairment of GH responsiveness that occur during starvation and sepsis. A clearer understanding of the complex nature of GH resistance should lead to the development of new therapeutic strategies aimed at restoring the beneficial effects of anabolic agents such as GH and IGF-I.
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PMID:Regulation of insulin-like growth factor-I in starvation and injury. 1043 29

Endotoxin (LPS), a membrane component of gram-negative bacteria produces multiple endocrine and metabolic effects that mimic those seen in acute sepsis. It induces species-dependent alterations of the growth hormone (GH) axis that may participate in the shift of the metabolism towards catabolic events. Humans and sheep show increased GH secretion in response to LPS, as opposed to rats, which have been the most studied. The purpose of our work was to evaluate the effects in intact rams of an acute intravenous administration of a high dose of LPS on the insulin-like growth factor (IGF)-I/IGF-binding proteins (IGFBPs) system and to analyse the temporal relationship of GH axis changes with those of several hormonal and metabolic parameters such as somatostatin, cortisol, insulin, and glucose. LPS induced a late moderate decrease of total IGF-I plasma levels following a 5-h steady-state period (-26.6+/-4. 2%, P<0.05, 9 h after LPS), despite a biphasic and sustained increase of GH secretion in the same animals (2.48+/-0.39 ng/ml 2 h after LPS and 2.7+/-0.37 ng/ml 5 h after LPS vs 0.77+/-0.10 before LPS; Briard et al. 1998a). Western ligand blot analysis in IGFBPs showed an early short-lasting increase in IGFBP-1 (188.8+/-39% P<0. 05, 3 h after LPS). No significant change was seen for either IGFBP-2, -3 or -4. We observed a marked and sustained increase in cortisol (128.18+/-7.21 ng/ml 3 h after LPS, vs 21.17+/-4.22 before LPS). Insulin also increased (27.69+/-3.90 microU/ml 3 h after LPS, vs 13.48+/-1.69 before LPS) and its burst coincided with that of IGFBP-1. Moderately decreased IGF-I and increased IGFBP-1 plasma levels contrasted with the sustained increase in GH secretion that we recently described, thereby suggesting that endotoxin causes a state of resistance to GH. This may be exacerbated by reduced IGF-I bioavailability and/or action, and which may participate in the pathophysiology of the catabolic state seen in sepsis. The temporal analysis of hormone responses suggests that endotoxin-induced alterations of the IGF-I/IGFBPs system may involve the prolonged and substantial somatostatin rise that we recently demonstrated, together with an increase in glucocorticoid and cytokine as more generally assumed.
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PMID:IGF-I/IGFBPs system response to endotoxin challenge in sheep. 1069 76

Sepsis and bacterial lipopolysaccharide (LPS) injection decrease circulating concentrations of insulin-like growth factor (IGF)-I and induce an increase in IGFBP-1 and IGFBP-4 that may have impact upon IGF-I anabolic actions. Although the mechanisms responsible for the IGFBP-1 increase in response to LPS have already been unraveled, the cause for the IGFBP-4 elevation is still unknown. The aim of this study was to characterize the regulation of IGFBP-4 by proinflammatory cytokines and glucocorticoids. In rat primary cultured hepatocytes, interleukin (IL)-6 strongly stimulated IGFBP-4 messenger RNA (mRNA) and protein levels in a dose- and time-dependent way (mRNA levels: 9-fold, P: < 0.01 and protein levels: approximately 3-fold at 24 h, with IL-6 10 ng/ml). Interleukin (IL)-1ss and tumor necrosis factor (TNF)-alpha blunted the IL-6 stimulation of IGFBP-4 mRNA (66% and 46% decrease, respectively) and protein levels (82% and 68% decrease, respectively). In contrast, dexamethasone induced IGFBP-4 mRNA and protein and potentiated the effect of IL-6 on IGFBP-4 mRNA (2.5-fold, P: < 0.01 vs. IL-6 alone). Both actinomycin and cycloheximide prevented the IL-6 induction of IGFBP-4 mRNA suggesting that the IL-6 effect on IGFBP-4 gene occurs probably at the transcriptional level and needs an ongoing protein synthesis. Administration of IL-6 to rats caused a 3-fold increase in liver IGFBP-4 mRNA (P: < 0.001) reflected in serum levels of IGFBP-4 (P: < 0.05). In conclusion, our results show that IL-6 stimulates hepatic IGFBP-4 gene expression and production in vitro and in vivo, thereby suggesting another mechanism by which cytokines could control IGF-I action.
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PMID:Interleukin-6 stimulates hepatic insulin-like growth factor binding protein-4 messenger ribonucleic acid and protein. 1114 87

Severe infection causes marked derangements in the flow of glutamine among organs, and these changes are accompanied by significant alterations in regional cell membrane transport and intracellular glutamine metabolism. Skeletal muscle, the major repository of glutamine, exhibits a twofold increase in glutamine release during infection, which is associated with a significant increase in endogenous glutamine biosynthesis. Despite an increase in glutamine synthetase activity in skeletal muscle, the intracellular glutamine pool becomes depleted, indicating that release rates exceed rates of synthesis. Simultaneously, the circulating pool of glutamine does not increase, indicating accelerated uptake by other organs. The liver appears to be the major organ of glutamine uptake in severe infection; studies in endotoxemic rodents have shown net hepatic glutamine uptake to increase by as much as 8- to 10-fold. This increase is due partially to increases in liver blood flow, but also to a three- to fourfold increase in hepatocyte System N activity in the liver. Cytokines and glucocorticoids mediate the increased uptake of glutamine by the liver in septic states as well as other compounds. Sepsis does not appear to induce an increase in System N gene expression, indicating that the increase in hepatic glutamine transport observed during severe infection is probably regulated at the protein level. The bowel displays a decrease in glutamine utilization during sepsis, a response that may be related to the decrease in circulating insulin-like growth factor-1 (IGF-1) levels that is characteristic of sepsis. Recent studies suggest that IGF-1 has a direct effect on stimulating glutamine transport across the gut lumen and thus may represent a therapeutic avenue for improving gut nutrition during severe infection. The cells of the immune system (lymphocytes, macrophages) are also major glutamine consumers during inflammatory states in which cell proliferation is increased. Under these conditions, glutamine availability can become rate limiting for key cell functions, such as phagocytosis and antibody production.
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PMID:Glutamine metabolism in sepsis and infection. 1153 8

During sepsis, growth hormone (GH) resistance contributes to the catabolism of muscle protein. To determine the role of tumor necrosis factor (TNF) as a mediator of GH resistance, we examined the effects of a TNF antagonist [TNF-binding protein (TNFbp)] on the GH/insulin-like growth factor (IGF) I system during abdominal sepsis. To investigate potential mechanisms, the effects of TNF on the IGF-I response to GH and GH signaling were examined in cultured rat hepatocytes (CWSV-1). Three groups of rats were studied: Control, Sepsis, and Sepsis + TNFbp. Liver, gastrocnemius, and plasma were collected on day 5. In gastrocnemius, neither sepsis nor TNFbp altered the abundance of IGF-I mRNA. However, septic rats demonstrated an increase in circulating GH and a reduction in plasma IGF-I concentrations that was ameliorated by pretreatment with TNFbp. Liver from septic rats demonstrated a 50% reduction in GH receptor (GHR) and IGF-I mRNA on day 5 that was attenuated by TNFbp. However, the abundance of GHR protein was not different in liver from Control, Sepsis, or Sepsis + TNFbp rats. Consequently, a decreased amount of hepatic GHR does not explain the GH-resistant septic state. In CWSV-1 hepatocytes, TNF-alpha had no effect on GHR protein level but inhibited the induction of IGF-I mRNA by GH. Nuclear protein from TNF-treated hepatocytes demonstrated similar levels of phosphorylated signal transducer and activator of transcription-5 (STAT5) and DNA binding relative to controls 5 min after GH treatment. However, both of these parameters were decreased (vs. control) in TNF-treated cells 60 min after GH treatment. Collectively, these results suggest that TNF mediates hepatic GH resistance during sepsis by inhibiting the duration of signaling via the janus kinase-2/STAT5 pathway.
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PMID:Tumor necrosis factor mediates hepatic growth hormone resistance during sepsis. 1216 40

Sepsis, excessive inflammation, multiple organ failure and weakness prolong the need for intensive care in critically ill patients. Furthermore, the risk of death is high in the prolonged critically ill patient (20% after two weeks and 30% after 3 weeks). In prolonged critical illness, protein hypercatabolism and relative preservation of adipose tissue with fatty infiltration of vital organ systems is present. In view of the crucial role of the hypothalamus-pituitary axis for metabolic homeostasis, we have studied this endocrine organ in the context of critical illness. The initial "adaptive" neuroendocrine response to critical illness illness consists primarily of activated anterior pituitary function. In the chronic phase of critical illness, a uniformly reduced pulsatile secretion of anterior pituitary hormones has been observed, whereby impaired function of target organs. A reduced availability of thyrotropin (TSH)-releasing hormone (TRH), gonadotropin (LH)-releasing hormone (GnRH), the endogenous ligand of the growth hormone (GH)-releasing peptide (GHRP) receptor (ghrelin) and, in very long-stay critically ill men also of GH-releasing hormone (GHRH), inferrentially appears involved. Pulsatile secretion of GH, TSH and LH can be re-amplified by relevant combinations of releasing factors which also substantially increases circulating levels of insulin-like growth factor (IGF)-I, GH-dependent IGF-binding proteins, thyroxine (T4), triiodothyronine (T3) and testosterone. Anabolism is only evoked when GH-secretagogues, TRH and GnRH are administered together whereas the effect of single hormone treatment is minor and accompanied by side effects. A remarkable observation was that a high serum concentration of IGF-binding protein 1 predicts death in the ICU. This observation challenged the classical dogma of adaptive hyperglycemia during critical illness. In a large prospective randomized clinical study (1548 patients), we showed that ICU mortality was reduced by 42% with strict normalization of glycemia using exogenous insulin infusion (N Engl J Med 2001). This was due to prevention of typical ICU complications such as sepsis, multiple organ failure and need for prolonged invasive organ support and intensive care. We conclude that the new concept of reduced stimulation of pituitary function in prolonged critically ill patients opens new therapeutic perspectives to reverse the paradoxical 'wasting syndrome' but that maintenance of strict normoglycemia with insulin is crucial to also increase the chances of survival of these patients.
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PMID:Endocrinology in intensive care medicine: new insights and therapeutic consequences. 1223 41

The catabolic response to sepsis, severe injury, and burn is characterized by whole-body protein loss, mainly reflecting increased breakdown of muscle proteins, in particular myofibrillar proteins. Glucocorticoids and various proinflammatory cytokines are important regulators of muscle proteolysis in stressed patients. There is evidence that breakdown of proteins by the ubiquitin-proteasome pathway plays an important role in muscle cachexia, although other mechanisms may participate, such as calcium- and calpain-dependent release of myofilaments from the sarcomere. Three types of treatments have been used to reduce or prevent the catabolic response to injury and sepsis: 1). nutritional, 2). hormonal, and 3). pharmacologic. With regard to nutrition support, it is generally believed that enteral feeding is superior to parenteral feeding and that early feeding is better than late feeding. Although "immune-enhancing" enteral nutrition has been shown in several recent studies to improve outcome in critically ill patients, the specific effects of these treatments on the catabolic response in muscle are not known. In addition to nutrition support, various hormones, including insulin, growth hormone, and insulin-like growth factor-1, may blunt the catabolic response in patients with stress. Experimental studies have indicated that other treatments may become available in the future, including cytokine antibodies, calcium antagonists, and induction of heat shock response. Methods to prevent or reduce the catabolic response to stress are important considering the significant clinical consequences of muscle cachexia.
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PMID:Catabolic response to stress and potential benefits of nutrition support. 1243 20

Sepsis and endotoxin (LPS or lipopolysaccharide) injection induce a state of growth hormone (GH) resistance leading to decreased circulating insulin-like growth factor (IGF)-I. Because the proinflammatory cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta inhibit the GH-stimulated IGF-I expression in vitro, it was tempting to speculate that these two cytokines might play an important role in the reduction of circulating IGF-I levels caused by LPS. Pentoxifylline, a methylxanthine usually used in the treatment of peripheral arterial circulatory disorders, has been reported to inhibit TNF-alpha synthesis. The goal of our study was to investigate whether inhibition of TNF-alpha production by pentoxifylline could prevent the decrease in IGF-I and the GH resistance caused by LPS injection. Because previous studies demonstrated that pentoxifylline can reduce muscle catabolism induced by sepsis, we also assessed whether pentoxifylline could exert its anticatabolic effect by preventing the decrease in circulating IGF-I. LPS injection in rats decreased serum IGF-I (-45% at 12 h; P<0.01 vs time 0) and its liver mRNA (-67% at 12 h; P<0.01 vs time 0) while it induced circulating TNF-alpha and IL-1beta and their hepatic expression (P<0.01). Pretreatment of LPS-treated animals by pentoxifylline abolished the LPS-induced rise in serum TNF-alpha (-98% at 90 min; P<0.001 vs LPS alone) and to a lesser extent in serum IL-1beta (-44% at 3 h; not significant vs LPS alone). Despite its dramatic inhibitory effect on TNF-alpha induction, however, pentoxifylline failed to suppress both the decrease in IGF-I and the GH resistance induced by LPS in rats. These results suggest that mediators other than TNF-alpha, in particular IL-1beta or IL-6, could contribute to the GH resistance induced by LPS. They also suggest that the anticatabolic effect of pentoxifylline is not due to prevention of the decline of circulating IGF-I.
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PMID:Inhibition of TNF-alpha production by pentoxifylline does not prevent endotoxin-induced decrease in serum IGF-I. 1284 41

Growth hormone (GH) and insulin-like growth factor (IGF)-I are potent regulators of muscle mass in health and disease. This somatomedin axis is markedly deranged in various catabolic conditions in which circulating and tissue levels of inflammatory cytokines are elevated. The plasma concentration of IGF-I, which is primarily determined by hepatic synthesis and secretion of the peptide hormone, is dramatically decreased during catabolic and inflammatory conditions. Moreover, many of these conditions are also associated with an inability of GH to stimulate hepatic IGF-I synthesis. This defect results from an impaired phosphorylation and activation of the traditional JAK2/STAT5 signal transduction pathway. Numerous lines of evidence support the role of tumor necrosis factor (TNF)-alpha as a prominent but probably not the sole mediator of the sepsis-induced impairment in basal and GH-stimulated IGF-I synthesis in liver. Additionally, catabolic conditions produce comparable alterations in skeletal muscle. However, in contrast to liver, the GH resistance in muscle is not mediated by a defect in STAT5 phosphorylation. Muscle is now recognized to respond to infectious stimuli with the production of numerous inflammatory cytokines, including TNF-alpha. Furthermore, myocytes cultured with TNF-alpha are GH resistant and this defect appears mediated via a STAT5-independent but JNK-dependent mechanism. Collectively, these changes act to limit IGF-I availability in muscle, which disturbs protein balance and results in the loss of protein stores in catabolic and inflammatory conditions.
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PMID:Cytokine inhibition of JAK-STAT signaling: a new mechanism of growth hormone resistance. 1554 17


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