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)

Inflammatory response leading to organ dysfunction and failure continues to be the major problem after injury in many clinical conditions such as sepsis, severe burns, acute pancreatitis, haemorrhagic shock, and trauma. In general terms, systemic inflammatory response syndrome (SIRS) is an entirely normal response to injury. Systemic leukocyte activation, however, is a direct consequence of a SIRS and if excessive, can lead to distant organ damage and multiple organ dysfunction syndrome (MODS). When SIRS leads to MODS and organ failure, the mortality becomes high and can be more than 50%. Acute lung injury that clinically manifests as acute respiratory distress syndrome (ARDS) is a major component of MODS of various aetiologies. Inflammatory mediators play a key role in the pathogenesis of ARDS, which is the primary cause of death in these conditions. This review summarizes recent studies that demonstrate the critical role played by inflammatory mediators such as tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, platelet activating factor (PAF), IL-10, granulocyte macrophage-colony stimulating factor (GM-CSF), C5a, intercellular adhesion molecule (ICAM)-1, substance P, chemokines, VEGF, IGF-I, KGF, reactive oxygen species (ROS), and reactive nitrogen species (RNS) in the pathogenesis of ARDS. It is reasonable to speculate that elucidation of the key mediators in ARDS coupled with the discovery of specific inhibitors would make it possible to develop clinically effective anti-inflammatory therapy.
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PMID:Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome. 1474 96

We investigated the impact of GH administration on endothelial adhesion molecules, vascular cell adhesion molecule-1 (VCAM-1) and E-selectin, in vivo and in vitro. Soluble VCAM-1, E-selectin, and C-reactive protein concentrations were measured before and after treatment in 25 healthy subjects and 25 adult GH-deficient (GHD) patients randomized to GH treatment or placebo. Furthermore, we studied the direct effect of GH and IGF-I and serum from GH-treated subjects on basal and TNF alpha-stimulated expression of VCAM-1 and E-selectin on cultured human umbilical vein endothelial cells. Baseline levels of VCAM-1, but not E-selectin, were significantly lower in GHD patients than in healthy subjects (362 +/- 15 microg/liter vs. 516 +/- 21 microg/liter, P < 0.001) and increased in GHD patients during GH treatment, compared with placebo [net difference between groups 151.8 microg/liter (95% confidence interval: 95.0-208.7 microg/liter); P < 0.0001]. In human umbilical vein endothelial cells, there was no direct stimulatory effect of either GH or IGF-I on the expression of VCAM-1 and E-selectin, but serum from GH-treated healthy subjects significantly increased the expression of VCAM-1 (P < 0.01). Our findings are compatible with the notion that GH may stimulate the expression of VCAM-1 indirectly through modulation of circulating factors. VCAM-1-mediated leukocyte extravasation is implicated in several illnesses including atherosclerosis and multiple-organ failure in sepsis, and we hypothesize that enhanced expression of VCAM-1 may contribute to the detrimental effects of GH in critically ill patients.
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PMID:Growth hormone increases vascular cell adhesion molecule 1 expression: in vivo and in vitro evidence. 1476 13

Infections direct amino acids away from growth and skeletal muscle accretion toward the hepatic synthesis of acute-phase proteins. The loss of skeletal muscle protein stores results in both a decrease in muscle function and an increase in mortality. In general, muscle protein synthesis is decreased in rodent models of sepsis, as well as after the injection of components of the bacterial cell wall, such as lipopolysaccharide. Although the overexpression of proinflammatory cytokines is known to hasten the loss of skeletal muscle protein, it is not known whether this represents a direct effect of cytokines or results from secondary changes in the IGF system. Plasma concentrations of IGF-I are dramatically lowered by infection in rats, mice, pigs, and steers. The drop in IGF-I often occurs despite an increase in the plasma concentration of somatotropin. Animals are therefore considered to be GH resistant. The IGF bioactivity is determined not only by the plasma concentration of the ligand, but also by IGFBP; IGFBP-3 is the most abundant of these binding proteins and undergoes proteolysis during some catabolic states. In contrast to IGFBP-3, the plasma concentration of inhibitory IGFBP, such as IGFBP-1, is increased during infection. Insulin-like growth factor-binding protein-1 accumulates in skeletal muscle, where it can potentially inhibit IGF-dependent protein synthesis. Insulin-like growth factor-I and IGFBP-1 are regulated at the level of gene transcription by proinflammatory cytokines. Recent studies demonstrate that bacterial components that activate immune cells also activate the innate immune response in skeletal muscle. Lipopolysaccharide increases proinflammatory cytokine messenger RNA expression in muscle from control mice, but not from mice with a mutation in the lipopolysaccharide receptor. Lipopolysaccharide also increases cytokine expression in human and mouse myoblasts. Local expression of cytokines in skeletal muscle may negatively regulate the autocrine synthesis of IGF-I. Current work is focused on deciphering the mechanism by which muscle becomes GH resistant and the development of therapies to maintain muscle protein stores during infection.
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PMID:Alteration of somatotropic function by proinflammatory cytokines. 1547 89

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

Sepsis results in hepatic "growth hormone (GH) resistance" with reductions in plasma IGF-I despite a two- to fourfold increase in circulating GH. In this study, we examine the effects of IL-1 on GH receptor (GHR) expression, GH signaling (via the JAK/STAT and MAPK pathways), and the induction of gene expression [IGF-I mRNA and serine protease inhibitor (Spi) 2.1] by GH in CWSV-1 hepatocytes. Incubation of cells with IL-1beta (10 ng/ml, 24 h) had no effect on the relative abundance of GHR or signaling proteins JAK2, STAT5b, and ERK1/2 in cell lysates. Baseline phosphorylation of GHR, JAK2, STAT5b, and ERK1/2 was minimal. After GH stimulation, tyrosine phosphorylation of GHR, JAK2, STAT5b, and ERK1/2 increased 2- to 10-fold. However, neither the time course nor the magnitude of GHR, JAK2, and ERK1/2 phosphorylation by GH were significantly altered by IL-1. The GH-induced translocation of STAT5b to the nucleus was not prevented by IL-1. Although phosphorylated STAT5 in nuclear extracts from GH + IL-1 cells was decreased by 24% (vs. controls) 15 min after GH stimulation, this did not result in reduced STAT5-DNA binding activity. Pretreatment with IL-1 did not significantly decrease IGF-I mRNA stability. We conclude that IL-1 only minimally affects the time course of JAK2/STAT5 and MAPK signaling by GH. Therefore, an inhibitory effect of IL-1 on IGF-I and Spi 2.1 mRNA synthesis by GH represents the most likely mechanism for IL-1-mediated GH resistance.
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PMID:Interleukin-1 inhibits the induction of insulin-like growth factor-I by growth hormone in CWSV-1 hepatocytes. 1583 12

Critical illness has an important impact on the human endocrine system. Very few studies have been performed to elucidate the alterations of the GH/IGF-I axis in acutely ill children. The aim of this study was to investigate several parameters of this axis in children with trauma (TRA) and sepsis (SEP) requiring admission to the pediatric intensive care unit (PICU). A total of 16 children, ten with TRA and six with SEP (age 1-10 years) as well as 18 healthy children (CS) of similar age and gender were included in the study. Two children, one with TRA and one with SEP, died. Serum IGF-I and -II, IGFBP-1 and -3, and GH levels were measured on days 1, 3 and 7 after admission. GH levels were higher in the patients than in CS (p = 0.04), with no difference between TRA and SEP, and were elevated during PICU stay (p = 0.05). Serum IGF-I, -II and IGFBP-3 were lower in the patients than in CS (p = 0.03, 0.02 and 0.001, respectively) with a tendency to increase up to day 7. Finally, IGFBP-1 levels were similar in the patients and CS. These findings indicate that critically ill children are characterized by low levels of IGF-I and -II as well as IGFBP-3 accompanied by elevated levels of GH, probably reflecting the development of peripheral GH resistance. No significant differences were found between the different catabolic conditions, sepsis and trauma.
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PMID:Activity of the growth hormone/insulin-like growth factor-I axis in critically ill children. 1584 70

The triglyceride content of lipid depots associated with the current feeding level is the primary determinant of leptin gene expression and the circulating leptin level. In laboratory rodents and primates the plasma leptin is influenced also by the age, gender and physiological status (puberty, pregnancy, lactation, postpartum period), and by the health condition such as sepsis due to Gram-negative (GN) bacteria. Some pathologic conditions with intensive cytokine release evoke an increase in plasma leptin, which is thought to depress the subsequent feed intake. However, the effect of these secondary factors may be species-dependent, with still unknown clinical relevance in ruminants. In our ovine and bovine models plasma leptin increased after castration and dexamethasone treatment, decreased after experimental administration of synthetic androgens in castrated rams, but remained unchanged throughout the ovarian cycle and after ovariectomy. The circulating leptin level increased temporarily during synthetic progestin (fluorogestone) treatment in ewes, but similar changes were not seen in progesterone-supplemented ewes and norgestomet-treated cows. In a second trial on dairy cows we wanted to study whether elevated plasma leptin levels are induced by experimental endotoxin mastitis, or by natural outbreak of GN mastitis and puerperal metritis. Experimental endotoxin mastitis resulted in some-hour elevation in cortisol and insulin, with a simultaneous decrease in IGF-I and thyroid hormones. In the first 14 days of lactation GN mastitis induced the same endocrine alterations as the experimental endotoxin challenge, but in natural cases these changes varied within a wider range, and were more protracted and robust. Cows with puerperal metritis had more obvious catabolic changes in the early weeks of lactation, than their healthy counterparts. However, both mastitis and puerperal metritis failed to increase the circulating leptin level, showing that in cows the plasma leptin is not responsible for the anorexia associated with these inflammatory diseases.
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PMID:Feeding-unrelated factors influencing the plasma leptin level in ruminants. 1588 61

Chronic septic abscess formation causes an inhibition of protein synthesis in gastrocnemius not observed in rats with a sterile abscess. Inhibition is associated with an impaired mRNA translation initiation that can be ameliorated by elevating IGF-I but not insulin. The present study investigated the ability of IGF-I signaling to stimulate protein synthesis in gastrocnemius by accelerating mRNA translation initiation. Experiments were performed in perfused hindlimb preparations from rats 5 days after induction of a septic abscess. Protein synthesis in gastrocnemius from septic rats was accelerated twofold by the addition of IGF-I (10 nM) to perfusate. IGF-I increased the phosphorylation of translation repressor 4E-binding protein-1 (4E-BP1). Hyperphosphorylation of 4E-BP1 in response to IGF-I resulted in its dissociation from the inactive eukaryotic initiation factor (eIF) 4E.4E-BP1 complex. Assembly of the active eIF4F complex (as assessed by the association eIF4G with eIF4E) was increased twofold by IGF-I in the perfusate. In addition, phosphorylation of eIF4G and ribosomal protein S6 kinase-1 (S6K1) was also enhanced by IGF-I. Activation of mammalian target of rapamycin, an upstream kinase implicated in phosphorylating both 4E-BP1 and S6K1, was also observed. Thus the ability of IGF-I to accelerate protein synthesis during sepsis may be related to a stimulation of signaling to multiple steps in translation initiation with an ensuing increased phosphorylation of eIF4G, eIF4E availability, and S6K1 phosphorylation.
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PMID:IGF-I stimulates protein synthesis in skeletal muscle through multiple signaling pathways during sepsis. 1615 Aug 39

The purpose of the present study was to determine whether catabolic stimuli that induce muscle atrophy alter the muscle mRNA abundance of insulin-like growth factor binding protein (IGFBP)-4 and -5, and if so determine the physiological mechanism for such a change. Catabolic insults produced by endotoxin (LPS) and sepsis decreased IGFBP-5 mRNA time- and dose-dependently in gastrocnemius muscle. This reduction did not result from muscle disuse because hindlimb immobilization increased IGFBP-5. Continuous infusion of a nonlethal dose of tumor necrosis factor-alpha (TNF-alpha) decreased IGFBP-5 mRNA 70%, whereas pretreatment of septic rats with a neutralizing TNF binding protein completely prevented the reduction in muscle IGFBP-5. The addition of LPS or TNF-alpha to cultured C(2)C(12) myoblasts also decreased IGFBP-5 expression. Although exogenously administered growth hormone (GH) increased IGFBP-5 mRNA 2-fold in muscle from control rats, muscle from septic animals was GH resistant and no such elevation was detected. In contrast, exogenous administration of IGF-I as part of a binary complex composed of IGF-I/IGFBP-3 produced comparable increases in IGFBP-5 mRNA in both control and septic muscle. Concomitant determinations of IGF-I mRNA content revealed a positive linear relationship between IGF-I and IGFBP-5 mRNA in the same muscle in response to LPS, sepsis, TNF-alpha, and GH treatment. Although dexamethasone decreased muscle IGFBP-5, pretreatment of rats with the glucocorticoid receptor antagonist RU486 did not prevent the sepsis-induced decrease in IGFBP-5 mRNA. In contrast, muscle IGFBP-4 mRNA abundance was not significantly altered by LPS, sepsis, or hindlimb immobilization. In summary, these data demonstrate that various inflammatory insults decrease muscle IGFBP-5 mRNA, without altering IGFBP-4, by a TNF-dependent glucocorticoid-independent mechanism. Finally, IGF-I appears to be a dominant positive regulator of IGFBP-5 gene expression in muscle under both normal and catabolic conditions.
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PMID:Sepsis and inflammatory insults downregulate IGFBP-5, but not IGFBP-4, in skeletal muscle via a TNF-dependent mechanism. 1633 87

Various atrophic stimuli increase two muscle-specific E3 ligases, muscle RING finger 1 (MuRF1) and atrogin-1, and knockout mice for these "atrogenes" display resistance to denervation-induced atrophy. The present study determined whether increased atrogin-1 and MuRF1 mRNA are mediated by overproduction of endogenous glucocorticoids or inflammatory cytokines in adult rats and whether atrogene expression can be downregulated by anabolic agents such as insulin-like growth factor (IGF)-I and the nutrient-signaling amino acid leucine. Both atrogin-1 and MuRF1 mRNA in gastrocnemius was upregulated dose and time dependently by endotoxin. Additionally, peritonitis produced by cecal ligation and puncture increased atrogin-1 and MuRF1 mRNA in gastrocnemius (but not soleus or heart) by 8 h, which was sustained for 72 and 24 h, respectively. Whereas the sepsis-induced increase in atrogin-1 expression was completely prevented by IGF-I, the increased MuRF1 was not altered. In contrast to the IGF-I effect, the sepsis-induced increased mRNA of both atrogenes was unresponsive to either acute or repetitive administration of leucine. Whereas exogenous infusion of TNF-alpha increased atrogin-1 and MuRF1 in gastrocnemius, pretreatment of septic rats with the TNF antagonist TNF-binding protein did not prevent increased expression of either atrogene. Similarly, whereas dexamethasone increased atrogene expression, pretreatment with the glucocorticoid receptor antagonist RU-486 failed to ameliorate the sepsis-induced increase in atrogin-1 and MuRF1. Thus, under in vivo conditions in mature adult rats, the sepsis-induced increase in muscle atrogin-1 and MuRF1 mRNA appears both glucocorticoid and TNF independent and is unresponsive to leucine.
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PMID:Hormone, cytokine, and nutritional regulation of sepsis-induced increases in atrogin-1 and MuRF1 in skeletal muscle. 1700 38


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