Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor alpha (TNF-alpha) has well-described effects on lipid metabolism in the context of acute inflammation, as in sepsis. Recently, increased TNF-alpha production has been observed in adipose tissue derived from obese rodents or human subjects and TNF-alpha has been implicated as a causative factor in obesity-associated insulin resistance and the pathogenesis of type 2 diabetes. Thus, current evidence suggests that administration of exogenous TNF-alpha to animals can induce insulin resistance, whereas neutralization of TNF-alpha can improve insulin sensitivity. Importantly, results from knockout mice deficient in TNF-alpha or its receptors have suggested that TNF-alpha has a role in regulating in vivo insulin sensitivity. However, the absence of TNF-alpha action might only partially protect against obesity-induced insulin resistance in mice. Multiple mechanisms have been suggested to account for these metabolic effects of TNF-alpha. These include the downregulation of genes that are required for normal insulin action, direct effects on insulin signaling, induction of elevated free fatty acids via stimulation of lipolysis, and negative regulation of PPAR gamma, an important insulin-sensitizing nuclear receptor. Although current evidence suggests that neutralizing TNF-alpha in type 2 diabetic subjects is not sufficient to cause metabolic improvement, it is still probable that TNF-alpha is a contributing factor in common metabolic disturbances such as insulin resistance and dyslipidemia.
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PMID:Potential role of TNF-alpha in the pathogenesis of insulin resistance and type 2 diabetes. 1087 50

Dyslipidemia seen in the critically ill patient is a common disturbance, poorly recognized by physicians in this setting. Shock states, sepsis, multifactorial systemic inflammatory response syndrome and ischemia-reperfusion injury are associated with important metabolic changes that contribute to this disturbance. As a result, the lipid concentration, including cholesterol, high-density lipoproteins and apo-lipoprotein A-I, diminishes. Previous reports correlate the disturbance in lipids with a higher risk of infection, systemic inflammatory response syndrome, multiple organic dysfunction syndrome, and raised mortality. The use of reconstituted high-density lipoprotein may be a therapeutic alternative for the management of this entity.
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PMID:[Dyslipidemia in the critically ill patient]. 1633 7

Dyslipidemia and insulin resistance are commonly associated with catabolic or lipodystrophic conditions (such as cancer and sepsis) and with pathological states of nutritional overload (such as obesity-related type 2 diabetes). Two common features of these metabolic disorders are adipose tissue dysfunction and elevated levels of tumour necrosis factor-alpha (TNF-alpha). Herein, we review the multiple actions of this pro-inflammatory adipokine on adipose tissue biology. These include inhibition of carbohydrate metabolism, lipogenesis, adipogenesis and thermogenesis and stimulation of lipolysis. TNF-alpha can also impact the endocrine functions of adipose tissue. Taken together, TNF-alpha contributes to metabolic dysregulation by impairing both adipose tissue function and its ability to store excess fuel. The molecular mechanisms that underlie these actions are discussed.
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PMID:TNF-alpha and adipocyte biology. 1803 76

Plasma VLDL accumulation in Gram-negative sepsis is partly ascribed to an increased hepatic VLDL production driven by pro-inflammatory cytokines. We previously showed that hepatocytes of the Kupffer cell (KC)-rich periportal area are major contributors to enhanced VLDL production in lipopolysaccharide (LPS)-injected rats. However, it remains to be established whether KC generated products directly affect the number (apoB) and composition of secreted VLDL. Using rat primary cells, we show here that hepatocytes respond to stimulation by soluble mediators released by LPS-stimulated Kupffer cells with enhanced secretion of apoB and triglycerides in phospholipid-rich VLDL particles. Unstimulated KC products also augmented the secretion of normal VLDL, doubling apoB mRNA abundance. IL-1beta treatment resulted in concentration-dependent increases of hepatocyte apoB mRNA and protein secretion, increases that were greater, but not additive, when combined with IL-6 and TNF-alpha. Lipid secretion and MTP mRNA levels were unaffected by cytokines. In summary: (i) enhanced secretion of phospholipid-rich VLDL particles is a net hepatocyte response to LPS-stimulated KC products, which gives a clue about the local role of Kupffer cells in septic dyslipidemia induction; and (ii) pro-inflammatory cytokines act redundantly to enhance apoB secretion involving translational apoB up-regulation, but other humoral components or KC mediators are necessary to accomplish increased lipid association.
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PMID:Kupffer cell products and interleukin 1beta directly promote VLDL secretion and apoB mRNA up-regulation in rodent hepatocytes. 1866 11

The traditional view of atherosclerosis has recently been expanded from a predominantly lipid retentive disease to a coupling of inflammatory mechanisms and dyslipidemia. Studies have suggested a novel role for polymorphonuclear neutrophil (PMN)-dominant inflammation in the development of atherosclerosis. Human neutrophil peptides (HNPs), also known as alpha-defensins, are secreted and released from PMN granules upon activation and are conventionally involved in microbial killing. Current evidence suggests an important immunomodulative role for these peptides. HNP levels are markedly increased in inflammatory diseases including sepsis and acute coronary syndromes. They have been found within the intima of human atherosclerotic arteries, and their deposition in the skin correlates with the severity of coronary artery diseases. HNPs form complexes with LDL in solution and increase LDL binding to the endothelial surface. HNPs have also been shown to contribute to endothelial dysfunction, lipid metabolism disorder, and the inhibition of fibrinolysis. Given the emerging relationship between PMN-dominant inflammation and atherosclerosis, HNPs may serve as a link between them and as a biological marker and potential therapeutic target in cardiovascular diseases including coronary artery diseases and acute coronary syndromes.
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PMID:Human neutrophil peptides: a novel potential mediator of inflammatory cardiovascular diseases. 1880 97

Statins are increasingly being used to treat solid-organ transplant recipients for posttransplantation metabolic complications. In addition to improving dyslipidemia, statins also have manifold non-lipid-lowering effects. With regard to sepsis or infection, these agents modify the inflammatory cascades by pleiotropic actions at multiple levels and exhibit activities against opportunistic bacteria, fungi, and viruses that can cause serious infections in solid-organ transplant recipients. They also have synergistic interactions with antimicrobial agents. Statins with antimicrobial and immunomodulatory attributes might improve morbidity and mortality attributable to sepsis or infection in solid-organ transplant recipients.
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PMID:Antimicrobial and immunomodulatory attributes of statins: relevance in solid-organ transplant recipients. 2000 24

There is currently no consensus about the indications for therapeutic apheresis, also due to the lack of large clinical trials. A registry where all the data can be organized and analyzed therefore becomes a priority for all professionals involved in apheresis. The Apheresis Study Group of the Italian Society of Nephrology has instituted a registry for data collection. This report describes data collected from 1994 to 2008 by 68 units of different specialties in 15 Italian regions. Data about 29,260 treatments on 2,503 patients were recorded. Plasma exchange accounted for 43.4% of the procedures; 37% of these were performed by filtration. Plasma treatment was used in 48% of procedures, in particular with protein A immunoadsorption (11%), LDL-cholesterol apheresis by dextran sulfate adsorption (13%), and semiselective cascade or double filtration (12.5%). Cell apheresis, limited to photopheresis and leukocytapheresis, was used in 3.6% of cases, and whole blood treatment, with different techniques, in 5% of cases for the treatment of dyslipidemia, liver failure and sepsis. These procedures account for about 20% of the estimated therapeutic apheresis performed in Italy according to the national survey performed for the year 2005 by the Italian Apheresis and Cell Manipulation Society. The data collected are sufficiently informative to show a definite trend to use plasma/whole blood treatments as often as possible. The registry not only is a tool for consultation and information, but also a platform to plan and realize interdisciplinary and multicenter clinical trials.
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PMID:[The Italian Registry for Therapeutic Apheresis: fifteen years of activity]. 1925 67

Dyslipidemia and hepatic overproduction of very low density lipoprotein (VLDL) are hallmarks of the septic response, yet the underlying mechanisms are not fully defined. We evaluated the lipoprotein subclasses profile and hepatic VLDL assembly machinery over 24 h in fasted LPS-treated rats. The response of serum non-esterified fatty acids (NEFA) and glucose to endotoxin was biphasic, with increased levels of NEFA and hypoglycemia in the first 12 h-phase, and low NEFA and high glucose in the second 12 h-phase. Hypertriglyceridemia was more marked in the first 12 h (6.8-fold), when triglyceride abundance increased in all lipoprotein subclasses, and preferentially in large VLDL. The abundance of medium-sized VLDL and the increase in the number of VLDL particles was higher in the second phase (10-fold vs 5-fold in the first phase); however, apoB gene transcript abundance increased only in the second phase. Analysis of putative pre-translational mechanisms revealed that neither increased Apob transcription rate nor increased transcript binding to mRNA stabilizing HuR (Hu antigen R) protein paralleled the increase in apoB transcripts. In conclusion, endotoxin challenge induces increases in plasma NEFA and large, triglyceride-rich VLDL. After approximately 12 h, the triglyceride-rich VLDLs are replaced by medium-sized, triglyceride-poor VLDL particles. Hepatic apoB mRNA abundance also increases during the second period, suggesting a role for apoB protein expression in the acute reaction against sepsis.
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PMID:Biphasic adaptative responses in VLDL metabolism and lipoprotein homeostasis during Gram-negative endotoxemia. 2111 81

Advances in immunotherapy have improved survival of patients with systemic lupus erythematosus who now face an increasing burden of chronic diseases including that of the kidney. As systemic inflammation is also thought to contribute directly to the progression of chronic kidney disease (CKD), we assessed this risk in patients with lupus, with and without a diagnosis of nephritis, and also identified modifiable risk factors. Accordingly, we enrolled 631 patients (predominantly Caucasian), of whom 504 were diagnosed with lupus within the first year and followed them an average of 11 years. Despite the presence of a chronic inflammatory disease, the rate of decline in renal function of 238 patients without nephritis was similar to that described for non-lupus patient cohorts. Progressive loss of kidney function developed exclusively in patients with lupus nephritis who had persistent proteinuria and dyslipidemia, although only six required dialysis or transplantation. The mortality rate was 16% with half of the deaths attributable to sepsis or cancer. Thus, despite the presence of a systemic inflammatory disease, the risk of progressive CKD in this lupus cohort was relatively low in the absence of nephritis. Hence, as in idiopathic glomerular disease, persistent proteinuria and dyslipidemia (modifiable risks) are the major factors for CKD progression in lupus patients with renal involvement.
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PMID:Persistent proteinuria and dyslipidemia increase the risk of progressive chronic kidney disease in lupus erythematosus. 2156 55

Dyslipidaemia is commonly observed in patients with active rheumatoid arthritis (RA), with lower total cholesterol levels as well as lower levels of high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) reported in these patients than in individuals without RA. This pattern is mirrored in sepsis and other inflammatory states, suggesting systemic inflammation has the general effect of lowering circulating lipid levels. In line with such observations, suppressing inflammation with DMARDs, biologic therapies and small-molecule Janus kinase inhibitors seems to elevate levels of lipid fractions in RA, albeit in a variable manner dependent presumably upon the mechanism of action of the different agents. In addition, limited epidemiological data in patients with RA suggest increased cardiovascular disease (CVD) risk at relatively low cholesterol levels, a pattern contrasting with that observed in the population without RA. Our understanding of the potential mechanisms behind these inflammation-associated lipid changes remains suboptimal and requires further study. In clinical terms, however, use of the total cholesterol to HDL-C ratio as the lipid component of CVD risk scoring in patients with RA would seem appropriate given that these lipid parameters generally change in parallel with inflammation and suppression of inflammation. Whether alternative lipid or lipoprotein measures (or simple markers of inflammation) could improve stratification of CVD risk in RA beyond the established risk factors requires future investigation.
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PMID:Changes in lipid levels with inflammation and therapy in RA: a maturing paradigm. 2377 6


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