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)

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

A patient with chronic lymphocytic leukaemia (CLL) progressive on fludarabine therapy and life-threatening anaemia related to immune haemolysis and pure red cell aplasia was treated with Campath-1H. The patient had sustained complete remission of both CLL and anaemia, but died of recurrent sepsis and cachexia 10 months after completion of the treatment. Campath-1H (alemtuzumab), a humanised anti-CD52 monoclonal antibody, is a potent therapeutic agent against advanced CLL and immune cytopenias. It could be indicated in the treatment of severe immune complications of CLL unresponsive to corticosteroids. Prolonged immunosuppression is a serious side-effect leading to severe infectious complication.
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PMID:Treatment of pure red cell aplasia and autoimmune haemolytic anaemia in chronic lymphocytic leukaemia with Campath-1H. 1269 69

Uncoupling protein 3 (UCP3) is a member of the mitochondrial transporter superfamily that is expressed primarily in skeletal muscle. UCP3 is upregulated in various conditions characterized by skeletal muscle atrophy, including hyperthyroidism, fasting, denervation, diabetes, cancer, lipopolysaccharide (LPS), and treatment with glucocorticoids (GCs). The influence of sepsis, another condition characterized by muscle cachexia, on UCP3 expression and activity is not known. We examined UCP3 gene and protein expression in skeletal muscles from rats after cecal ligation and puncture and from sham-operated control rats. Sepsis resulted in a two- to threefold increase in both mRNA and protein levels of UCP3 in skeletal muscle. Treatment of rats with the glucocorticoid receptor antagonist RU-38486 prevented the sepsis-induced increase in gene and protein expression of UCP3. The UCP3 mRNA and protein levels were increased 2.4- to 3.6-fold when incubated muscles from normal rats were treated with dexamethasone (DEX) and/or free fatty acids (FFA) ex vivo. In addition, UCP3 mRNA and protein levels were significantly increased in normal rat muscles in vivo with treatment of either DEX or FFA. The results suggest that sepsis upregulates the gene and protein expression of UCP3 in skeletal muscle, which may at least in part be mediated by GCs and FFA.
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PMID:Expression of uncoupling protein 3 is upregulated in skeletal muscle during sepsis. 1272 Nov 57

Tumor necrosis factor (TNF; formerly known as TNFalpha) and lymphotoxin (LT)alpha, originally characterized by their ability to induce tumor cell apoptosis and cachexia, are now considered as central mediators of a broad range of biological activities. These activities encompass beneficial effects for the host in inflammation and in protective immune responses against a variety of infectious pathogens. TNF family members on the other hand also exert host-damaging effects in sepsis, in tumor cachexia as well as in autoimmune diseases. In addition, the essential roles of the core members of the TNF superfamily, LTalpha, LTbeta, TNF, and LIGHT as well as their receptors during the organogenesis of secondary lymphoid organs and the maintenance of the architecture of lymphatic tissues now becomes appreciated. The elucidation of the biological functions of these cytokines and their specific cell surface receptors has been crucially advanced by the study of gene-targeted mouse strains. This presentation summarizes the roles of TNFR and TNF-like cytokines in infection, sepsis and autoimmunity as well as the pivotal involvement of these molecules in the development of secondary lymphoid organs.
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PMID:Biological functions of tumor necrosis factor cytokines and their receptors. 1278 58

Evidence from a recent study indicates that glucocorticoids (GCs) mediate skeletal muscle proteolysis during sepsis via the GC receptor (GR) pathway. Attempts to identify the mechanisms regulating GR gene expression in skeletal muscle during sepsis have been hampered by the lack of an appropriate in vitro model system that can mimic in vivo septic conditions. In the present study, we report that GR gene transcription in L6 myocytes in vitro is up-regulated by treatment with sera from septic rats in a manner similar to that measured in septic rats in vivo. Sera from septic rats were collected from animals in which sepsis was induced by caecal ligation and puncture and from control rats that were sham-operated. Finally, by treating L6 myotubes with the GR antagonist RU 38486, thereby preventing sepsis-induced GR transcription, we confirmed that the possible septic effect on the GR was due to increased GCs. L6 myocytes treated with sera from septic rats might therefore be useful as an experimental model for identifying the molecular mechanisms by which the GR regulates muscle cachexia during sepsis. Furthermore, RU 38486 inhibited the sepsis-induced increase in total and myofibrillar energy-dependent protein breakdown rates in incubated extensor digitorum longus muscles from septic and sham-operated rats, as measured by release of tyrosine and 3-methylhistidine respectively. Our results demonstrate for the first time that sepsis induces GR transcription in skeletal muscle, and supports the hypothesis that the GC-induced proteolysis under sepsis is partially a consequence of GR activation.
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PMID:Sepsis induces the transcription of the glucocorticoid receptor in skeletal muscle cells. 1565 87

The loss of lean body mass (muscle wasting) is initiated by cascades or events that precipitate increased proteolysis. Muscle wasting is stimulated by internal and external factors. Humorally related feedback loops stimulated by disease states, e.g., cancer, inflammatory myopathies, leukemia, or sepsis, and initiated as a response to systemic inflammatory response syndrome can cause a downward progression of events, resulting in chronic illness or even death. This article discusses the pathogenesis of muscle wasting, which is often referred to as cachexia.
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PMID:Muscle wasting. 1296 68

To study the impact of T-box transcription factor (T-bet) on initiation and progression of Staphylococcus aureus sepsis and arthritis, T-bet-deficient mice (T-bet(-/-)) and their wild-type controls (T-bet(+/+)) were intravenously inoculated with 8 x 10(6) S. aureus. Already 48 h after inoculation of S. aureus, T-bet-deficient mice displayed increased frequency (62% versus 19%, P = 0.002) as well as severity of arthritis compared with wild-type controls. The bacterial counts were significantly increased in T-bet(-/-) mice compared with T-bet(+/+) as measured in kidneys 72 h after the inoculation (4.3 +/- 1.8 x 10(7) versus 3.2 +/- 3.2 x 10(6) colony-forming units (CFU); P = 0.003). As expected, T-bet-deficient mice displayed significantly decreased production of IFN-gamma (10-15-fold) at 24 and 72 h after bacterial inoculation compared with wild-type mice. Interestingly, in the absence of T-bet, serum IL-4 was decreased at 24 h. IL-6 did not differ at early stage of infection but was sixfold increased in T-bet(-/-) mice over T-bet(+/+) animals at 72 h postinoculation. Ten days after the inoculation, T-bet(-/-) mice still displayed significantly more pronounced weight loss and increased serum IL-6 levels, probably due to increased bacterial burden compared with T-bet(+/+) mice. The cumulative mortality was 19% in T-bet mice (5/27) and 0% (0/27) in control animals (P = 0.05). In conclusion, T-bet plays an important role in early response to S. aureus infection, protecting against bacterial accumulation, cachexia and septic death. Furthermore T-bet downregulates joint inflammation in the early phase of disease.
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PMID:T-box transcription-factor-deficient mice display increased joint pathology and failure of infection control during staphylococcal arthritis. 1515 85

The members of the tumour necrosis factor (TNF)/tumour necrosis factor receptor (TNFR) superfamily are critically involved in the maintenance of homeostasis of the immune system. The biological functions of this system encompass beneficial and protective effects in inflammation and host defence as well as a crucial role in organogenesis. At the same time, members of this superfamily are responsible for host damaging effects in sepsis, cachexia, and autoimmune diseases. This review summarizes recent progress in the immunobiology of the TNF/TNFR superfamily focusing on results obtained from animal studies using gene targeted mice. The different modes of signalling pathways affecting cell proliferation, survival, differentiation, apoptosis, and immune organ development as well as host defence are reviewed. Molecular and cellular mechanisms that demonstrate a therapeutic potential by targeting individual receptors or ligands for the treatment of chronic inflammatory or autoimmune diseases are discussed.
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PMID:The intriguing biology of the tumour necrosis factor/tumour necrosis factor receptor superfamily: players, rules and the games. 1581 93

Atrophy of skeletal muscle is common to a number of conditions, including cancer, sepsis, AIDS, renal failure, diabetes, severe trauma, and burns. In all cases, protein synthesis in skeletal muscle is depressed, whereas protein degradation is increased through an increase in activity and expression of the ubiquitin-proteasome proteolytic pathway. This pathway is not responsive to simple nutritional intervention. Certain agents, including glucocorticoids, cytokines, proteolysis-inducing factor (PIF), and oxidative stress, are thought to be responsible for the induction of the ubiquitin-proteasome pathway in skeletal muscle in catabolic conditions. Insulin suppresses activation of this pathway, and loss of insulin action in diabetes leads to muscle wasting. Cytokines, PIF, and reactive oxygen species (ROS) are thought to induce proteasome expression through activation of the transcription factor nuclear factor kappa B (NF-kappaB). Targets for therapeutic intervention include antagonists of the inducers of proteasome expression, intracellular signaling pathways leading to activation of NF-kappaB, and the enzymes inducing ubiquitin conjugation to the substrate protein (myosin), as well as the proteasome itself. Anticytokine and anti-PIF antibodies are effective in attenuating muscle protein degradation in certain experimental animal models,and glucocorticoid receptor antagonists are effective in the treatment of sepsis. Agents that inhibit NF-kappaB activation, such as resveratrol, thalidomide, ibuprofen, eicosapentaenoic acid, and beta-hydroxy-beta-methylbutyrate, are effective in the preservation of skeletal muscle mass in cachexia. These results suggest that the ubiquitin-proteasome pathway is an appropriate therapeutic target to prevent muscle wasting.
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PMID:The ubiquitin-proteasome pathway as a therapeutic target for muscle wasting. 1591 24

Skeletal muscle atrophy in response to a number of muscle wasting conditions, including disuse, involves the induction of increased protein breakdown, decreased protein synthesis, and likely a variable component of apoptosis. The increased activation of specific proteases in the atrophy process presents a number of potential therapeutic targets to reduce muscle atrophy via protease inhibition. In this study, mice were provided with food supplemented with the Bowman-Birk inhibitor (BBI), a serine protease inhibitor known to reduce the proteolytic activity of a number of proteases, such as chymotrypsin, trypsin, elastase, cathepsin G, and chymase. Mice fed the BBI diet were suspended for 3-14 days, and the muscle mass and function were then compared with those of the suspended mice on a normal diet. The results indicate that dietary supplementation with BBI significantly attenuates the normal loss of muscle mass and strength following unloading. Furthermore, the data reveal the existence of yet uncharacterized serine proteases that are important contributors to the evolution of disuse atrophy, since BBI inhibited serine protease activity that was elevated following hindlimb unloading and also slowed the loss of muscle fiber size. These results demonstrate that targeted reduction of protein degradation can limit the severity of muscle mass loss following hindlimb unloading. Thus BBI is a candidate therapeutic agent to minimize skeletal muscle atrophy and loss of strength associated with disuse, cachexia, sepsis, weightlessness, or the combination of age and inactivity.
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PMID:Attenuation of skeletal muscle atrophy via protease inhibition. 1597 55


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