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)

The present investigation sought to determine the cellular mechanisms directly dependent on long-term severe sepsis/septic shock that could lead to myocardial structural changes in humans. Human hearts from eight cases of long-term severe sepsis/septic shock arising from infection, as defined by the ACCP/SCCM Consensus Conference; eight cases of acute necrotizing pancreatitis and acute lung injury, a noninfectious pathologic cause of systemic inflammatory response; and three cases of accidental death without thoracic injury selected from autopsies were studied. Transmural blocks of myocardial tissue were excised from the middle portion of the left ventricular free wall and were fixed in formalin or were frozen. Histochemical and immunohistochemical methods were used to evaluate the cross-striations of the myocardial cells, the number and size of interstitial macrophages, the intracardiomyocyte accumulation of lipid, the actin/myosin contractile apparatus, and the expression of iNOS, nitrotyrosine, and TNF-alpha in the myocardia of septic and control hearts. Greater interstitial cellular infiltration composed of larger and elongated macrophages and TNF-alpha protein expression in myofibers, interstitial macrophage cell types, and smooth muscle cells and endothelial cell in the vessels; intracardiomyocyte lipid accumulation; scattered foci of actin/myosin contractile apparatus disruption; and increased expression for iNOS and nitrotyrosine in myocytes and interstitial macrophage cell types could be observed in long-term human septic myocardium as compared with normal and acute pancreatitis control myocardia. These findings give support to an opinion that structural changes could be responsible for long-term sepsis-induced myocardial dysfunction. The higher number of macrophages, most of them with morphological features of "activation," and TNF-alpha protein expression could favor the reduction of cardiac function in septic hearts. The intramyocyte lipid accumulation in these hearts very likely reflects myocardium ventricular contractile dysfunction. In addition, the increased expression of iNOS and the evidence for the significant presence of peroxynitrite in cardiomyocytes and interstitial macrophage cell types suggest that oxidative damage may play a role in actin/myosin disruption in the hearts of septic patients.
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PMID:Myocardial structural changes in long-term human severe sepsis/septic shock may be responsible for cardiac dysfunction. 1717 74

Diastolic heart failure is an underestimated pathology with a high risk of acute decompensation during the perioperative period. This article reviews the epidemiology, risk factors, pathophysiology, and treatment of diastolic heart failure. Although frequently underestimated, diastolic heart failure is a common pathology. Diastolic heart failure involves heart failure with preserved left ventricular (LV) function, and LV diastolic dysfunction may account for acute heart failure occurring in critical care situations. Hypertensive crisis, sepsis, and myocardial ischaemia are frequently associated with acute diastolic heart failure. Symptomatic treatment focuses on the reduction in pulmonary congestion and the improvement in LV filling. Specific treatment is actually lacking, but encouraging data are emerging concerning the use of renin-angiotensin-aldosterone axis blockers, nitric oxide donors, or, very recently, new agents specifically targeting actin-myosin cross-bridges.
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PMID:Diastolic heart failure in anaesthesia and critical care. 1746 92

Skeletal muscle atrophy is associated with situations of acute and chronical illness, such as sepsis, surgery, trauma and immobility. Additionally, it is a common problem during the physiological process of aging. The myofibrillar proteins myosin and actin, which are essential for muscle contraction, are the major targets during the process of protein degradation. This leads to a general loss of muscle mass, muscle strength and to increased muscle fatigue. In critically ill or immobile patients skeletal muscle atrophy is accompanied by enhanced inflammation, reduced wound healing, weaning complications and difficulties in mobilisation. During aging it results in falls, fractures, physical injuries and loss of mobility. Relating to the primary stimulators - hormones, muscle lengthening, stress, inflammation, neuronal activity - research is now focusing on the investigation of the signal transduction pathways, which influence protein synthesis and protein degradation during skeletal muscle atrophy.
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PMID:[Cellular regulation of anabolism and catabolism in skeletal muscle during immobilisation, aging and critical illness]. 1763 90

Muscle fiber inexcitability and myosin loss underlie weakness in critical illness myopathy (CIM). Nitric oxide (NO) takes part in the maintenance of muscle fiber resting potential and, in pathological conditions accompanied by oxidative stress, may damage proteins through peroxynitrite generation. Sepsis and other conditions associated with CIM may differentially affect expression of NO synthases (NOSs), so that both downregulation and upregulation with excessive peroxynitrite production can be hypothesized. In six patients with CIM we studied NOS1, NOS2, and NOS3 protein expression by immunohistochemistry and Western blot. To investigate peroxynitrite production, we performed immunohistochemistry for nitrotyrosine and measured nitrotyrosine levels by enzyme-linked immunosorbent assay. In three patients, sarcolemmal staining for NOS1 was selectively absent. In the others, it was absent in atrophic fibers and absent or reduced in non-atrophic fibers. Total NOS1 protein content was reduced by 41% in patients compared to controls, whereas no significant changes were found in levels and localization of NOS2, NOS3, and nitrotyrosine. Further studies are warranted to determine whether NOS1 loss plays a role in the pathophysiology of CIM, possibly reducing the release of NO at the sarcolemma and affecting muscle fiber excitability.
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PMID:Possible role for nitric oxide dysregulation in critical illness myopathy. 1792 42

Muscle wasting in chronic kidney disease (CKD) and other catabolic diseases (e.g. sepsis, diabetes, cancer) can occur despite adequate nutritional intake. It is now known that complications of these various disorders, including acidosis, insulin resistance, inflammation, and increased glucocorticoid and angiotensin II production, all activate the ubiquitin-proteasome system (UPS) to degrade muscle proteins. The initial step in this process is activation of caspase-3 to cleave the myofibril into its components (actin, myosin, troponin, and tropomyosin). Caspase-3 is required because the UPS minimally degrades the myofibril but rapidly degrades its component proteins. Caspase-3 activity is easily detected because it leaves a characteristic 14kD actin fragment in muscle samples. Preliminary evidence from several experimental models of catabolic diseases, as well as from studies in patients, indicates that this fragment could be a useful biomarker because it correlates well with the degree of muscle degradation in dialysis patients and in other catabolic conditions.
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PMID:Muscle wasting in chronic kidney disease: the role of the ubiquitin proteasome system and its clinical impact. 1798 22

Although loss of endothelial barrier function is a hallmark of every acute inflammation and contributes to fatal loss of organ function during severe infections, there is no sufficient therapy for stabilization of endothelial barrier function. Endogenous peptide adrenomedullin (AM) serum levels were shown to be increased during severe infection including sepsis and septic shock. In different in-vitro and in-vivo models AM acted as a potent therapeutic endothelial barrier function-stabilizing agent. Activation of specific receptors by AM results in elevation of second messenger cAMP. AM inhibits actin-myosin based endothelial cell contraction and junctional disassembly, thereby preventing paracellular permeability and oedema formation. The peptide furthermore possesses several protective cardiovascular qualities, including protection of the microcirculation during inflammation, and was proven as an efficient counter-regulatory molecule in various models of sepsis and septic shock. Overall, AM may be an attractive molecule to combat against cardiovascular malfunction during severe infection.
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PMID:Adrenomedullin and endothelial barrier function. 1800 May 97

With better survival of critically ill patients, 'de novo' arising neuromuscular complications like critical illness myopathy or polyneuropathy have been increasingly observed. Prolonged hospitalization not only imposes risks like pneumonia or thrombosis on patients but also represents a real budget threat to modern intensive-care medicine. Clinical symptoms like muscle weakness and weaning failure are common to critical illness myopathy and critical illness polyneuropathy and do not allow for distinction. Specific therapies are not yet available, and the quest for the pathomechanisms has proved more complicated than anticipated. Especially for critical illness myopathy, multiple sites of disturbances to the excitation-contraction coupling cascade are possible causes of muscle weakness. The present review summarizes the epidemiological, clinical and diagnostic features of critical illness myopathy and then focuses on current concepts of the presumed pathomechanisms of critical illness myopathy. Sepsis was shown to be a major cause of critical illness myopathy and special emphasis will be placed on how sepsis and inflammatory mediators influence (i) the membrane excitability at the level of voltage-gated ion channels and (ii) the intracellular protein signalling that results in selective loss of myosin protein content and muscle wasting. For (i), critical illness myopathy represents a new type of acquired channelopathy affecting the inactivation properties of Na+ channels. For (ii), both protein proteolysis and protein build up at the transcriptional level seem to be involved. Findings from different studies are put into a common context to propose a model for cytokine-mediated failure of muscle in severe sepsis. This can open a series of new possible trials to test specific therapeutic strategies in the future.
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PMID:Critical illness myopathy: sepsis-mediated failure of the peripheral nervous system. 1828 21

Muscle wasting in sepsis reflects activation of multiple proteolytic mechanisms, including lyosomal and ubiquitin-proteasome-dependent protein breakdown. Recent studies suggest that activation of the calpain system also plays an important role in sepsis-induced muscle wasting. Perhaps the most important consequence of calpain activation in skeletal muscle during sepsis is disruption of the sarcomere, allowing for the release of myofilaments (including actin and myosin) that are subsequently ubiquitinated and degraded by the 26S proteasome. Other important consequences of calpain activation that may contribute to muscle wasting during sepsis include degradation of certain transcription factors and nuclear cofactors, activation of the 26S proteasome, and inhibition of Akt activity, allowing for downstream activation of Foxo transcription factors and GSK-3beta. The role of calpain activation in sepsis-induced muscle wasting suggests that the calpain system may be a therapeutic target in the prevention and treatment of muscle wasting during sepsis. Furthermore, because calpain activation may also be involved in muscle wasting caused by other conditions, including different muscular dystrophies and cancer, calpain inhibitors may be beneficial not only in the treatment of sepsis-induced muscle wasting but in other conditions causing muscle atrophy as well.
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PMID:Calpain activity and muscle wasting in sepsis. 1849 80

Acquired neuromuscular disorders have been shown to be very common in critically ill patients receiving prolonged mechanical ventilation in the intensive care unit (ICU). Acute Quadriplegic Myopathy (AQM) is a specific acquired myopathy in ICU patients. Patients with AQM are characterized by severe muscle weakness and atrophy of spinal nerve innervated limb and trunk muscles, while cranial nerve innervated craniofacial muscles, sensory and cognitive functions are spared or less affected. The muscle weakness is associated with altered muscle membrane properties and a preferential loss of the motor protein myosin and myosin-associated thick filament proteins. Prolonged mechanical ventilation, muscle unloading, postsynaptic block of neuromuscular transmission, sepsis and systemic corticosteroid hormone treatment have been suggested as important triggering factors in AQM. However, the exact mechanisms underlying the loss of thick filament proteins are not known, though enhanced myofibrillar protein degradation in combination with a downregulation of protein synthesis at the transcriptional level play important roles.
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PMID:Acute quadriplegic myopathy: an acquired "myosinopathy". 1918 Oct 96

We have previously reported protective effects of atrial natriuretic peptide (ANP) against endothelial cell (EC) permeability induced by thrombin via suppression of Rho GTPase pathway of barrier dysfunction by protein kinase A and Epac-Rap1-Tiam1-Rac signaling cascades. This study tested effects of ANP on EC barrier dysfunction induced by inflammatory mediators lipopolysaccharide (LPS) and TNFalpha and linked them with activation of mitogen-activated protein kinase (MAPK) and NFkappaB signaling cascades known to promote EC hyperpermeability in the models of lung inflammation and sepsis. LPS and TNFalpha increased permeability in human pulmonary EC monitored by measurements of transendothelial electrical resistance, and caused disruption of EC monolayer integrity monitored by immunofluorescence staining for adherens junction marker protein VE-cadherin. Both disruptive effects were markedly attenuated by ANP. Both LPS and TNFalpha caused sustained activation of p38 and ERK1/2 MAP kinases, increased phosphorylation and degradation of negative regulator of NFkappaB signaling IkBalpha, and increased Rho-kinase mediated phosphorylation of myosin phosphatase MYPT1 leading to accumulation of phosphorylated myosin light chains. Consistent with protective effects on EC permeability and monolayer integrity, ANP dramatically attenuated activation of inflammatory signaling by LPS and TNFalpha in pulmonary EC. These results strongly suggest inhibitory effects of ANP on the LPS and TNFalpha induced inflammatory signaling as additional mechanism of EC barrier preservation in the models of acute lung injury and sepsis.
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PMID:ANP attenuates inflammatory signaling and Rho pathway of lung endothelial permeability induced by LPS and TNFalpha. 1993 45


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