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)

We recently demonstrated that early administration of rat adrenomedullin (AM), a vasoactive peptide, in combination with its binding protein (human AMBP-1) produces various beneficial effects in sepsis. Human AM is a 52-amino acid peptide, but rat AM differs from human AM, having only 50 amino acid residues, with two amino acid deletions and six substitutions. It remains unknown whether a combination of human AM and human AMBP-1 (AM/AMBP-1) is also beneficial in sepsis and, if so, whether human AM/AMBP-1 reverses established sepsis in rats. To test the effects of human AM/AMBP-1, we induced sepsis in male adult rats by cecal ligation and puncture (CLP). At 10 h after CLP (i.e., severe sepsis), human AM (12-48 microg/kg body weight) was administered in combination with human AMBP-1 (40-160 microg/kg body weight). Vehicle-treated animals received a nonspecific human plasma protein (albumin). Blood and intestinal samples were collected at 20 h for various measurements. In additional groups of septic animals, the gangrenous cecum was surgically excised at 20 h after CLP. The 10-day survival was recorded. Our results showed that tissue injury, as evidenced by increased levels of transaminases and lactate, was present at 20 h after CLP. Proinflammatory cytokines tumor necrosis factor-alpha and interleukin-6 were significantly elevated. Gut barrier dysfunction, manifested by increased mucosal permeability to hydrophilic macromolecules and increased bacterial translocation to mesenteric lymph nodes, also occurred at 20 h after CLP. Administration of human AM/AMBP-1 in established sepsis markedly attenuated tissue injury, reduced proinflammatory cytokine levels, ameliorated intestinal-barrier dysfunction, and improved the survival rate from 47% to 67%-80%. Thus, human AM/AMBP-1 can be further developed as a safe and effective therapy for patients with established sepsis.
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PMID:Reversing established sepsis in rats with human vasoactive hormone adrenomedullin and its binding protein. 1900 24

Leakage of the gut mucosal barrier in the critically ill patient may allow translocation of bacteria and their virulence factors, thereby perpetuating sepsis and inflammation. Present evidence suggests that adrenomedullin (AM) improves endothelial barrier function and stabilizes circulatory function in systemic inflammation. We tested the hypothesis that exogenously applied AM stabilizes gut epithelial barrier function. Infusion of Staphylococcus aureus alpha-toxin induced septic shock in rats. AM infusion in a therapeutic setting reduced translocation of labeled dextran from the gut into the systemic circulation in this model. AM also reduced alpha-toxin and hydrogen peroxide (H2O2)-related barrier disruption in Caco-2 cells in vitro and reduced H2O2-related rat colon barrier malfunction in Ussing chamber experiments. AM was shown to protect endothelial barrier function via cAMP elevation, but AM failed to induce cAMP accumulation in Caco-2 cells. cAMP is degraded via phosphodiesterases (PDE), and Caco-2 cells showed high activity of cAMP-degrading PDE3 and 4. However, AM failed to induce cAMP accumulation in Caco-2 cells even in the presence of sufficient PDE3/4 inhibition, whereas adenylyl cyclase activator forskolin induced strong cAMP elevation. Furthermore, PDE3/4 inhibition neither amplified AM-induced epithelial barrier stabilization nor affected AM cAMP-related rat colon short-circuit current, furthermore indicating that AM may act independently of cAMP in Caco-2 cells. Finally, experiments using chemical inhibitors indicated that PKC, phosphatidylinositide 3-kinase, p38, and ERK did not contribute to AM-related stabilization of barrier function in Caco-2 cells. In summary, during severe inflammation, elevated AM levels may substantially contribute to the stabilization of gut barrier function.
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PMID:Adrenomedullin reduces intestinal epithelial permeability in vivo and in vitro. 1942 49

This review aims to provide physicians with an overview of the potential of procalcitonin to guide antibiotic therapy in respiratory tract infections and in sepsis. Knowledge of the strengths and weaknesses of procalcitonin are prerequisites for a rational and safe use in clinical routine. In most infections a true gold standard for diagnosis does not exist, therefore physicians must remain sceptical towards observational studies evaluating procalcitonin. Interpretation of procalcitonin levels must always include the clinical setting and knowledge of assay characteristics, particularly the setting of specific cut-off ranges and functional assay sensitivities. Highly sensitive procalcitonin measurements, embedded in a clearly defined setting and prospectively validated with clinical algorithms were repeatedly effective in markedly reducing the (over)-utilisation of antimicrobial therapy. Today, this concept has been proven for lower respiratory tract infections and in pilot studies for meningitis and critically ill patients with sepsis. The higher the absolute risk for adverse outcome of a patient, the more cautious physicians must remain and empirical antibiotic therapies must be considered despite initial low procalcitonin levels at the initial presentation. In these patients a procalcitonin-guided shortening of antibiotic courses seems appropriate. The prognostic utility of initial procalcitonin measurement in respiratory tract infections is suboptimal. Other biomarkers including cortisol, human growth hormone and prohormones from adrenomedullin and vasopressin ("copeptin") have a superior predictive potential to estimate the risk for short and long term mortality and other adverse outcomes in different diseases. An accurate prognostic assessment has the potential to optimise the management of patients and the allocation of our limited health care resources by lowering unnecessary hospitalisations and associated cost. Future intervention studies must prove if these biomarkers indeed improve clinical decision making and thus the overall medical management of patients.
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PMID:Procalcitonin and other biomarkers to improve assessment and antibiotic stewardship in infections--hope for hype? 1952 89

Sepsis is a serious complication for patients with obstructive jaundice. Although administration of adrenomedullin (AM) in combination with its binding protein (AMBP-1) is protective after injury, it remains unknown whether AM/AMBP-1 ameliorates sepsis-induced organ injury and mortality in the setting of biliary obstruction. The aim of this study is, therefore, to test the efficacy of human AM/AMBP-1 in a rat model of obstructive jaundice and polymicrobial sepsis. To study this, obstructive jaundice was induced in male adult rats (275-325g) by common bile duct ligation (BDL). One week after BDL, the rats were subjected to sepsis by cecal ligation and puncture (CLP). Plasma levels of AM and AMBP-1 were measured at 20h after CLP. In additional groups of BDL+CLP rats, human AM/AMBP-1 (24/80microg/kg body weight (BW)) or vehicle (i.e., human albumin) was administered intravenously at 5h after CLP. Blood and tissue samples were collected at 20h after CLP for various measurements. To determine the long-term effect of human AM/AMBP-1 after BDL+CLP, the gangrenous cecum was removed at 20h after CLP and 7-day survival was recorded. Our results showed that plasma levels of AM were significantly increased while AMBP-1 levels were markedly decreased after BDL+CLP (n=8, P<0.05). Administration of human AM/AMBP-1 attenuated tissue injury and inflammatory responses after BDL+CLP. Moreover, human AM/AMBP-1 significantly increased the survival rate from 21% (n=14) to 53% (n=15). Thus, human AM/AMBP-1 ameliorates sepsis-induced organ injury and mortality in jaundiced rats. Human AM/AMBP-1 can be further developed as a novel treatment for sepsis in jaundiced patients.
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PMID:Human adrenomedullin and its binding protein ameliorate sepsis-induced organ injury and mortality in jaundiced rats. 2013 52

Sepsis and septic shock are great challenges for the doctors who treat critically ill patients. A big part of the scientific community is performing researches about the pathophysiology and treatment of this clinical problem. The endothelium has a very significant role in the alterations that sepsis causes especially to the circulatory system. The disorders of the normal function of the endothelium include derangement of the vascular tone, increase of endothelium permeability, activation of the endothelial cells, production of various regulators and disorders of coagulation. Nitric oxide is the modulator that mediates the action of most vasodilators. The overproduction of nitric oxide during sepsis is possibly the most important cause of the vasopressor-resistant hypotension which characterizes septic shock. The levels of natriuretic peptides are also increased. These peptides act through several ways on the circulatory system both peripherally and directly on the myocardium. Endothelin, vasopressin, adrenomedullin and prostacyclin are vasoactive substances that have their own role in the regulation of the circulatory system during sepsis.
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PMID:The role of endothelium and endogenous vasoactive substances in sepsis. 2059 62

Severe systemic infections induce ubiquitous calcitonin (CALC) gene expression with release of calcitonin peptides, namely procalcitonin, calcitonin gene-related peptide and adrenomedullin. Using an in vitro model for bacterial infection, we tested the hypothesis that intracellular calcium concentration ([Ca(2+)](i)) is elevated after lipopolysaccharide (LPS) stimulation and is responsible for the LPS-mediated increase in CALC gene expression and protein secretion. In our human adipocyte model, LPS did not show any cytotoxic effects and induced increased CALC-I gene mRNA expression. Additionally, LPS provoked an elevation in [Ca(2+)](i). The LPS-induced increase in CALC-I gene mRNA was partially blocked with verapamil, an L-type calcium channel blocker and blocked almost completely with 2-aminoethoxydiphenyl borate, a blocker of store-operated calcium entry and inositol triphosphate-mediated calcium release. Treatment of cells with substances elevating [Ca(2+)]( i) led to an increased CALC-I mRNA expression level. The combination of LPS with substances raising [Ca(2+)](i) even potentiated this increase. At the same time, elevated [Ca(2+)](i) attenuated the expression level of the CALC-V gene. These findings indicate that, in human adipocytes, changes in [Ca(2+)](i) are involved in LPSregulated expression of CALC genes, thereby strengthening previous findings postulating a crucial role of intracellular calcium homeostasis in the state of bacterial infection and sepsis.
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PMID:Role of calcium in lipopolysaccharide-induced calcitonin gene expression in human adipocytes. 2068 85

Receptor-activity modifying proteins (RAMPs) belong to a single family of transmembrane proteins. RAMPs determine ligand specificity of G-protein coupled receptors; calcitonin receptor and the calcitonin-receptor like receptor (CLR). To date, three members of RAMP family (RAMP-1, -2, -3) have been identified. The co-expression of RAMP-1 with CLR constitutes the calcitonin gene related peptide receptor whereas the association of the RAMP-2 or RAMP-3 with CLR forms the adrenomedullin (AM) receptor. Alterations in signaling and subcellular distribution of G-protein coupled receptors can be responsible for the regulation of many disease conditions. These changes may be mediated by the different isoforms of RAMPs associated with such receptors. In this chapter, we describe the differential responses associated with upregulation of RAMPs in disease conditions. For instance, the upregulation of all three RAMP isoforms contributes to the cardioprotective effects of the CLR/RAMP ligands. On the other hand, strong evidence exists for the involvement of AM in various cancers and that its action is mediated by the upregulation of RAMP isoforms, RAMP-2 and -3. Though limited, a few studies have been reported on the differential response associated with the upregulation of RAMP in other disease conditions such as sepsis, liver cirrhosis, glomerulonephritis, Type 1 diabetes and Parkinson's disease. Thus, the regulation of RAMP expression is involved in the pathophysiology associated with various diseases.
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PMID:Regulation of RAMP expression in diseases. 2243 10

Sepsis is a leading healthcare problem, accounting for the vast majority of fatal events in critically ill patients. Beyond early diagnosis and appropriate treatment, this condition requires a multifaceted approach for monitoring the severity, the potential organ failure as well as the risk of death. Monitoring of the efficacy of treatment is also a major issue in the emergency department (ED). The assessment of critically ill conditions and the prognosis of patients with sepsis is currently based on some scoring systems, which are, however, inefficient to provide definite clues about organ failure and prognosis in general. The discretionary and appropriate use of some selected biomarkers such as procalcitonin, inducible protein 10 (IP10), Group IV phospholipase A2 type II (PLA2 II), neutrophil gelatinase-associated lipocalin (NGAL), natriuretic peptides, mature adrenomedullin (ADM), mid-regional pro-adrenomedullin (MR-proADM), copeptin, thrombopoietin, Mer receptor and even red blood cell distribution width (RDW) represent thereby an appealing perspective in the diagnosis and management of patients with sepsis. Nevertheless, at the moment, it is not still clear if it is better to use a multimarkers approach or if a single, most appropriate, biomarker exists. This collective opinion paper is aimed at providing an overview about the potential clinical usefulness of some innovative biomarkers of sepsis in its diagnosis and prognosis, but also in the treatment management of the disease. This manuscript represents a synopsis of the lectures of Third Italian GREAT Network Congress, that was hold in Rome, 15-19 October 2012.
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PMID:Opinion paper on innovative approach of biomarkers for infectious diseases and sepsis management in the emergency department. 2338 11

Adrenomedullin is a vasodilatory polypeptide with pleiotropic effects secreted by various organs. Adrenomedullin is produced first as a prepropeptide, and then cleaved into mature adrenomedullin and mid-regional proadrenomedullin. Whereas levels of the latter have been shown to correlate with severity of sepsis and carry prognostic value, adrenomedullin plays a role in vascular tone homeostasis. In the previous issue of Critical Care, the infusion of exogenous adrenomedullin is suggested to protect against increased lung endothelial permeability and end-organ dysfunction in a model of pneumococcal pneumonia in mechanically ventilated mice, possibly by stabilizing vascular endothelia. Since adrenomedullin is a strong vasodilatory molecule, further studies are needed to evaluate its potential as a future treatment of sepsis.
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PMID:Adrenomedullin: a vasodilator to treat sepsis? 2473 Dec 44

Levels of the peptide hormone adrenomedullin (AM) are elevated during normal pregnancy, but whether this differs during complications of pregnancy remains unresolved. AM can be quantified by measuring its pre-prohormone byproduct, midregional pro-adrenomedullin (MR-proADM). MR-proADM has shown prognostic value as a biomarker of heart failure, sepsis, and community-acquired pneumonia. Given the relevance of AM to pregnancy, we tested the hypothesis that MR-proADM provides a biomarker for preeclampsia. We find that MR-proADM plasma concentrations are blunted in severe preeclampsia and that MR-proADM is similarly effective as established biomarkers endoglin and placental growth factor at discriminating patients with severe preeclampsia from controls.
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PMID:Midregional pro-adrenomedullin plasma concentrations are blunted in severe preeclampsia. 2504 91


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