Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We developed a one-step two-site immunoradiometric assay (IRMA) using two kinds of monoclonal antibodies, which enables us to directly measure the entire molecules of adrenomedullin (AM) (the sum of mature-type AM (abbreviated, m-AM) amidated at the C-terminus and Gly-extended non-amidated AM) in human plasma using a small amount of sample (100 microl) without prior extraction. The detection limit of this assay was 0.5 pmol/l for a 100-microl sample. Intra- and inter-assay precisions were 3.4-7.3% and 5.8-7.6%, respectively. The dilution curves of plasma samples showed good linearity and analytical recovery was 89-118%. The mean total AM in plasma of healthy subjects was 9.00+/-2.13 pmol/l, whereas m-AM was 1.05+/-0.24 pmol/l. This method, together with our previously reported simplified method to specifically measure m-AM (Ohta et al., Clin Chem 1999;45:244-251), allows facile estimation of the plasma concentration of AM-Gly by subtracting m-AM from the total AM measured by the procedure described in this paper. We were able to show that the concentration of total AM in patients with sepsis was markedly higher than that in the healthy controls and that the ratios of m-AM/total AM were significantly different between the controls and patients.
 ...
PMID:A simple immunoradiometric assay for measuring the entire molecules of adrenomedullin in human plasma. 1050 2

Plasma concentrations of adrenomedullin (AM) are markedly increased during sepsis, but the role of AM has not been clarified. Coexpression of calcitonin receptor-like receptor (CRLR) and receptor activity modifying protein (RAMP) 2 or 3 have been reported to form the adrenomedullin (AM) specific receptor. We examined the expression of CRLR and RAMP1, 2, and 3 in several tissues from mice in a sepsis model induced by lipopolysaccharide (LPS). High expression of CRLR and RAMP2 mRNA was observed in lungs of normal mice, but it was markedly decreased in endotoxemic mice. It is suggested that the abundant binding sites of AM in lungs are formed by CRLR and RAMP2 in healthy subjects and that their reduction should contribute to the increase of plasma AM concentrations during sepsis. In contrast, LPS treatment markedly increased RAMP3 gene expression in lungs, spleen, and thymus. It is revealed that the distributions of receptor or binding sites of AM are changed in sepsis, and it is suggested that AM plays distinct roles in the clinical course of this syndrome.
 ...
PMID:Decreased gene expression of adrenomedullin receptor in mouse lungs during sepsis. 1077 2

Polymicrobial sepsis is characterized by an early, hyperdynamic phase followed by a late, hypodynamic phase. Although studies have suggested that endothelins (ETs) contribute to the development of shock after a bolus injection of endotoxin, little is known about the role of ETs in the transition from the hyperdynamic phase to the hypodynamic phase of sepsis. To study this, male adult rats were subjected to sepsis by cecal ligation and puncture (CLP) followed by fluid resuscitation. Plasma levels of ET-1 and ET-2 were measured by radioimmunoassay at 2, 5, 10 h (i.e. the early stage of sepsis), and 20 h (late stage) following CLP or sham operation. Tissue levels of ET-1 and ET-2 were determined in the heart, lungs, small intestine, and spleen at 5 h after CLP or sham operation. In addition, preproendothelin-1 (precursor of ET-1) gene expression was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) at 5 h in the heart, lungs, small intestine, spleen, and liver. The results indicate that plasma levels of ET-1 and ET-2 were not different from values of sham groups at 2 and 20 h, but were significantly higher than the sham values at 5 and 10 h after CLP. While there were no significant increases in tissue levels of ET-1 and ET-2 at 5 h post-CLP, RT-PCR analysis indicates a significant upregulation of preproendothelin-1 gene expression in the heart, spleen, and liver (but not in the lungs or small intestine) at 5 h after the onset of sepsis. These results indicate that the heart, spleen, and liver appear to be important ET-producing organs during the early stage of sepsis. The lack of significant increases in tissue ET levels could be due to the possibility that the newly converted peptide is quickly transferred to the bloodstream. Since the hyperdynamic phase of sepsis occurs at 2-10 h and the hypodynamic phase occurs at 20 h after CLP, the increased plasma levels of ET at 5 and 10 h suggest that mediators other than ETs (such as adrenomedullin) are responsible for producing the biphasic hemodynamic responses during the progression of polymicrobial sepsis.
 ...
PMID:The dissociation between upregulated endothelins and hemodynamic responses during polymicrobial sepsis. 1083 94

Although the hemodynamic response to polymicrobial sepsis is characterized by an early, hyperdynamic phase followed by a late, hypodynamic phase, the factors responsible for producing the transition from the hyperdynamic to the hypodynamic stage are not fully understood. The failure to recognize or prevent this transition may lead to progressive deteriorations in cell and organ functions and ultimately result in multiple organ failure. Despite the fact that several vasoactive mediators (i.e., nitric oxide, prostacyclin, calcitonin gene-related peptide) have been implicated in producing cardiovascular alterations during sepsis, recent studies have indicated that adrenomedullin (AM), a novel vasodilatory peptide, plays an important role in initiating the hyperdynamic response during the early stage of polymicrobial sepsis. In addition, the reduced vascular responsiveness appears to be responsible for producing the transition from the early, hyperdynamic phase to the late, hypodynamic phase of sepsis. Moreover, modulation of AM vascular responsiveness reduces sepsis-induced mortality. In this review the physiological effects of AM, mechanisms of its action, and regulation of its production under various pathophysiological conditions will be discussed. Furthermore, the role of AM in producing the biphasic hemodynamic responses observed during polymicrobial sepsis and approaches for pharmacologically modulating vascular responsiveness and hemodynamic stability under such conditions will be described.
 ...
PMID:The role of adrenomedullin in producing differential hemodynamic responses during sepsis. 1455 33

Previous studies have shown that adrenomedullin (AM), a potent vasodilatory peptide, is upregulated during sepsis. However, it remains unknown whether the increased AM observed under such conditions is solely due to the elevated levels of circulating lipopolysaccharide (LPS). To determine this, an Alzet micro-osmotic pump, containing a low dose of Escherichia coli LPS or vehicle (sterile normal saline), was implanted in the peritoneal cavity of the normal male adult rat. At 10 h after the pump implantation, samples of blood and small intestine were harvested for the determination of AM by radioimmunoassay. In additional groups, rats were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP). LPS binding agent polymyxin B was administrated intramuscularly at 1 h prior to as well as 5 h after the onset of sepsis. At 10 h after CLP or sham-operation, blood and intestinal samples were harvested and levels of AM were then determined. Plasma levels of LPS were also measured by Limulus amebocyte lysate assay. The results indicate that administration of a low dose of LPS via the peritoneal cavity in normal animals (which did not significantly alter cardiac output, blood pressure or heart rate) markedly increased plasma and intestinal levels of AM. In addition, plasma and tissue levels of AM increased significantly at 10 h after CLP. Administration of polymyxin B, however, attenuated the increase in AM levels under such conditions. Similarly, the increased plasma levels of LPS was significantly reduced by polymyxin B during sepsis. These results, taken together, suggest that the upregulated AM observed during polymicrobial sepsis is at least in part due to the increase in circulating levels of endotoxin.
 ...
PMID:The role of lipopolysaccharide in stimulating adrenomedullin production during polymicrobial sepsis. 1156 60

The typical cardiovascular response to polymicrobial sepsis is characterized by an early, hyperdynamic phase followed by a late, hypodynamic phase. Although the factors and/or mediators responsible for producing the transition from the hyperdynamic to the hypodynamic stage are not fully understood, recent studies have suggested that adrenomedullin (AM), a potent vasodilatory peptide, appears to play an important role in initiating the hyperdynamic response following the onset of sepsis. In addition, the reduced vascular responsiveness to AM may result in the transition from the early, hyperdynamic phase to the late, hypodynamic phase of sepsis. It is possible that changes in newly reported AM receptors calcitonin receptor-like receptor (CRLR) and receptor activity modifying protein-2 or -3 (RAMP2, RAMP3) as well as AM binding protein-1 (AMBP-1) may also play distinct roles in the biphasic cardiovascular response observed during sepsis. Although it remains unknown whether AM gene delivery or a chronic increase in vascular AM production in transgenic animals attenuates the development of hypodynamic sepsis and septic shock, it has been shown that modulation of AM vascular responsiveness with pharmacologic agents reduces sepsis-induced mortality. It has been recently demonstrated that AMBP-1 enhances AM's physiologic effects and plasma levels of AMBP-1 decrease following infections. We therefore propose that downregulation of AMBP-1 and the reduced AM receptor responsiveness are crucial factors responsible for the transition from the hyperdynamic phase to the hypodynamic phase of sepsis.
 ...
PMID:Andrenomedullin and cardiovascular responses in sepsis. 1175 70

The upregulation of adrenomedullin (AM) gene expression and increases in systemic circulatory as well as localized tissue AM concentrations is well coordinated with the onset and progression of trauma, infection, and sepsis. As such, the coordinated change in AM suggests a key role for this peptide in the inflammatory response. By clinical definition, the process of inflammation constitutes an orchestrated cascade of localized tissue and systemic responses to immunological challenges. Classical responses to the onset of disease stresses are manifested in the timely elaboration of humoral, blood-borne signal effectors (such as adrenocortical and locally produced tissue hormones, immune cytokines, and inorganic signals such as nitric oxide) as well as patterned migration and infiltration of circulating bone marrow-derived cells (mononuclear cells such as monocyte-macrophages and polymorphonuclear cells like neutrophils) largely associated with or delivered through the vascular system. The body's attempts to combat acute infection to restore homeostatic equilibrium are further compromised by underlying disease situations. Atherosclerosis, diabetes, and cardiovascular disease, as well as nutritional metabolic derangements and persistent subclinical infection perturb the regulatory feedback loops necessary for proper control of response effectors like hormones and cytokines. When imbalances occur, tissue necrosis can ensue as driven by free radical damage to cell components. A true appreciation of the inflammatory response can only be grasped through an integrative approach in which the relationship between the different physiological systems is viewed in terms of a changing, dynamic interaction. In essence, the inflammatory response can be thought of in three phases: a period of severity assessment, a period of remediation, and a period of homeostatic restoration. Indeed, AM has differential effects on cellular metabolism, immune function, endocrine function, and cardiovascular function. This peptide appears to play a pivotal role in both reprioritizing the biological needs of tissues and organs during the three phases of inflammatory response as well as a role in restoring homeostatic equilibrium to the body.
 ...
PMID:Adrenomedullin has multiple roles in disease stress: development and remission of the inflammatory response. 1192 63

Sepsis and its complications are leading causes of morbidity and mortality. A better understanding of the mechanisms responsible for the shift from the early, hyperdynamic phase of sepsis to the late hypodynamic phase could lead to novel therapies that might improve the outcome of the septic patient. Adrenomedullin is a vasodilatory peptide which shows sustained elevation starting early in sepsis and is important in initiating the hyperdynamic response. As sepsis progresses, however, the vascular response to adrenomedullin is blunted and this decreased sensitivity is important in producing the shift to the late, hypodynamic phase. The decline in the vascular response to adrenomedullin is related to a sepsis-induced decrease in the binding protein for adrenomedullin (i.e., adrenomedullin binding protein-1) rather than a change in gene expression of the components of adrenomedullin receptors. Treatment of septic animals with the combination of adrenomedullin and its binding protein prevents the transition to the late phase of sepsis, maintains cardiovascular stability, and reduces sepsis-induced mortality. We propose that the mechanisms responsible for the beneficial effect of adrenomedullin and adrenomedullin binding protein-1 in sepsis are associated with downregulation of proinflammatory cytokines (TNF-alpha, IL-1beta, IL-6), maintainence of endothelial constitutive nitric oxide synthase, and reduction of vascular endothelial cell apoptosis.
 ...
PMID:The cardiovascular response in sepsis: proposed mechanisms of the beneficial effect of adrenomedullin and its binding protein (review). 1195 48

Endothelial hyperpermeability induced by inflammatory mediators is a hallmark of sepsis and adult respiratory distress syndrome. Increased levels of the regulatory peptide adrenomedullin (ADM) have been found in patients with systemic inflammatory response. We analyzed the effect of ADM on the permeability of cultured human umbilical vein endothelial cell (HUVEC) and porcine pulmonary artery endothelial cell monolayers. ADM dose-dependently reduced endothelial hyperpermeability induced by hydrogen peroxide (H2O2), thrombin, and Escherichia coli hemolysin. Moreover, ADM pretreatment blocked H2O2-related edema formation in isolated perfused rabbit lungs and increased cAMP levels in lung perfusate. ADM bound specifically to HUVECs and porcine pulmonary artery endothelial cells and increased cellular cAMP levels. Simultaneous inhibition of cAMP-degrading phosphodiesterase isoenzymes 3 and 4 potentiated ADM-dependent cAMP accumulation and synergistically enhanced ADM-dependent reduction of thrombin-induced hyperpermeability. However, ADM showed no effect on endothelial cGMP content, basal intracellular Ca2+ levels, or the H2O2-stimulated, thrombin-stimulated, or Escherichia coli hemolysin-stimulated Ca2+ increase. ADM diminished thrombin- and H2O2-related myosin light chain phosphorylation as well as stimulus-dependent stress fiber formation and gap formation in HUVECs, suggesting that ADM may stabilize the barrier function by cAMP-dependent relaxation of the microfilament system. These findings identify a new function of ADM and point to ADM as a potential interventional agent for the reduction of vascular leakage in sepsis and adult respiratory distress syndrome.
 ...
PMID:Adrenomedullin reduces endothelial hyperpermeability. 1236 90

Despite intensive research, septic shock is still the most common cause of death in surgical intensive care, and its incidence keeps increasing. No curative treatment is yet available. The critical aspect of septic shock is the refractory hypotension that develops during its late phase which leads to a progressive deterioration of cell and organ functions, and in most instances, death. During septic shock, following the overproduction of cytokines, many factors such as nitric oxide and adrenomedullin (ADM) are produced in abnormally large quantities, but our understanding of their contribution to the pathophysiology of sepsis is limited. Here we show that adrenomedullin (22-52), an adrenomedullin receptor antagonist, improves the contractility of myocytes isolated from lipopolysaccharide (LPS)-treated rats, whereas in normal myocytes, adrenomedullin, acting through an adrenomedullin (22-52) sensitive receptor, decreases their contractility. In addition, adrenomedullin antiserum and inducible nitric oxide (NO) synthase inhibitor improve the survival of LPS-treated rats. The data indicate that adrenomedullin is a cardiac depressant factor, which along with NO precipitates ventricular failure during septic shock.
 ...
PMID:Adrenomedullin: a cardiac depressant factor in septic shock. 1254 81


<< Previous 1 2 3 4 5 6 Next >>