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)

Adrenomedullin (AM) is a 52-amino-acid multifunctional peptide that circulates in the plasma in the low picomolar range and can exert a multitude of biological effects through an autocrine/paracrine mode of action. The mechanism by which AM transduces its signal represents a novel and pharmacologically tractable paradigm in G protein-coupled receptor signaling. Since its discovery in 1993, the study of AM has emerged into a new field of research with nearly 1800 publications that rivals the renown of other common factors like angiopoetin (1015 publications) and ghrelin (1550 publications). Despite the tremendous strides made in recent years toward unveiling the biochemical and cellular functions of AM, we are still lagging in our understanding of the essential roles of AM in normal and disease physiology. As discussed in this current review, a concerted effort to combine information from clinical, genomic, biochemical, and genetic mouse model sources can provide a focused view to help define the physiological functions of AM. Specifically, we find that certain conditions, such as pregnancy, cardiovascular disease, and sepsis, are associated with robust and dynamic changes in the expression of AM and AM receptor proteins, which together represent an elegant mechanism for altering the physiological responsiveness or function of AM. Thus, the modulation of AM signaling may be further exploited for therapeutic strategies in the management and treatment of human disease.
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PMID:Receptor activity-modifying proteins: RAMPing up adrenomedullin signaling. 1705 41

Adrenomedullin (ADM) is a 52-amino acid peptide with structural homology to calcitonin gene-related peptide (CGRP) initially isolated from human pheochromocytoma. ADM is synthesized and is secreted from many mammalian tissues, including the adrenal medulla, endothelial and vascular smooth muscle cells, as well as the myocardium and central nervous system. ADM has been implicated as a mediator of several diseases such as cardiovascular and renal disorders, sepsis, inflammation, diabetes and cancer. ADM is also expressed in a variety of tumors, including breast, endometrial and prostate cancer. ADM has been shown to be a mitogenic factor capable of stimulating growth of several cancer cell types. In addition, ADM is a survival factor for certain cancer cells and an indirect suppressor of the immune response. ADM plays an important role in environments subjected to low oxygen tension, which is a typical feature of solid tumors. Under these conditions, ADM is up regulated and acts as a potent angiogenic factor promoting neovascularization. The major focus of this review will be on the role of ADM in cancer, with emphasis on its utility in diagnostic and prognostic terms, along with its relevance as a therapeutic target.
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PMID:Adrenomedullin: a tumor progression factor via angiogenic control. 1710 May 69

Adrenomedullin (AM) is a potent vasodilator peptide in plasma at picomolar levels. Polymorphisms in the human AM gene have been associated with genetic predisposition to diabetic nephropathy and proteinuria with essential hypertension, and numerous studies have demonstrated that endogenous AM plays a role in protecting the heart and kidneys from fibrosis resulting from cardiovascular disease. Elevated plasma levels of AM are associated with pregnancy and sepsis and with cardiovascular stress and hypertension. However, there are no reports of the effects of genetic differences in the expression of the endogenous AM gene and of gender on blood pressure in these circumstances or on the pathological changes accompanying hypertension. To address these questions, we have generated mice having genetically controlled levels of AM mRNA ranging from approximately 50% to approximately 140% of wild-type levels. These modest changes in AM gene expression have no effect on basal blood pressure. Although pregnancy and sepsis increase plasma AM levels, genetically reducing AM production does not affect the transient hypotension that occurs during normal pregnancy or that is induced by treatment with lipopolysaccharide. Nor does the reduction of AM affect chronic hypertension caused by a renin transgene. However, 50% normal expression of AM enhances cardiac hypertrophy and renal damage in male, but not female, mice with a renin transgene. These observations suggest that the effect of gender on the role of AM in counteracting cardiovascular damage in humans merits careful evaluation.
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PMID:Adrenomedullin gene expression differences in mice do not affect blood pressure but modulate hypertension-induced pathology in males. 1736 Jun 61

Adrenomedullin (ADM) is a vasodilator peptide that has a variety of effects, including antithrombotic activities and resistant roles to lipopolysaccharide (LPS)-induced septic shock. During sepsis, LPS triggers the development of disseminated intravascular coagulation (DIC) via the tissue factor-dependent pathway of coagulation. It is unknown whether the antithrombotic activities of ADM contribute to its resistance to sepsis. In the present study, we investigated the effects of ADM on tissue factor pathway inhibitor (TFPI) (primary anticoagulant factor) expression in human umbilical vein endothelial cells (HUVECs) exposed to LPS, and the possible underlying mechanism for these effects. Exposure of HUVECs to LPS for 12 hours caused significant decrease of TFPI protein activities and mRNA expression. These effects were abolished by treatment with ADM (10(-10) to 10(-6) M), cAMP analogue and calcium antagonist. Accordingly, cAMP antagonist inhibited the counteraction effect of ADM on LPS in TFPI expression. Electrophoresis mobility shift assay (EMSA) and Western blot analysis showed that the protein level of GATA-2 and SP1 transcriptional factors and their binding to the corresponding regulatory sequences decreased by LPS treatment. And these effects of LPS were antagonized by ADM. Promoter-reporter assays and mutational analysis also confirmed the roles of GATA-2 and SP1 motifs from -1247 to -381 bp promoter sequence in TFPI inducible expression. Taken together, these results indicate that ADM antagonizes the effect of LPS on TFPI expression, which is mediated by affecting transcriptional factor GATA-2 and SP1 through cAMP and calcium signaling pathway.
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PMID:Crucial roles of GATA-2 and SP1 in adrenomedullin-affected expression of tissue factor pathway inhibitor in human umbilical vein endothelial cells exposed to lipopolysaccharide. 1747 96

Polymicrobial sepsis is characterized by an early, hyperdynamic phase followed by a late hypodynamic phase. Adrenomedullin (AM), a vasodilatory peptide, inhibits this transition from the early phase to the late phase. Adrenomedullin binding protein-1 (AMBP-1) enhances AM-mediated activities. The decrease of AMBP-1 levels in late sepsis reduces the vascular response to AM and produces the hypodynamic phase. Studies have indicated that the administration of LPS downregulates AMBP-1 production in the liver. Since hepatocytes are the primary source of AMBP-1 biosynthesis in the liver, we employed a co-culture strategy using hepatocyte and Kupffer cells to determine whether LPS directly or by increasing pro-inflammatory cytokines from Kupffer cells downregulates AMBP-1 production. Hepatocytes and Kupffer cells isolated from rats were co-cultured and treated with LPS for 24 h. LPS significantly attenuated AMBP-1 protein expression in a dose-dependent manner. Since AMBP-1 is basically a secretory protein, cell supernatants from co-culture cells treated with LPS were examined for AMBP-1 protein levels. LPS treatment caused a dose related decrease in AMBP-1 protein secretion. Similarly, LPS treatment produced a significant decrease in AMBP-1 protein expression in hepatocytes and Kupffer cells cultured using transwell inserts. LPS had no direct effect on AMBP-1 levels in cultured hepatocytes or Kupffer cells alone. To confirm that the observed effects in co-culture were due to the cytokines released from Kupffer cells, hepatocytes were treated with IL-1beta or TNF-alpha for 24 h and AMBP-1 expression was examined. The results indicated that both cytokines significantly inhibited AMBP-1 protein levels. Thus, pro-inflammatory cytokines released from Kupffer cells are responsible for downregulation of AMBP-1.
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PMID:Pro-inflammatory cytokines from Kupffer cells downregulate hepatocyte expression of adrenomedullin binding protein-1. 1749 Aug 66

Metabolic disorders and endocrine changes are common and relevant in critically ill patients. Thereby, endocrinopathies, electrolyte or metabolic derangements may either pre-exist or develop, and left unattended, may lead to significant morbidity and mortality. The homeostatic corrections which have emerged in the course of human evolution to cope with the catastrophic events during critical illness involve a complex multisystem endeavour, of which the endocrine contribution is an integral component. Although the repertoire of endocrine changes has been probed in some detail, discerning the vulnerabilities and failures of this system is far more challenging. The ensuing endocrine topics illustrate some of the current issues reflecting attempts to gain an improved insight and clinical outcome for critical illness. Disturbances in glucose and cortisol homeostasis during critical illness are two controversially debated topics in the current literature. The term "hormokine" encompasses the cytokine like behaviour of hormones during inflammation and infections. The concept is based on an ubiquitous expression of calcitonin peptides during sepsis. Adrenomedullin, another member of the calcitonin peptide superfamily, was shown to complement and improve the current prognostic assessment in lower respiratory tract infections. Procalcitonin is the protopye of "hormokine" mediators circulating procalcitonin levels increase several 10,000-fold during sepsis improve the clinical assessment especially of respiratory tract infections and sepsis safely and markedly reduces antibiotic usage in non-bacterial respiratory tract infections and meningitis. Adrenomedullin, another member of the calcitonin peptide superfamily, was shown to complement and improve the current prognostic assessment in lower respiratory tract infections. Hormokines are not only biomarkers of infection. Hormokines are also pivotal inflammatory mediators. Like all mediators, their role during systemic infections is basically beneficial, possibly to combat invading microbes. Yet, with increasing levels they can become harmful for their host. Multiple mechanisms of action were proposed. In several animal models the modulation and neutralization of hormokines during infection was shown to improve survival and thus might open new treatment options for severe infections, especially of the respiratory tract.
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PMID:Endocrine aspects of critical illness. 1766 55

Adrenomedullin (ADM) is upregulated in cardiac tissue under various pathophysiological conditions, particularly in septic shock. The intracellular mechanisms involved in the effect of ADM on adult rat ventricular myocytes are still to be elucidated. Ventricular myocytes were isolated from adult rats 4 h after an intraperitoneal injection of lipopolysaccharide (LPS, 10 mg/kg). Membrane potential and L-type calcium current (I(Ca,L)) were determined using whole cell patch-clamp methods. APD in LPS group was significantly shorter than control values (time to 50% repolarization: LPS, 169 +/- 2 ms; control, 257 +/- 2 ms, P < 0.05; time to 90% repolarization: LPS, 220 +/- 2 ms; control, 305 +/- 2 ms, P < 0.05). I(Ca,L) density was significantly reduced in myocytes from the LPS group (-3.2 +/- 0.8 pA/pF) compared with that of control myocytes (-6.7 +/- 0.3 pA/pF, P < 0.05). The ADM antagonist ADM-(22-52) reversed the shortened APD and abolished the reduction of I(Ca,L) in shock myocytes. In myocytes from control rats, incubating with ADM for 1 h induced a marked decrease in peak I(Ca,L) density. This effect was reversed by ADM-(22-52). The G(i) protein inhibitor, pertussis toxin (PTX), the protein kinase A (PKA) inhibitor, KT-5720, and the specific cyclooxygenase 2 (COX-2) inhibitor, nimesulide, reversed the LPS-induced reduction in peak I(Ca,L). The results suggest a COX-2-involved PKA-dependent switch from G(s) coupled to PTX-sensitive G(i) coupling by ADM in adult rat ventricular myocytes. The present study delineates the intracellular pathways involved in ADM-mediated effects on I(Ca,L) in adult rat ventricular myocytes and also suggests a role of ADM in sepsis.
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PMID:The effect of adrenomedullin on the L-type calcium current in myocytes from septic shock rats: signaling pathway. 1776 82

Used appropriately, biomarkers improve the assessment of respiratory tract infections and sepsis. Most prominently, circulating procalcitonin levels increase by a factor of several tens of thousands during sepsis. Using a sensitive assay, procalcitonin safely and markedly reduces antibiotic usage in respiratory tract infections and nonbacterial meningitis. Procalcitonin is the protopye of hormokine mediators. The term "hormokine" encompasses the cytokine-like behaviour of hormones during inflammation and infections. The concept is based on a ubiquitous expression of calcitonin peptides during sepsis. Adrenomedullin, another member of the calcitonin peptide superfamily, was shown to complement and improve the current prognostic assessment in lower respiratory tract infections. Other peptides share some features of hormokines, e.g. natriuretic peptide and copeptin. Hormokines are not only biomarkers of infection but are also pivotal inflammatory mediators. Like all mediators, their role during systemic infections is basically beneficial, possibly to combat invading microbes. However, at increased levels they can become harmful for their host. Multiple mechanisms of action were proposed. In several animal models the modulation and neutralisation of hormokines during infection was shown to improve survival, and thus might open new treatment options for severe infections, especially of the respiratory tract.
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PMID:Biomarkers in respiratory tract infections: diagnostic guides to antibiotic prescription, prognostic markers and mediators. 1776 33

Adrenomedullin (AM) is a highly conserved peptide that can act as a potent vasodilator, anti-microbial factor and anti-inflammatory factor. Several studies have implicated diverse roles for AM in regulating the inflammatory and hemodynamic responses to septic shock. Moreover, during sepsis the receptors that mediate AM signaling [calcitonin receptor-like receptor (calcrl) and receptor activity modifying proteins (RAMP) 2 and 3] undergo dynamic and robust changes in their expression. Although numerous studies have used animal models to study the role of administered or increased AM in septic animals, genetic studies to determine the consequences of reduced AM during septic shock have not yet been performed. Here, we used a murine model of lipopolysaccharide (LPS)-induced septic shock to assess the inflammatory response in mice heterozygous for the AM gene. Following LPS challenge, AM(+/-) mice had higher expression of TNF-alpha and IL-1beta than LPS-treated wild-type (WT) controls. Consequently, serum TNF-alpha was also significantly elevated in LPS-treated AM(+/-) mice compared to WT LPS-treated mice. We also observed higher serum levels of liver enzymes, suggesting more advanced end-organ damage in mice with genetically reduced AM. Finally, we found that RAMP2 and calcrl expression levels were markedly reduced in LPS-treated mice, whereas RAMP3 expression was significantly elevated. Importantly, these changes in receptor gene expression were conserved in AM(+/-) mice, demonstrating that AM peptide itself does not impact directly on the expression of the genes encoding its receptors. We, therefore, conclude that during septic shock the dynamic modulation of AM and its receptors primarily functions to dampen the inflammatory response.
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PMID:Mice heterozygous for adrenomedullin exhibit a more extreme inflammatory response to endotoxin-induced septic shock. 1788 65

Plasma levels of endothelin-1 (ET-1) and adrenomedullin (ADM), two opposingly acting peptides, correlate with mortality in endotoxemia, but their measurement is cumbersome. New sandwich assays have been introduced that measure more stable precursor fragments. The objective of this study was to investigate the counterplay of their precursor peptides in septic patients and to compare them with disease severity and other biomarkers. Blood samples of an observational study in 95 consecutive critically ill patients admitted to the intensive care unit (ICU) were analyzed. CT-proET-1 and MR-proADM concentrations on admission were measured using new sandwich immunoassays. Depending on the clinical severity of the infection, both CT-proET-1 and MR-proADM levels exhibited a gradual increase from Systemic Inflammatory Response Syndrome (SIRS) to sepsis and septic shock (p < .001). Compared to the group of survivors, the group of nonsurvivors had higher median values of MR-proADM (5.7 nmol/L [range 0.4 to 21.0] versus 1.9 nmol/L [range 0.3 to 17.1], p < .02) and similar CT-proET-1 levels (56.0pmol/L [range 0.5 to 271.0] versus 54.1pmol/L [range 1.0 to 506.0], p = .86). Receiver operating characteristics (ROC) curve analysis showed a higher prognostic accuracy of the calculated ratio of both counteracting substances as compared to CT-proET-1 (p = 0.001) and C-reactive protein (CRP) (p = .001) and in the range of MR-proADM (p = .51), procalcitonin (p = 0.22), and the APACHE II score (p = .61). Endothelin-1 and adrenomedullin precursor peptides gradually increase with increasing severities of infection in critically ill patients. The ratio of the two counteracting peptides correlates with mortality and shows a prognostic accuracy to predict adverse outcome comparable to the APACHE II score.
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PMID:Circulating precursor levels of endothelin-1 and adrenomedullin, two endothelium-derived, counteracting substances, in sepsis. 1808 Aug 71


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