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)

Altered phosphorylation and Ca(2+) sensitivity of cardiac myofibrillar proteins during different phases of sepsis were investigated. Sepsis was induced by cecal ligation and puncture (CLP). The results show that phosphorylation of troponin I (TnI) was increased by 268% during the early phase (9 h after CLP) but decreased by 46% during the late phase (18 h after CLP) of sepsis. Phosphorylation of C protein was increased by 76% during the early phase but decreased by 41% during the late phase of sepsis. Phosphorylation of myosin light chain-2 (MLC-2) remained unaltered during the early phase but was decreased by 38% during the late phase of sepsis. Phosphorylation of TnT was unaffected during the progression of sepsis. The increases in the phosphorylation of TnI and C protein during early sepsis were associated with the decrease in the Ca(2+) sensitivity of myofilaments and the increases in myocardial changes in tension development (+dP/dt(max)) and cAMP level. The decreases in the phosphorylation of TnI and C protein during late sepsis coincided with the declines in the activities of myofibrillar ATPase, Ca(2+) sensitivity of myofilaments, myocardial +/-dP/dt(max), and cAMP content. The increases and the decreases in the phosphorylation of TnI and C protein, +/-dP/dt(max), and the tissue cAMP level were sensitive to isoproterenol stimulation and propranolol inhibition. These findings suggest that alterations in the phosphorylation of myofibrillar proteins, such as TnI, C protein, and MLC-2, and changes in the activities and the Ca(2+) sensitivity of myofibrillar ATPase may contribute to the altered cardiac function during the progression of sepsis. Furthermore, the sepsis-induced alterations in the phosphorylation and Ca(2+) sensitivity of cardiac myofibrillar proteins were mediated via a beta-adrenergic receptor pathway.
 ...
PMID:Altered phosphorylation and calcium sensitivity of cardiac myofibrillar proteins during sepsis. 1144 42

Innate immunity not only mediates early host defenses to infection, but also contributes to septic hemodynamic compromise through nitric oxide synthase (NOS2) induction and inhibition of cardiovascular adrenergic responses. Because of increased age-related susceptibility to sepsis, we hypothesized that hearts from old (28-29 months) adult rats would exhibit greater beta-adrenergic hyporesponsiveness than young (6-8 months) following lipopolysaccharide (LPS, 6 mg/kg) with and without interferon gamma (INF-gamma, 5000 units). LPS/INF-gamma depressed baseline +dP/dt and isoproterenol-stimulated inotropy in both old and young hearts. beta-adrenergic inotropic (+dP/dt) and lusitropic responses were more depressed in old v young LPS/INF-gamma hearts. Additionally isoproterenol-stimulated cAMP elaboration was less in old (1950+/-160 fmol/min/g) v young (2440+/-170 fmol/min/g, P=0.05) LPS/INF-gamma hearts. LPS alone also depressed basal +dP/dt and prolonged myocardial relaxation in old and young hearts, but suppressed isoproterenol +dP/dt responses only in old hearts. Depressed beta-adrenergic inotropic responses were augmented with the selective NOS2 inhibitor N-iminoethyl-L-lysine. To establish biochemical mechanisms for this, we tested whether induction of NOS2 and innate immune system receptors (CD14 and Toll-like receptor 4, TLR4) were enhanced in old v young hearts. Induction of myocardial NOS2 and CD14 (not present in control) by LPS/INF-gamma was approximately 2-3-fold greater in old compared to young animals. TLR4 was constitutively expressed in old and young hearts and was unaffected by LPS/INF-gamma. These findings indicate that advanced age is associated with augmented cardiac beta-adrenergic depression and enhanced CD14-NOS2 signaling in response to cytokines. Upregulation of cardiovascular innate immunity may have clinical implications for increased mortality in older individuals with systemic inflammatory response syndromes.
 ...
PMID:Augmented age-associated innate immune responses contribute to negative inotropic and lusitropic effects of lipopolysaccharide and interferon gamma. 1160 26

Riemerella anatipestifer is responsible for exudative septicemia in ducks. The genetic determinant of the CAMP cohemolysin, cam, from a strain of R. anatipestifer was cloned and expressed in Escherichia coli. Chromosomal DNA from serotype 19 strain 30/90 was used to construct a gene library in pBluescript II SK(-) vector in E. coli XL-1-Blue strain. The clones containing recombinant plasmids were screened for the CAMP reaction with Staphylococcus aureus. Those that showed cohemolysis were chosen for further analysis by sequencing. One of these clones, JFRA8, was subcloned to identify the smallest possible DNA fragment containing the CAMP cohemolysin determinant, which was located on a 3,566-bp BamHI-BstXI fragment which specified a 1,026-bp open reading frame. Clones containing recombinant plasmids carrying cam obtained by PCR cloning into E. coli M15 strain secreted an active CAMP cohemolysin. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blot analyses confirmed that the recombinant strain expressed a protein with a molecular mass of 37 kDa and that strains from serotypes 1, 2, 3, 5, 6, and 19 expressed the cohemolysin. The deduced amino acid sequence showed high homology to those of O-sialoglycoprotein endopeptidases. Hydrolysis of radioiodinated glycophorin A confirmed that Cam is a sialoglycoprotease.
 ...
PMID:Identification and characterization of CAMP cohemolysin as a potential virulence factor of Riemerella anatipestifer. 1188

The purpose of this study was to investigate alterations of phospholamban phosphorylation and its interaction with Ca2+ transport(Ca2+-ATPase activity and Ca2+ uptake) in sarcoplasmic reticulum (SR) during the progression of sepsis. Sepsis was induced by cecal ligation and puncture (CLP). Phospholamban phosphorylation was studied by the labeling of the myocardial ATP pool by perfusing isolated rat hearts with [32P]H3PO4 followed by identification of the phosphorylated phospholamban. Results show that phospholamban phosphorylation was increased by 153% during the early hyperdynamic phase (9 h after CLP), while it was decreased by 51% during the late hypodynamic phase (18 h after CLP) of sepsis. The increase in phospholamban phosphorylation during early sepsis was associated with increases in +dP/dt(max) and tissue cAMP content, while Ca2+ transport, left ventricular developed pressure (LVDP), and -dP/dt(max) remained unchanged. The decrease in phospholamban phosphorylation during late sepsis was accompanied by decreases in Ca2+ transport, LVDP, +/-dP/dt(max), and tissue cAMP content. When isoproterenol was present in the perfusion medium, all parameters measured were stimulated in all three experimental groups (control, early sepsis, and late sepsis) except that Ca2+-ATPase activity and SR Ca2+ uptake were unresponsive in the early and the late septic groups. These findings demonstrate that during the late hypodynamic phase of sepsis, the observed decrease in myocardial contractility was due to the decrease in phospholamban phosphorylation, which resulted in decreased Ca2+ transport across the SR. In contrast, during the early hyperdynamic phase of sepsis, the increase in phospholamban phosphorylation did not correlate with increases in Ca2+ uptake and Ca2+-ATPase activity. Thus, the interaction between phospholamban phosphorylation and Ca2+ transport across the SR was disrupted during the early phase of sepsis.
 ...
PMID:Altered phospholamban-calcium ATPase interaction in cardiac sarcoplasmic reticulum during the progression of sepsis. 1202 59

Lipopolysaccharide (LPS) is a known causative agent of sepsis. In previous studies, we have shown that it reduces L-leucine mediated transport across the rabbit jejunum by about 30%. In this study, the mechanism(s) of LPS inhibition on amino acid transport were analysed in detail. LPS did not inhibit L-leucine transport across brush border membrane vesicles, suggesting the need for an intracellular step. The inhibitory effect of LPS was not altered by the addition of protein kinase A (PKA) inhibitor (IP(20), 10(-7) M) or an analog of cAMP (DB-cAMP, 3 x 10(-4) M), indicating that the PKA signal transduction pathway was not involved in the LPS effect. However, the inhibitory effect of LPS was suppressed by trifluoroperazine (10(-7) M), a Ca(2+)/calmodulin inhibitor and staurosporine (10(-7) M), an protein kinase C (PKC) inhibitor. Likewise, LPS inhibition disappeared in media without calcium. These results suggest that LPS could inhibit the intestinal uptake of L-leucine across the small intestine in vitro by intracellular processes related to calcium, involving PKC and calmodulin protein.
 ...
PMID:Cellular mechanism underlying LPS-induced inhibition of in vitro L-leucine transport across rabbit jejunum. 1202 52

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

Mucosal and enterocyte IL-6 production is increased during sepsis and endotoxemia. Recent studies suggest that cAMP potentiates IL-6 production in endotoxin- or IL-1beta-stimulated enterocytes, but the molecular mechanisms are not known. We examined the role of the transcription factors NF-kappaB, activator protein (AP)-1, CCAAT/enhancer binding protein (C/EBP), and cAMP response element-binding protein (CREB) in cAMP-induced IL-6 production in cultured Caco-2 cells, a human intestinal epithelial cell line. In addition, the role of the protein kinase A (PKA), protein kinase C (PKC), and mitogen-activated protein (MAP) kinase signaling pathways was examined. Treatment of the cells with IL-1beta increased IL-6 production and activated the IL-6 promoter in cells transfected with a luciferase reporter plasmid containing a wild-type IL-6 promoter. These effects of IL-1beta were significantly potentiated by cAMP. When the binding sites for the individual transcription factors in the IL-6 promoter were mutated, results indicated that all four transcription factors may be involved in the cAMP-induced activation of the IL-6 gene. Treatment of the Caco-2 cells with cAMP increased the DNA binding activity of CREB, C/EBP, and AP-1, but not NF-kappaB. By using specific blockers, evidence was found that both PKA and p38 MAP kinase (but not PKC or p42/44 MAP kinase) may be involved in the cAMP-induced potentiation of IL-6 production. The present results suggest that cAMP activates multiple transcription factors involved in the regulation of the IL-6 gene and that the activation of these transcription factors may at least in part explain why cAMP potentiates IL-6 production in stimulated enterocytes.
 ...
PMID:Multiple transcription factors regulating the IL-6 gene are activated by cAMP in cultured Caco-2 cells. 1237 7

G protein-coupled adenosine receptors are the subject of intense study as immunomodulators of inflammation especially since the recent demonstration that the A2a receptor acts to down-regulate inflammation and inhibit tissue damage in vivo [Nature 414 (6866) (2001) 916]. The adverse effects of overactive inflammation are evident in diseases e.g. sepsis, rheumatoid arthritis, and multiple sclerosis underscoring the importance of inhibiting inflammation or selectively enhancing inflammatory processes. It has been shown recently that the A2a adenosine receptor is a critical component of an endogenous "immunosuppressive loop" in which extracellular adenosine that accumulates due to local hypoxia caused by inflammatory insult signals through cAMP-elevating A2a receptors in a delayed negative feedback manner. Understanding how tissues regulate inflammation will provide the information necessary to allow for the engineering, or selective targeting, of endogenous inflammatory pathways. Recognition of A2a receptors as "natural" or endogenous brakes of inflammation provides the intellectual scaffolding needed to pursue these goals.
 ...
PMID:Targeting G protein-coupled A2a adenosine receptors to engineer inflammation in vivo. 1256 2

Changes in the protein level of various subunits of GTP-binding protein and the activity of adenylate cyclase in the rat heart during different phases of sepsis were studied. Sepsis was induced by cecal ligation and puncture (CLP). Experiments were divided into three groups: control, early sepsis, and late sepsis. Early and late sepsis refers to those animals sacrificed at 9 and 18 h, respectively, after CLP. The protein levels of various subunits of GTP-binding protein were determined by Western blot analysis. The activity of adenylate cyclase was measured based on the rate of formation of cAMP from [alpha-32P]ATP. The results show that protein levels of G alphas and G beta remained stable during the early and the late phases of sepsis. The protein levels of G alpha i-2 and G alpha i-3 remained relatively unaltered during the early phase of sepsis, but they were increased by 46.5% (P < 0.05) and 61.3% (P < 0.01), respectively, during the late phase of sepsis. The basal adenylate cyclase activity remained unchanged during the early phase while it was decreased by 25.7% (P < 0.05) during the late phase of sepsis. The isoproterenol-stimulated adenylate cyclase activity was unchanged during early sepsis while it was decreased by 44.6% (P < 0.01) during late sepsis. These data demonstrate that during the late hypodynamic phase of sepsis, myocardial G alpha i-2 and G alpha i-3 protein levels were increased and the increases were coupled with a reduction in adenylate cyclase activity. Because GTP-binding proteins mediate sympathetic control of cardiac function, the present findings may have a pathophysiological significance in contributing to the understanding of the pathogenesis of cardiac dysfunction during the late stage of sepsis.
 ...
PMID:G protein and adenylate cyclase complex-mediated signal transduction in the rat heart during sepsis. 1278 8

The mechanisms by which parenchymal cells interact with immune cells, particularly after removal of LPS, remain unknown. Lung explants from rats, mice deficient in the TNF gene, or human lung epithelial A549 cells were treated with LPS and washed, before naive alveolar macrophages, bone marrow monocytes, or PBMC, respectively, were added to the cultures. When the immune cells were cocultured with LPS-challenged explants or A549 cells, TNF production was greatly enhanced. This was not affected by neutralization of LPS with polymyxin B. The LPS-induced increase in the expression of ICAM-1 on A549 cells correlated with TNF production by PBMC. The cellular cross talk leading to the TNF response was blunted by an anti-ICAM-1 Ab and an ICAM-1 antisense oligonucleotide. In A549 cells, a persistent decrease in the concentration of intracellular cAMP was associated with colocalization of LPS into Toll-like receptor 4 and the Golgi apparatus, resulting in increased ICAM-1 expression. Inhibition of LPS internalization by cytochalasin D or treatment with dibutyryl cAMP attenuated ICAM-1 expression and TNF production by PBMC. In conclusion, lung epithelial cells are not bystanders, but possess memory of LPS through the expression of ICAM-1 that interacts with and activates leukocytes. This may provide an explanation for the failure of anti-LPS therapies in sepsis trials.
 ...
PMID:Intercellular adhesion molecule-1 mediates cellular cross-talk between parenchymal and immune cells after lipopolysaccharide neutralization. 1468 73


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>