Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UMLS:C0036690 (sepsis)
59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We hypothesized that modulation of endothelin-converting enzyme-1 (ECE-1) activity would affect phosphorylation of p38-mitogen activated protein kinase (p38-MAPK) and potentiate apoptosis in adult rat ventricular myocytes (ARVMs) during sepsis. The activity of ECE-1 in ARVMs was altered by increasing the substrate availability for ECE-1 by exogenous administration of bigendothelin-1 (bigET-1, 100 nM) and by inhibiting ECE-1 using FR901533 (10 microM) for 24-h. FR901533 significantly decreased the concentration of ET-1 in both sham and sepsis groups. FR901533 decreased p38-MAPK phosphorylation in sepsis but not in sham group. BigET-1 upregulated p38-MAPK phosphorylation, produced hypertrophy, decreased cell viability and reversed FR901533-induced down-regulation of p38-MAPK phosphorylation in both groups. Although, FR901533 did not affect cell cross-sectional area, it significantly reduced the viability of ARVM in both groups. The peak shortening of sham ARVMs was elevated by bigET-1, FR901533 and pretreatment with FR901533 followed by bigET-1. However, the contractility of septic ARVMs was not altered by either bigET-1 or FR901533 treatments per se. Septic ARVM exhibited significantly increased caspase-3 activity at 12 and 24-h. Pretreatment with FR901533 significantly elevated caspase-3 activity in both sham and sepsis group. The data demonstrated that bigET-1-induced hypertrophy in septic ARVM correlates with an ECE-1 dependent-activation of p38-MAPK. The results suggest that non-responsiveness of ARVM to bigET-1 is due to ECE-1 dependent apoptosis. We concluded that ECE-1 may play a crucial role in ARVM dysfunction via increased caspase-3 activity and p38-MAPK phosphorylation during sepsis.
...
PMID:Endothelin-converting enzyme-1-mediated signaling in adult rat ventricular myocyte contractility and apoptosis during sepsis. 1573 12

Kinins are proinflammatory peptides that mediate numerous vascular and pain responses to tissue injury. Two pharmacologically distinct kinin receptor subtypes have been identified and characterized for these peptides, which are named B1 and B2 and belong to the rhodopsin family of G protein-coupled receptors. The B2 receptor mediates the action of bradykinin (BK) and lysyl-bradykinin (Lys-BK), the first set of bioactive kinins formed in response to injury from kininogen precursors through the actions of plasma and tissue kallikreins, whereas the B(1) receptor mediates the action of des-Arg9-BK and Lys-des-Arg9-BK, the second set of bioactive kinins formed through the actions of carboxypeptidases on BK and Lys-BK, respectively. The B2 receptor is ubiquitous and constitutively expressed, whereas the B1 receptor is expressed at a very low level in healthy tissues but induced following injury by various proinflammatory cytokines such as interleukin-1beta. Both receptors act through G alpha(q) to stimulate phospholipase C beta followed by phosphoinositide hydrolysis and intracellular free Ca2+ mobilization and through G alpha(i) to inhibit adenylate cyclase and stimulate the mitogen-activated protein kinase pathways. The use of mice lacking each receptor gene and various specific peptidic and nonpeptidic antagonists have implicated both B1 and B2 receptors as potential therapeutic targets in several pathophysiological events related to inflammation such as pain, sepsis, allergic asthma, rhinitis, and edema, as well as diabetes and cancer. This review is a comprehensive presentation of our current understanding of these receptors in terms of molecular and cell biology, physiology, pharmacology, and involvement in human disease and drug development.
...
PMID:International union of pharmacology. XLV. Classification of the kinin receptor family: from molecular mechanisms to pathophysiological consequences. 1573 27

Sex hormones are important modifiers of the acute inflammatory response to injury, an important aspect of myocardial depression and apoptosis following ischemia or endotoxemia. Hemorrhage, trauma, ischemia/reperfusion, burn and sepsis each lead to cardiac dysfunction. Gender has been shown to influence the inflammatory response as well as outcomes following acute injury. The mechanisms by which sex affects the inflammatory response and the outcome to acute injury are being actively investigated. It is now recognized that myocardial inflammation plays a crucial role in I/R-induced myocardial dysfunction. Inflammatory mediators, such as TNF-alpha are produced by cardiomyocytes and contribute to myocardial functional depression and apoptosis. Gender differences in the inflammatory response following burn injury have been demonstrated. However, gender differences in the setting of acute I/R-induced inflammation are unclear. In addition, a critical component of the signal transduction pathway leading to myocardial inflammation is the activation of p38 mitogen-activated protein kinase (MAPK). In other systems, it appears that gender differences exist in the p38 MAPK signaling pathway. The inflammatory response, including the p38 MAPK signaling cascade and expression of proinflammatory cytokines such as TNF-alpha and IL-1beta, may precipitate cardiomyocyte apoptosis following I/R injury. Apoptosis may be an essential component in the pathogenesis of heart failure, and there is evidence that myocyte apoptosis in the failing human heart is markedly lower in women than in men. The prevention of cell death attenuates I/R-induced injury on myocardial anatomy and performance. This review will: 1) examine evidence for gender differences in the outcome to acute injury; 2) explain the myocardial inflammatory response to acute injury; and 3) elucidate the various mechanisms by which gender and sex hormones affect the myocardial response to acute injury.
...
PMID:Intracellular signaling mechanisms of sex hormones in acute myocardial inflammation and injury. 1576 71

Sepsis results in hepatic "growth hormone (GH) resistance" with reductions in plasma IGF-I despite a two- to fourfold increase in circulating GH. In this study, we examine the effects of IL-1 on GH receptor (GHR) expression, GH signaling (via the JAK/STAT and MAPK pathways), and the induction of gene expression [IGF-I mRNA and serine protease inhibitor (Spi) 2.1] by GH in CWSV-1 hepatocytes. Incubation of cells with IL-1beta (10 ng/ml, 24 h) had no effect on the relative abundance of GHR or signaling proteins JAK2, STAT5b, and ERK1/2 in cell lysates. Baseline phosphorylation of GHR, JAK2, STAT5b, and ERK1/2 was minimal. After GH stimulation, tyrosine phosphorylation of GHR, JAK2, STAT5b, and ERK1/2 increased 2- to 10-fold. However, neither the time course nor the magnitude of GHR, JAK2, and ERK1/2 phosphorylation by GH were significantly altered by IL-1. The GH-induced translocation of STAT5b to the nucleus was not prevented by IL-1. Although phosphorylated STAT5 in nuclear extracts from GH + IL-1 cells was decreased by 24% (vs. controls) 15 min after GH stimulation, this did not result in reduced STAT5-DNA binding activity. Pretreatment with IL-1 did not significantly decrease IGF-I mRNA stability. We conclude that IL-1 only minimally affects the time course of JAK2/STAT5 and MAPK signaling by GH. Therefore, an inhibitory effect of IL-1 on IGF-I and Spi 2.1 mRNA synthesis by GH represents the most likely mechanism for IL-1-mediated GH resistance.
...
PMID:Interleukin-1 inhibits the induction of insulin-like growth factor-I by growth hormone in CWSV-1 hepatocytes. 1583 12

Between one-third and one-half of all cases of sepsis are known to be caused by gram-positive microorganisms through the cell wall component, e.g. lipoteichoic acid (LTA). Gram-positive bacteria are also known to induce encephalomyelitis and meningeal inflammation, and enhance the production of nitric oxide (NO) via expression of inducible nitric oxide synthase (iNOS) in murine tissue macrophages. It remains to be explored if LTA could activate microglia considered to be resident brain macrophages. We report here that LTA derived from gram-positive bacteria (Staphylococcus aureus) significantly induces NO release and iNOS expression in primary microglia. LTA-induced NO accumulation was detected at 2 h in microglial culture and was significantly attenuated by pretreatment with anti-CD14, complement receptor type 3 (CR3) or scavenger receptor (SR) antibodies. LTA activated mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinase, p38 MAPK or c-Jun N-terminal kinase in cultured microglia. LTA-elicited microglial NO production was also drastically suppressed by SB203580 (p38 MAPK inhibitor) or pyrrolidine dithiocarbamate (an inhibitor of nuclear factor kappaB), indicating that p38 MAPK and nuclear factor kappaB were involved in microglial NO release after LTA challenge. These results suggest that gram-positive bacterial product such as LTA can activate microglia to release NO via the signal transduction pathway involving multiple LTA receptors (e.g. CD14, CR3 or SR), p38 MAPK and nuclear factor kappaB. The in vivo study further confirmed that administered intracerebrally LTA induced considerable noticeable iNOS, phospho-IkappaB and phospho-p38 MAPK expression in microglia/macrophages.
...
PMID:Signal transduction pathways of nitric oxide release in primary microglial culture challenged with gram-positive bacterial constituent, lipoteichoic acid. 1587 5

Earlier we have demonstrated that inhibition of endothelin biosynthesis ameliorates endotoxemia-induced inducible nitric oxide synthase (iNOS) activation and phosphorylation of p38-mitogen activated protein kinase (pp38-MAPK). Therefore, in the present study, we tested the hypothesis that activation of endothelin (ET)-1 biosynthesis using bigET-1 during early sepsis would upregulate iNOS and affect myocardial function in the rat. Male Sprague-Dawley rats (350-400 g) were anesthetised using Nembutal (50 mg/kg, i.p.) and jugular vein, tail artery (Mean arterial pressure, MAP) and right carotid arteries (advanced to left ventricle, LV) were cannulated. The rats were randomly divided into saline-, bigET-1- and C-terminal fragment of bigET-1 (bigET-1(22-38))-treated groups. Sepsis was induced using i.p. injection of cecal inoculum obtained from a donor rat (200 mg/kg in 5 ml 5% sterile dextrose water, D5W). Sham animals received an i.p. injection of D5W (5 ml/kg). MAP and LVP were recorded and cardiodynamic parameters were calculated at 0, 2, 6, 12 and 24 h post sham or sepsis-induction. A significant elevation in LV isovolumic relaxation rate constant (tau), LV end diastolic pressure (LVEDP) and rate pressure product (RPP) was observed in vehicle-treated septic group at 24 h. BigET-1 significantly increased concentration of LV ET-1 both in sham and septic groups. BigET-1 elevated tau and LVEDP both in sham and septic animals as early as 12 h which persisted through 24 h. However, bigET-1(22-38) elevated LVEDP in septic group at 24 h but not in sham group. BigET-1 accentuated the levels of plasma nitric oxide byproduct (NOx) levels in both sham and septic animals at 6, 12 and 24 h. Sepsis increased myocardial iNOS at 24 h. BigET-1 significantly upregulated expression of myocardial iNOS and pp38-MAPK. The data suggest that increased substrate availability for ET-1 at the time of sepsis-induction contributes in diastolic dysfunction, iNOS activation and p38-MAPK phosphorylation.
...
PMID:Bigendothelin-1 (1-21) fragment during early sepsis modulates tau, p38-MAPK phosphorylation and nitric oxide synthase activation. 1588 74

Macrophage prostaglandin E2 (PGE2) production is important in cellular immune suppression and in affecting the potential development of sepsis after trauma. We hypothesized that macrophage PGE2 production after trauma is regulated by mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-kappaB). Mice were subjected to trauma and splenic macrophages isolated 7 days later. Macrophages from traumatized mice showed increased cyclooxygenase-2 (COX-2) mRNA, protein expression, and PGE2 production compared with controls. Increased phosphorylation of extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), and p38 kinase was observed in macrophages from traumatized mice. Pharmacologic inhibition of MAPK blocked trauma-induced COX-2 expression, and PGE2 production. Trauma macrophages showed increased IkappaBalpha phosphorylation and NF-kappaB binding to DNA. Inhibiting IkappaBalpha blocked trauma-induced NF-kappaB activity, COX-2 expression and PGE2 production. This suggests that trauma-induced PGE2 production is mediated through MAPK and NF-kappaB activation and offers potential for modifying the macrophages' responses following injury.
...
PMID:Enhanced expression of cyclooxygenase-2 and prostaglandin E2 in response to endotoxin after trauma is dependent on MAPK and NF-kappaB mechanisms. 1589 Mar 24

We tested the hypothesis that exogenous administration of the ET-1 precursor, bigET-1, would regulate adult rat ventricular myocyte (ARVM) contractility in a p38-mitogen activated protein kinase (p38-MAPK)-dependent mechanism during sepsis. Ventricular myocytes from adult rat hearts (both sham and septic) were stimulated to contract at 0.5 Hz and mechanical properties were evaluated using an IonOptix Myocam system. Immunoblot analysis was used to determine the phosphorylation of p38-MAPK and extracellular signal-regulated kinase 1/2 (ERK1/2). ARVMs were treated with vehicle, bigET-1 and inhibitors for 24 h and then subjected to functional and biochemical estimations. Septic ARVM displayed a distorted cell membrane and irregular network within the cells along with increased cell contractility as evidenced by elevated peak shortening (PS), maximal velocity of shortening (+dL/dt) and relengthening (-dL/dt) in comparison to sham ARVM. BigET-1 treatment caused ARVM enlargement in both sham and sepsis groups. BigET-1 (100 nM) produced an increase in ARVM contractility in sham group as compared to vehicle treatment. However, septic ARVM treated with bigET-1 exhibited unaltered ARVM contractility, and upregulated ET(B) receptors as compared to respective sham group. BigET-1 increased the concentration of ET-1 and upregulated phosphorylation of p38-MAPK but not of ERK1/2 in sham and septic ARVM. Furthermore, inhibition of p38-MAPK by SB203580 (10 microM) increased ARVM contractility in sham but not in sepsis group. BigET-1 reversed SB203580-induced increase in PS in sham group but accentuated it in sepsis group. BigET-1 also reversed SB203580-induced inhibition of p38-MAPK phosphorylation in sham but not in septic ARVM. SB203580 pretreatment followed by bigET-1 administration significantly decreased p38-MAPK phosphorylation and downregulated ET(B) receptor expression as compared to bigET-1 treatment per se in sepsis group but not in sham. We concluded that a bigET-1-induced non-responsive effect on septic ARVM contractile function could be due to upregulation of p38-MAPK phosphorylation and ET(B) receptor expression.
...
PMID:Bigendothelin-1 via p38-MAPK-dependent mechanism regulates adult rat ventricular myocyte contractility in sepsis. 1595 56

Despite advances in the understanding of pathophysiological mechanisms, there are limited pharmacotherapeutic options for sepsis, septic shock, and related pathologies. It is surprising that although sepsis-induced myocardial depression is documented in clinics, the cellular mechanisms are from clear. Alterations in molecular signaling mechanisms activated by cytokines and potent mediators such as ET-1 could pose the risk for myocardial dysfunction in sepsis. Our laboratory data suggest that the septic heart, in vivo, exhibits an increased time constant of left ventricular relaxation, tau, along with changes in LVEDP. We also observed that bigET-1-induced elevation of ET-1 correlates with cardiodynamic alterations, induction of apoptosis, and activation of p38-MAPK phosphorylation during sepsis. In light of these evidences, we emphasize that these molecular alterations in heart, both at organ and cellular level during early sepsis, need to be elucidated thoroughly.
...
PMID:Chronic peritoneal sepsis: myocardial dysfunction, endothelin and signaling mechanisms. 1597 May 72

In sepsis, and in models of sepsis including endotoxemia, impaired neutrophil recruitment and chemotaxis have been reported. The inability of the endotoxemic neutrophil to chemotax could be attributed to the fact that intracellular signaling via LPS overrides signals from endogenous chemokines or, alternatively, that sequestration of neutrophils into lungs prevents access to peripheral tissues. Using both in vitro and in vivo chemotaxis assays the authors established that neutrophils from healthy mice chemotaxed in vivo toward MIP-2, whereas endotoxemic neutrophils did not. Since LPS activates leukocytes via the p38 MAPK pathway, SKF86002, a p38 MAPK inhibitor, was given to endotoxemic animals. SKF86002 significantly reversed the LPS-induced impairment in emigration of endotoxic neutrophils in response to MIP-2. Neutrophil chemotaxis in vitro was also impaired by LPS, via a p38 MAPK-dependent pathway, and this impairment could be reversed via p38 MAPK inhibition. Although neutrophil numbers dropped in the circulation and trapped in lungs during endotoxemia, SKF86002 did not reverse these parameters, demonstrating that p38 MAPK inhibition did not release trapped neutrophils from the lungs. In conclusion, the data suggest that the impaired emigration and chemotaxis of neutrophils at peripheral sites during endotoxemia may be partially due to a p38 MAPK-mediated inhibition of neutrophil responses to endogenous chemokines.
...
PMID:Lipopolysaccharide: a p38 MAPK-dependent disrupter of neutrophil chemotaxis. 1602 Mar 90


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

---