UMLS:C0036690 - FACTA Search

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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.
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PMID:Endothelin-converting enzyme-1-mediated signaling in adult rat ventricular myocyte contractility and apoptosis during sepsis. 1573 12

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.
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PMID:Bigendothelin-1 (1-21) fragment during early sepsis modulates tau, p38-MAPK phosphorylation and nitric oxide synthase activation. 1588 74

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.
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PMID:Bigendothelin-1 via p38-MAPK-dependent mechanism regulates adult rat ventricular myocyte contractility in sepsis. 1595 56

Inflammatory mediators have been implicated as a cause of reversible myocardial depression in septic shock. We previously reported that the release of lysozyme-c (Lmz-S) from leukocytes from the spleen or other organs contributes to myocardial dysfunction in Escherichia coli septic shock in dogs by binding to a cardiac membrane glycoprotein. However, the mechanism by which Lzm-S causes this depression has not been elucidated. In the present study, we tested the hypothesis that the binding of Lzm-S to a membrane glycoprotein causes myocardial depression by the formation of nitric oxide (NO). NO generation then activates soluble guanylyl cyclase and increases cyclic guanosine monophosphate (cGMP), which in turn triggers contractile impairment via activation of cGMP-dependent protein kinase (PKG). We examined these possibilities in a right ventricular trabecular preparation in which isometric contraction was used to measure cardiac contractility. We found that Lzm-S's depressant effect could be prevented by the non-specific NO synthase (NOS) inhibitor N(G)-monomethyl-l-arginine (l-NMMA). A guanylyl cyclase inhibitor (ODQ) and a PKG inhibitor (Rp-8-Br-cGMP) also attenuated Lzm-S's depressant effect as did chemical denudation of the endocardial endothelium (EE) with Triton X-100 (0.5%). In EE tissue, we further showed that Lzm-S caused NO release with use of 4,5 diaminofluorescein, a fluorescent dye that binds to NO. The present study shows that the binding of Lzm-S to EE generates NO, and that NO then activates the myocardial guanosine 3',5' monophosphate pathway leading to cardiac depression in sepsis.
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PMID:Lysozyme binding to endocardial endothelium mediates myocardial depression by the nitric oxide guanosine 3',5' monophosphate pathway in sepsis. 1608 90

LPS is known to modulate macrophage responses during sepsis, including cytokine release, phagocytosis, and proliferation. Although agents that elevate cAMP reverse LPS-induced macrophage functions, whether LPS itself modulates cAMP and whether LPS-induced decreases in proliferation are modulated via a cAMP-dependent pathway are not known. Murine macrophages (RAW264.7 cells) were treated with LPS in the presence or absence of inhibitors of prostaglandin signaling, protein kinases, CaM, Gi proteins, and NF-kappaB translocation or transcription/translation. LPS effects on CaMKII phosphorylation and the expression of relevant adenylyl cyclase (AC) isoforms were measured. LPS caused a significant dose (5-10,000 ng/ml)- and time (1-8 h)-dependent increase in forskolin-stimulated AC activity that was abrogated by pretreatment with SN50 (an NF-kappaB inhibitor), actinomycin D, or cycloheximide, indicating that the effect is mediated via NF-kappaB-dependent transcription and new protein synthesis. Furthermore, LPS decreased the phosphorylation state of CaMKII, and pretreatment with a CaM antagonist attenuated the LPS-induced sensitization of AC. LPS, cAMP, or PKA activation each independently decreased macrophage proliferation. However, inhibition of NF-kappaB had no effect on LPS-induced decreased proliferation, indicating that LPS-induced decreased macrophage proliferation can proceed via PKA-independent signaling pathways. Taken together, these findings indicate that LPS induces sensitization of AC activity by augmenting the stimulatory effect of CaM and attenuating the inhibitory effect of CaMKII on isoforms of AC that are CaMK sensitive.
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PMID:Lipopolysaccharide-induced sensitization of adenylyl cyclase activity in murine macrophages. 1612 Jun 52

Apoptosis and inflammation play an important role in the pathogenesis of direct/pulmonary acute lung injury (ALI). However, the role of the Fas receptor-driven apoptotic pathway in indirect/nonpulmonary ALI is virtually unstudied. We hypothesized that if Fas or caspase-8 plays a role in the induction of indirect ALI, their local silencing using small interfering RNA (siRNA) should be protective in hemorrhage-induced septic ALI. Initially, as a proof of principle, green fluorescent protein-siRNA was administered intratracheally into transgenic mice overexpressing green fluorescent protein. Twenty-four hours after siRNA delivery, lung sections revealed a significant decrease in green fluorescence. Intratracheally administered Cy-5-labeled Fas-siRNA localized primarily in pulmonary epithelial cells. Intratracheal instillation of siRNA did not induce lung inflammation via toll-like receptor or protein kinase PKR pathways as assessed by lung tissue interferon-alpha, tumor necrosis factor-alpha, and interleukin (IL)-6 levels. Mice subjected to hemorrhagic shock and sepsis received either Fas-, caspase-8-, or control-siRNA intratracheally 4 hours after hemorrhage. Fas- or caspase-8-siRNA significantly reduced lung tissue Fas or caspase-8 mRNA, respectively. Only Fas-siRNA markedly diminished lung tissue tumor necrosis factor-alpha, IL-6, IL-10, interferon-gamma, IL-12, and caspase-3 activity. Fas-siRNA also preserved alveolar architecture and reduced lung neutrophil infiltration and pulmonary epithelial apoptosis. These data indicate the pathophysiological significance of Fas activation in nonpulmonary/shock-induced ALI and the feasibility of intrapulmonary administration of anti-apoptotic siRNA in vivo.
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PMID:Silencing of Fas, but not caspase-8, in lung epithelial cells ameliorates pulmonary apoptosis, inflammation, and neutrophil influx after hemorrhagic shock and sepsis. 1631 69

Adrenomedullin (ADM) acts as an autocrine or a paracrine factor in the regulation of cardiac function. The intracellular mechanisms involved in the direct effect of ADM on adult rat ventricular myocytes (ARVMs) are still to be elucidated. In ARVMs from normal rats, ADM produced an initial (< 30 min) increase in cell shortening and Ca2+ transients and a marked decrease in both on prolonged incubation (> 1 h). Both effects were sensitive to ADM antagonist ADM-(22-52). Treatment with SQ-22536, an inhibitor of adenylate cyclase, blocked the positive inotropic effect of ADM and potentiated its negative inotropic effect. The negative inotropic effect was sensitive to inhibition by pertussis toxin (PTX), an inhibitor of Gi proteins and KT-5720, an inhibitor of PKA. The observations suggest a switch from Gs-coupled to PTX-sensitive, PKA-dependent Gi coupling by ADM in ARVMs. The ADM-mediated Gi-signaling system involves cAMP-dependent pathways because SQ-22536 further increased the negative inotropic actions of ADM. Also, because ADM is overproduced by ARVMs in our rat model of septic shock, ARVMs from LPS-treated rats were subjected to treatment with ADM-(22-52) and PTX. The decrease in cell shortening and Ca2+ transients in LPS-treated ARVMs could be reversed back with ADM-(22-52) and PTX. This indicates that ADM plays a role in mediating the negative inotropic effect in LPS-treated ARVM through the activation of Gi signaling. This study delineates the intracellular pathways involved in ADM-mediated direct inotropic effects on ARVMs and also suggests a role of ADM in sepsis.
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PMID:Gs and Gi coupling of adrenomedullin in adult rat ventricular myocytes. 1632 20

Glycogen synthase kinase 3beta (GSK-3beta) is a serine/threonine protein kinase that has recently emerged as a key regulatory switch in the modulation of the inflammatory response. Dysregulation of GSK-3beta has been implicated in the pathogenesis of several diseases including sepsis. Here we investigate the effects of 2 chemically distinct inhibitors of GSK-3beta, TDZD-8 and SB216763, on the circulatory failure and the organ injury and dysfunction associated with hemorrhagic shock. Male Wistar rats were subjected to hemorrhage (sufficient to lower mean arterial blood pressure to 35 mmHg for 90 min) and subsequently resuscitated with shed blood for 4 h. Hemorrhage and resuscitation resulted in an increase in serum levels of (a) creatinine and, hence, renal dysfunction, and (b) alanine aminotransferase and aspartate aminotransferase and, hence, hepatic injury. Treatment of rats with either TDZD-8 (1 mg/kg, i.v.) or SB216763 (0.6 mg/kg, i.v.) 5 min before resuscitation abolished the renal dysfunction and liver injury caused by hemorrhagic shock. In addition, TDZD-8, but not SB216763, attenuated the increase caused by hemorrhage and resuscitation in plasma levels of the proinflammatory cytokine interleukin 6 and also of the anti-inflammatory cytokine interleukin 10. Neither of the GSK-3beta inhibitors however affected the delayed fall in blood pressure caused by hemorrhagic shock. Thus, we propose that inhibition of GSK-3beta may represent a novel therapeutic approach in the therapy of hemorrhagic shock.
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PMID:Glycogen synthase kinase-3beta inhibitors protect against the organ injury and dysfunction caused by hemorrhage and resuscitation. 1668 13

The incidence of sepsis is expected to increase at a rate of 1.5% per year. Advances in our understanding of the sepsis syndrome have enabled researchers to identify new therapeutic targets and design therapies for existing mediators of sepsis. Drotrecogin alfa (activated) was the first biological treatment for serious sepsis approved by the Food and Drug Administration in 2001. There have also been promising research results involving ethyl pyruvate, glycogen synthase kinase-3 inhibitors and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Here, we review these four compounds and compound classes as examples of emerging pharmacological treatments of severe sepsis and describe the current status of sepsis research.
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PMID:Promising therapeutic agents for sepsis. 1711 61

Electrical coupling along the endothelium is central in the arteriolar conducted response and in control of vascular resistance. It has been shown that exposure of endothelium to lipopolysaccharide (LPS, an initiating factor in sepsis) reduces intercellular communication in vitro and in vivo. The molecular basis for this reduction is not known. We examined the effect of LPS on electrical coupling in monolayers of cultured mouse microvascular endothelial cells (MMEC) derived from the mouse hindlimb skeletal muscle. To assess coupling, we measured the spread of electrical current injected into the monolayer and computed the monolayer intercellular resistance (inverse measure of coupling). LPS (10 microg/ml, 1 h) reduced coupling (i.e., increased resistance) in MMEC isolated from wild-type, connexin37 (Cx37) null and Cx43(G60S) (nonfunctional mutant) mice, but not in MMEC derived from Cx40 null mice. LPS also activated JNK1/2, p38 and ERK1/2 MAP kinases. Pretreatment of WT monolayers with ERK1/2 inhibitor U0126 (20 microM, 1 h) prevented the LPS-induced decrease in coupling, while inhibition of JNK1/2 with SP600125 (20 microM, 1 h) and p38 with a p38 inhibitor (10 nM, 1 h) had no effect. Furthermore, inhibition of tyrosine kinases with PP-2 (10 nM, 1 h), activation of PKA by 8-bromo-cAMP (1 mM, 5 min), and activation of PKC by bryostatin-2 (10 nM, 1 h) also prevented the reduction in coupling. We propose that LPS reduces inter-endothelial electrical coupling via tyrosine-, ERK1/2-, PKA-, and PKC-dependent signaling that targets Cx40. We suggest that this mechanism contributes to compromised arteriolar function following LPS exposure.
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PMID:Lipopolysaccharide reduces electrical coupling in microvascular endothelial cells by targeting connexin40 in a tyrosine-, ERK1/2-, PKA-, and PKC-dependent manner. 1714 6

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