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)

To investigate whether the inhibition of protein kinases including protein kinase C can antagonize endotoxicosis, the in vivo effects of K252a, a potent inhibitor of protein kinases, on endotoxin-induced lethality and glucose dyshomeostasis were determined in conscious rats. Sprague-Dawley rats (260-340 g) were divided into the following four groups: Group DS, 2.5% dimethyl sulfoxide (DMSO), 6 ml/kg iv + 0.9% saline, 2 ml/kg iv; group KS, K252a in 2.5% DMSO, 4 mg/kg iv + 0.9% saline; group DE, 2.5% DMSO + endotoxin (E. coli), 15 mg/kg iv; and group KE, K252a in 2.5% DMSO + endotoxin. A quarter of DMSO or K252a solution was continuously infused over a 15 min period before a bolus injection of either saline or endotoxin. The remaining dose was administered over a 180 min period after saline or endotoxin. All animals in the DS and KS groups survived for 24 hrs. K252a significantly improved endotoxic lethality. It attenuated the initial hyperglycemia, and late hypoglycemia, hyperlactacidemia, and base deficit after endotoxin. However, K252a had no influence on the endotoxic alterations of blood pressure, PaCO2 or PaO2. These results suggest that the activations of protein kinases, particularly protein kinase C, are involved in the pathogenesis of lethal endotoxicosis and sepsis.
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PMID:K252a, a potent protein kinase inhibitor, improves endotoxic lethality and glucose dyshomeostasis. 846 75

Stimulation of human neutrophils by LPS is central to the pathogenesis of sepsis and the adult respiratory distress syndrome. The intracellular signaling pathway that results in cellular responses following LPS stimulation in neutrophils is unknown. We report that exposure of neutrophils to LPS results in the phosphorylation and activation of a p38 mitogen-activated protein (MAP) kinase, occurring in a concentration-dependent manner, with maximum response at 20 to 25 min. Partial purification of a p38 MAP kinase by ion exchange chromatography established it as distinct from the p42/p44 (extracellular signal-regulated kinases (ERK-1 and ERK-2) MAP kinases). Activation of the p38 MAP kinase by LPS in human neutrophils occurs via CD14, a proposed LPS receptor, and requires the presence of plasma containing the LPS-binding protein. This intracellular signaling pathway is independent of protein kinase C and does not involve Raf, MAP/ERK kinase kinase-1, MAP/ERK kinase-1, or MAP/ERK kinase-2 and does not result in the activation of the p42/p44 ERK MAP kinases or the c-jun N-terminal kinases.
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PMID:Activation of a p38 mitogen-activated protein kinase in human neutrophils by lipopolysaccharide. 864 36

The immune and endocrine mediators that are released during sepsis (e.g., tumor necrosis factor [TNF] alpha, interleukin [IL]-1, IL-6, transforming growth factor [TGF] beta, prostaglandin [PG] E2, catecholamines, vasopressin, glucagon, insulin, and glucocorticoids) can produce inappropriate detrimental cellular responses contributing to exacerbation of septic injury. Examples of such sepsis-related inappropriate responses are: exaggerated hepatic acute-phase protein (APP) expression and release skeletal muscle insulin resistance, and suppressed T-lymphocyte proliferation. The studies discussed in this article present evidence that the generation of the sepsis-related hepatic, skeletal muscle, and T-lymphocyte responses emanate from alterations in intracellular Ca2+ (Ca2+i) homeostasis. In hepatocytes, there is indication of a sepsis-mediated increase in Ca2+ influx from the extracellular milieu leading to a sustained increase in the apparent resting cell Ca2+i concentration ([Ca2+]i) and its depressed elevation on stimulation with Ca2+-mobilizing hormones such as catecholamines and vasopressin. These Ca(2+)- related changes can affect not only the signaling pathways in which Ca2+i itself serves as a signaling component, but also the signaling systems turned on by other sepsis-induced agonists which may not be dependent on Ca2+ signaling. TGF-beta, IL-1, TNF alpha, and IL-6 activate a primarily protein kinase C (PKC)-dependent intracellular signal system for the elicitation of a normal hepatic APP response (APPR). The increased apparent basal [Ca2+]i in sepsis can hypersensitize PKC activation and thus lead to an exaggerated APPR. In the skeletal muscle, an evident increase in Ca2+ membrane flux during sepsis pointed to an increase in the basal [Ca2+]i resulting from a plausible cytokine-mediated overactivation of the voltage-sensitive Ca2+ channels. The increased basal [Ca2+]i can negatively modulate the insulin-mediated stimulation of GLUT4-dependent glucose transport despite the possibility that Ca2+i might not participate as a component in the insulin-receptor-regulated signaling pathway. Increased [Ca2+]i in skeletal myocytes can either directly promote the phosphorylation of GLUT4 or prevent its dephosphorylation, both of which effectively block insulin stimulation of glucose uptake, thereby contributing to insulin resistance. In T lymphocytes, septic injury appears to induce an attenuation in the mitogen and, thus, presumably a T-cell antigen receptor (TCR)-mediated elevation in [Ca2+]i without affecting the basal [Ca2+]i. This decrease in TCR-related Ca2+i mobilization evidently contributes to the suppression of T lymphocyte proliferation during sepsis, probably via an in vivo action of prostaglandin (PG) E2 on the T cells during sepsis. The blockade of PGE2 production after indomethacin administration to septic animals prevents alterations in both T-cell Ca2+i mobilization and proliferation. PGE2 probably acts through its second messenger, cyclic adenosine 3'5'-monophosphate, which can antagonize Ca2+i signaling in T cells.
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PMID:Alterations in calcium signaling and cellular responses in septic injury. 868 77

Alterations in protein kinase C (PKC) activity have been implied in the pathogenesis of common variable immunodeficiency (CVID). We analyzed amiloride-sensitive red blood cell Na+/H+ exchange (sodium-proton antiport, SPA) and its response to protein kinase stimulation in a patient with CVID. Compared with healthy subjects or patients with sepsis, a unique pattern of SPA activation has been shown. The patient's SPA was decreased and unresponsive to PKC stimulation, whereas stimulation by insulin, a tyrosine kinase activator, restored SPA activity. An alteration of serine-threonine phosphorylation is suggested as a possible mechanism for the immune failure.
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PMID:Common variable immunodeficiency associated with myelocathexis and altered membrane sodium-proton antiport. 920 Jan 89

The purpose of the present study was to determine the effect of chronic sepsis on alpha-adrenergic responsiveness in the coronary microcirculation. Male Sprague-Dawley rats (n = 6) were made septic by intraperitoneal implantation of a gelatin capsule containing 35 mg sterile rat feces and 1 x 10(8) viable colony-forming units of Escherichia coli (strain Sm 018). Control rats (n = 6) were implanted with capsules containing only sterile feces. Forty-eight hours after surgery, subepicardial coronary arterioles (80-170 mm) were isolated. In vitro arteriolar responses were studied in a pressurized, no-flow state with video-microscopy. Chronic sepsis decreased the contractile responses to the alpha 1-adrenoceptor agonist phenylephrine and the protein kinase C (PKC) activator 12-deoxyphorbol 13-isobutyrate 20-acetate. Relaxation responses to the alpha 2-adrenoceptor agonist clonidine, the endothelium-dependent vasodilator adenosine 5'-diphosphate, and the PKC inhibitor staurosporine were reduced, but the relaxation to the endothelium-independent cyclic GMP-mediated vasodilator sodium nitroprusside was preserved. Relaxation to clonidine was inhibited by endothelial denudation or after blockade of nitric oxide synthase. Chronic sepsis may reduce alpha 2-adrenoceptor-mediated relaxation of coronary microvessels by causing endothelial dysfunction. The alpha 1-adrenergic mechanism is downregulated, possibly due to alterations in the receptor and/or downstream signal transduction via PKC.
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PMID:Chronic septicemia alters alpha-adrenergic mechanisms in the coronary circulation. 920 48

Changes in the number of calcium channels in two subcellular fractions, the sarcolemma and the light vesicle, of rat cardic cells were studied during sepsis. Sepsis was induced by cecal ligation and puncture (CLP). The results showed that some of the calcium channels in the light vesicle translocated to the sarcolemma during the early sepsis (9 h after CLP) while during the late sepsis (18 h after CLP), some of these in the sarcolemma translocated to the light vesicle. The mechanisms of redistribution of the calcium channels in the sarcolemma and the light vesicle during sepsis was not associated to the phosphorylation of the calcium channels by cAMP dependent protein kinase (PKA), Ca2+/calmodulin dependent protein kinase (PKM) and protein kinase C (PKC). Since beta-adrenergic receptors, muscarinic cholinergic receptors and Na+/K(+)-ATPase were also redistributed during sepsis, it is suggested that the redistribution might be non-specific.
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PMID:[Changes in the calcium channels in rat cardiac cells during sepsis]. 938 65

A critical feature of sepsis-induced adult respiratory distress syndrome (ARDS) is the release of cytokines (such as interleukin [IL]-6, IL-8, and tumor necrosis factor [TNF]) from endotoxin (lipopolysaccharide [LPS])-activated alveolar macrophages (AM). Nuclear factor kappa B (NF-kappaB) is activated in AM from patients with ARDS, and it is essential for the transcription of many cytokine genes. In these studies, we evaluated the regulation of LPS-induced cytokine release and the activation of NF-kappaB in human AM. We found that the activation of NF-kappaB and the release of IL-6, IL-8, and TNF from AM exposed to LPS was protein kinase C-independent and tyrosine kinase- and phosphatidylcholine-specific phospholipase C-dependent. We also found that LPS-induced activation of NF-kappaB was enhanced in AM cultured in serum or in the presence of LPS-binding protein, simulating conditions in the lung that are present in ARDS. In addition, LPS triggered the activation of several different NF-kappaB complexes in AM, and different forms of NF-kappaB bound to the IL-6, IL-8, and TNF promoter sequences. These observations suggest that physiologic abnormalities present in the lungs of patients with ARDS facilitate the activation of NF-kappaB and local release of cytokines.
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PMID:Lipopolysaccharide-induced NF-kappaB activation and cytokine release in human alveolar macrophages is PKC-independent and TK- and PC-PLC-dependent. 949 Jun 56

This study was performed to assess the effects of subacute sepsis in rats on the in vitro reactivity of arterioles (internal diameter, 100-150 microm) to alpha1- and alpha2-adrenergic stimulation and to angiotensin II. Male Sprague-Dawley rats were rendered septic by intraperitoneal implantation of a gelatin capsule containing sterile rat feces and 1 x 10(6) viable colony forming units of Escherichia coli. Control rats underwent sham laparotomy and implantation of a gelatin capsule containing only sterile feces. In vitro reactivity of arterioles from mesentery and skeletal muscle were studied 48 h later in a pressurized (50 mmHg) no flow state using videomicroscopy. Subacute sepsis decreased the contractile response of nonprecontracted microvessels from both anatomical sites to phenylephrine (both p < .01 versus control) and blunted the relaxation response to staurosporine (both p < .01), an inhibitor of protein kinase C. The small contraction to angiotensin II of mesenteric vessels was inhibited by sepsis (p < .05) but was unaltered in the skeletal muscle microcirculation. In the precontracted mesenteric microvessels from septic rats, endothelium-dependent relaxation to clonidine and to adenosine 5'-diphosphate were decreased (both p < .01 versus control), whereas in skeletal muscle microvessels, clonidine and adenosine 5'-diphosphate elicited constriction (both p < .01). Relaxation to the endothelium independent vasodilators sodium nitroprusside and pinacidil was preserved across all vessels. In conclusion, mesenteric and skeletal muscle microvascular responses to angiotensin II and alpha1- and alpha2-adrenergic stimulation are altered in subacute sepsis. This may in part lead to systemic hypotension and altered organ perfusion during states of chronic sepsis.
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PMID:Mesenteric and skeletal muscle microvascular responsiveness in subacute sepsis. 952 25

Changes in protein kinase C (PKC) (calcium- and phospholipid-dependent protein kinase) activity in rat heart during different cardiodynamic phases of sepsis were studied in an attempt to understand the pathophysiology of altered myocardial function during sepsis. Sepsis was induced by cecal ligation and puncture. 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 cecal ligation and puncture. Cardiac PKC was extracted and partially purified by ammonium sulfate fractionation and diethylaminoethyl-cellulose chromatography. PKC activity was assayed on the basis of the rate of incorporation of 32P from [gamma-32P]adenosine triphosphate into histone. The results show that during early sepsis, cytosolic PKC activity was increased by 42-73%, whereas membrane associated PKC activity was unchanged. During late sepsis, both cytosolic and membrane associated PKC activities remained unchanged. Kinetic analysis of the data on cytosolic PKC during the early phase of sepsis reveals that the Vmax (maximal velocity) values for Ca2+, phosphatidylserine, and diacylglycerol were increased by 58, 42, and 50%, respectively, with no changes in their Km (substrate concentration required for half-maximal enzyme activity) values. These data indicate that cytosolic PKC activity was activated in rat heart during the early hyperdynamic phase of sepsis. Because PKC mediated phosphorylation plays an important role in regulating myocardial contractility, an activation in cytosolic PKC may contribute to the development of a hypercardiodynamic state during the early phase of sepsis.
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PMID:Protein kinase C activity is increased in rat heart during the early hyperdynamic phase of sepsis. 952 27

Group B streptococci (GBS) are an important cause of neonatal sepsis, pneumonia and meningitis. In the early phase of infection, macrophages and polymorphonuclear cells (PMN) are the first immune cells that interact with GBS. In this in vitro study, to gain insight into GBS-macrophage interaction in the absence of type-specific antibodies, we examined the features of GBS survival in thioglycollate-elicited murine peritoneal macrophages and the effect of GBS on the protein kinase C (PKC)-dependent transduction pathway. Our results demonstrate that type Ia GBS, strain 090 (GBS-Ia) and type III GBS strain COH 31r/s (GBS-III), after in vitro phagocytosis survive and persist intracellularly in macrophages for up to 24 and 48 hr, respectively. However, macrophage activation by interferon-gamma (IFN-gamma) and lipopolysaccharide from Escherichia coli (LPS) caused a significant reduction in the time of intracellular persistence. Macrophage activation by IFN-gamma and LPS seems to be a multifactorial event involving multiple intracellular signal pathways also including PKC. Since PKC is one of the components in the signal network leading to macrophage activation and an important target for several intracellular micro-organisms, we wondered whether PKC could have a role in intracellular GBS survival. Both PKC depletion by treatment with phorbol 12-myristate 13-acetate (PMA) for 18 hr and PKC inhibition by Calphostin C rendered macrophages more permissive for the intracellular GBS survival. Furthermore, GBS-infected macrophages were unable to respond to PMA and LPS, activators of PKC, by inducing antimicrobial activity. The ability of GBS to impair PKC-dependent cell signalling was also demonstrated by the reduced c-fos gene expression in GBS-infected macrophages with respect to control macrophages, after LPS stimulation. In conclusion, our results indicate that GBS survive in macrophages and impairment of PKC signal transduction contributes to their intracellular survival.
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PMID:Group B streptococci persist inside macrophages. 953 23


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