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)

Studies investigating the role of bradykinin in disease states such as hypertension, sepsis, and asthma have been confounded by difficulties in measuring the concentration of this short-lived peptide. The purpose of this study was to determine a stable metabolite of bradykinin in the systemic circulation of humans. Bradykinin (containing trace concentrations of [(3)H]bradykinin) was administered i.v. into three human volunteers in increasing amounts up to a maintenance rate of 200 ng/kg/min until a total dose of 1 mg was given. Metabolic products were purified and identified by HPLC and by electrospray ionization mass spectrometry. Infused bradykinin was rapidly degraded, such that no exogenous bradykinin was detected in venous plasma sampled during infusion. BK1-5 (Arg-Pro-Pro-Gly-Phe), the 1-to-5 amino acid fragment of bradykinin, was identified as a major stable plasma metabolite of bradykinin. Plasma concentrations of BK1-5 correlated with dose of bradykinin infused and concentrations at the end of bradykinin infusion were 1510 to 4600 fmol/ml of blood. BK1-5 was cleared from blood with a terminal half-life of 86 to 101 min. Thus, in humans, bradykinin is rapidly degraded in vivo to BK1-5, a stable metabolite. Measurement of this metabolite could provide a tool to assess pathophysiologic and pharmacologic alterations in systemic bradykinin generation associated with human disease.
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PMID:Metabolism of bradykinin In vivo in humans: identification of BK1-5 as a stable plasma peptide metabolite. 1087 21

Extensive research has provided few therapeutic agents for the treatment of septicemia. Bradykinin, an endogenous vasodepressor hormone, is a key mediator in the hypotension seen with septicemia. The present investigation shows that a stable metabolic fragment of bradykinin, arginine-proline-proline-glycine-phenylalanine (RPPGF), prevents the deleterious effects of endotoxin [lipopolysaccharide (LPS); a component of the membrane of Gram negative bacteria], the signaling agent responsible for the effects of septicemia, in both anesthetized rats and in isolated rat aortic segments. Survival time of rats treated with LPS (12 mg/kg) was significantly (p < 0.05) prolonged by pretreatment with RPPGF [140.3 +/- 16 min (n = 10)] compared with rats receiving saline and LPS [93.2 +/- 8 min (n = 39)]. Prolongation of survival was not seen when rats were pretreated with either bradykinin or with PRGFP (proline-arginine-glycine-phenylalanine-proline). Isolated aortic segments treated with LPS (30 microg/ml) showed a significantly reduced ability to contract in response to phenylephrine compared with control segments not receiving LPS. Pretreatment of the segments with RPPGF significantly reversed the LPS-induced reduction in contractile response of the segments. Removal of the endothelial layer did not alter the protection provided by RPPGF. These results demonstrate the ability of a stable metabolic fragment of bradykinin, RPPGF, to protect against the deleterious effects produced by LPS. The findings presented here may provide the basis for a new developmental area for novel therapeutic agents in the treatment of septicemia.
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PMID:A metabolic fragment of bradykinin, Arg-Pro-Pro-Gly-Phe, protects against the deleterious effects of lipopolysaccharide in rats. 1112 64

Neutrophils exposed to low concentrations of gram-negative lipopolysaccharide (LPS) become primed and have an increased oxidative response to a second stimulus (e.g., formyl-methionyl-leucyl-phenylalanine [fMLP]). In studies aimed at understanding newborn sepsis, we have shown that neutrophils of newborns are not primed in response to LPS. To further understand the processes involved in LPS-mediated priming of neutrophils, we explored the role of extracellular signal-related protein kinases (ERK 1 and 2) of the mitogen-activated protein kinase family. We found that LPS activated ERK 1 and 2 in cells of both adults and newborns and that activation was plasma dependent (maximal at > or =5%) through LPS-binding protein. Although fibronectin in plasma is required for LPS-mediated priming of neutrophils of adults assessed by fMLP-triggered oxidative burst, it was not required for LPS-mediated activation of ERK 1 and 2. LPS-mediated activation was dose and time dependent; maximal activation occurred with approximately 5 ng of LPS per ml and at 10 to 40 min. We used the inhibitor PD 98059 to study the role of ERK 1 and 2 in the LPS-primed fMLP-triggered oxidative burst. While Western blotting showed that 100 microM PD 98059 completely inhibited LPS-mediated ERK activation, oxidative response to fMLP by a chemiluminescence assay revealed that the same concentration inhibited the LPS-primed oxidative burst by only 40%. We conclude that in neutrophils, LPS-mediated activation of ERK 1 and 2 requires plasma and that this activation is not dependent on fibronectin. In addition, we found that the ERK pathway is not responsible for the lack of LPS priming in neutrophils of newborns but may be required for 40% of the LPS-primed fMLP-triggered oxidative burst in cells of adults.
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PMID:Activation of extracellular signal-related protein kinases 1 and 2 of the mitogen-activated protein kinase family by lipopolysaccharide requires plasma in neutrophils from adults and newborns. 1129 34

Modulins represent microbial products that stimulate cytokine production in host cells. The modulins responsible for gram-positive sepsis remain poorly understood. Staphylococci release a factor (or factors) that activates nuclear factor-kappa B and stimulates cytokine production in cells of macrophage lineage. This factor, termed phenol-soluble modulin (PSM), has been recently isolated from culture supernatant of Staphylococcus epidermidis. We examined the effects of PSM on proinflammatory properties of human neutrophils and monocytes in vitro. PSM activated the respiratory (oxidative) burst in neutrophils and primed neutrophils for enhanced respiratory burst activity in response to formyl-methionyl-leucyl-phenylalanine. PSM also stimulated neutrophil degranulation as reflected by increased surface expression of CD11b and CD18, which was accompanied by rapid shedding of L-selectin. Spontaneous apoptosis of both neutrophils and monocytes was inhibited by PSM. Furthermore, PSM also functioned as a chemoattractant factor for both neutrophils and monocytes. Thus, the proinflammatory properties of PSM resemble those of both lipopolysaccharide and bacterial chemotactic peptides. These findings suggest that PSM may play a role in the pathogenesis and systemic manifestations of sepsis caused by staphylococci.
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PMID:Stimulation of human neutrophils and monocytes by staphylococcal phenol-soluble modulin. 1143 91

We have investigated sequential changes in skeletal muscle and hepatic protein synthesis following sepsis, and their relationship to changes in circulating and tissue glutamine concentrations. Male Wistar rats underwent caecal ligation and puncture (CLP) or sham operation, with starvation, and were killed 24, 72 or 96 h later. A group of non-operated animals were killed at the time of surgery. Protein synthesis was determined using a flooding dose of L-[4-(3)H] phenylalanine, and glutamine concentrations were measured by an enzymic fluorimetric assay. Protein synthesis in gastrocnemius muscle fell in all groups. Gastrocnemius total protein content was reduced after CLP and at 72 and 96 h after sham operation. After CLP, protein synthesis was lower at 24 h, and total protein content was lower at 72 and 96 h, than in sham-operated animals. CLP was associated with increased liver protein synthesis at all time points, whereas there was no change after sham operation. Liver protein content did not change after CLP, but was lower at 72 and 96 h after sham operation than in non-operated animals. Plasma glutamine concentrations were reduced at 24 h after sham operation, and at 72 and 96 h after CLP. Muscle glutamine concentrations were reduced in all groups, with the decrease being greater following CLP than after sham operation. In the liver, glutamine concentrations were unchanged after CLP, but increased after sham operation. In rats with sepsis, decreases in muscle protein synthesis and content are associated with markedly reduced muscle glutamine concentrations. Plasma glutamine concentrations are initially maintained, but fall later. In liver, protein synthesis is increased, while glutamine concentrations are preserved. These results support a peripheral-to-splanchnic glutamine flux in sepsis.
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PMID:Sequential changes in in vivo muscle and liver protein synthesis and plasma and tissue glutamine levels in sepsis in the rat. 1152 47

Pathological nitric oxide (NO) generation in sepsis, inflammation, and stroke may be therapeutically controlled by inhibiting NO synthases (NOS). Here we targeted the (6R)-5,6,7,8-tetrahydro-l-biopterin (H(4)Bip)-binding site of NOS, which, upon cofactor binding, maximally increases enzyme activity and NO production from substrate l-arginine. The first generation of H(4)Bip-based NOS inhibitors employed a 4-amino pharmacophore of H(4)Bip analogous to antifolates such as methotrexate. We developed a novel series of 4-oxo-pteridine derivatives that were screened for inhibition against neuronal NOS (NOS-I) and a structure-activity relationship was determined. To understand the structural basis for pterin antagonism, selected derivatives were docked into the NOS pterin binding cavity. Using a reduced 4-oxo-pteridine scaffold, derivatives with certain modifications such as electron-rich aromatic phenyl or benzoyl groups at the 5- and 6-positions, were discovered to markedly inhibit NOS-I, possibly due to hydrophobic and electrostatic interactions with Phe(462) and Ser(104), respectively, within the pterin binding pocket. One of the most effective 4-oxo compounds and, for comparisons an active 4-amino derivative, were then co-crystallized with the endothelial NOS (NOS-III) oxygenase domain and this structure solved to confirm the hypothetical binding modes. Collectively, these findings suggest (i) that, unlike the antifolate principle, the 4-amino substituent is not essential for developing pterin-based NOS inhibitors and (ii), provide a steric and electrostatic basis for their rational design.
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PMID:Structural basis for pterin antagonism in nitric-oxide synthase. Development of novel 4-oxo-pteridine antagonists of (6R)-5,6,7,8-tetrahydrobiopterin. 1159 Jan 64

Vascular injury brings tissue factor (TF) into contact with blood and its natural ligands, factors VII (FVII) and VIIa (FVIIa). This results in localized FVIIa activity on TF-expressing cells, initiating coagulation, and nonhemostatic activities. Activation of transcription factors, expression of genes for inflammation, tissue remodeling, and wound healing follow, but these mechanisms for maintaining vascular integrity may lead to pathophysiologic states. Recombinant FVIIa is converted into a catalytically inert protein by reactive site residues reacting with Phe-Phe-Arg-chloromethyl ketone. Active site-inhibited FVIIa (ASIS) retains its affinity for TF and competes for FVIIa and FVII binding to TF, blocking FVIIa activity and FVII to FVIIa activation. It therefore acts as an antithrombotic agent and has been shown in previous studies on animal models of sepsis to prevent organ failure associated with fibrin deposition. Mitigation of inflammatory response and prolonged survival were remarkable and additional effects of TF blockage by ASIS not observed with inhibitors of downstream coagulation factors Xa and thrombin. This suggests that FVIIa/TF exerts a noncoagulopathic effect on cellular activities, attenuated by ASIS blocking FVIIa-induced signaling. The precise mechanism remains elusive but blockade of TF/FVIIa activity provides an attractive possibility for pharmaceutical intervention. In vitro measurements of ASIS-TF binding and FVIIa/TF inhibition are described, together with investigation of the FVIIa-induced signaling pathway and gene expression. Additionally, possible implications of ASIS blockage for hemostatic and nonhemostatic aspects of the pathophysiology associated with vascular stress and injury are discussed.
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PMID:Active site-inhibited seven: mechanism of action including signal transduction. 1173 9

The reduced pressure response to vasopressin during acute sepsis has directed our interest to the regulation of vasopressin V(1A) receptors. Rats were injected with lipopolysaccharide for induction of experimental gram-negative sepsis. V(1A) receptor gene expression was downregulated in the liver, lung, kidney, and heart during endotoxemia. Inasmuch as the concentrations of proinflammatory cytokines such as interleukin-1beta, tumor necrosis factor-alpha, and interferon-gamma were highly increased during sepsis, the influence of these cytokines on V(1A) receptor expression was investigated in primary cultures of hepatocytes and in the aortic vascular smooth muscle cell line A7r5. V(1A) receptor expression was downregulated by the cytokines in a nitric oxide-independent manner. Blood pressure dose-response studies after injection of endotoxin showed a diminished responsiveness to the selective V(1) receptor agonist Phe(2),Ile(3),Orn(8)-vasopressin. Our data show that sepsis causes a downregulation of V(1A) receptors and suggest that this effect is likely mediated by proinflammatory cytokines. We propose that this downregulation of V(1A) receptors contributes to the attenuated responsiveness of blood pressure in response to vasopressin and, therefore, contributes to the circulatory failure in septic shock.
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PMID:Cytokine-mediated downregulation of vasopressin V(1A) receptors during acute endotoxemia in rats. 1189

Ubiquitin-proteasome-dependent protein degradation plays a central role in sepsis-induced muscle wasting. Because the proteasome degrades proteins into small peptides rather than free amino acids, it is likely that additional mechanisms downstream of the proteasome are involved in sepsis-induced muscle proteolysis. Recent studies suggest that the extralysosomal peptidase tripeptidyl-peptidase II (TPP II) degrades peptides generated by the proteasome. We hypothesized that TPP II expression and activity are increased in skeletal muscle during sepsis. Sepsis was induced in rats by cecal ligation and puncture. Control rats were sham-operated. TPP II activity was determined by using the specific substrate Ala-Ala-Phe-7-amido-4-methylcoumarin (AAF-AMC). TPP II protein and gene expression were determined by Western blot and real-time PCR, respectively. Sepsis resulted in increased activity and protein and gene expression of TPP II in extensor digitorum longus muscles. This result was blunted by the glucocorticoid receptor antagonist RU 38486, indicating that glucocorticoids participate in the upregulation of TPP II in skeletal muscle during sepsis. The results suggest that proteolytic mechanisms downstream of the proteasome may be important for the complete degradation of muscle proteins during sepsis.
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PMID:Tripeptidyl-peptidase II expression and activity are increased in skeletal muscle during sepsis. 1214 24

Patients with sepsis and acute lung injury have increased interleukin (IL)-18 levels systemically. We hypothesize that IL-18 stimulates neutrophils (PMNs) at physiologic concentrations. IL-18 primed the oxidase at 15 min (10-100 ng/ml), 30 min (0.1-100 ng/ml), and 60 min (100 ng/ml; P<0.05) and caused translocation of p47(phox) to the membrane similar to lipopolysaccharides. CD11b surface expression was increased by IL-18 in a time- and concentration-dependent manner. IL-18 caused up-regulation of the formyl-Met-Leu-Phe receptor, changes in PMN size, and elastase release. Investigation of signaling demonstrated IL-18-mediated activation of p38 mitogen-activated protein (MAP) kinase in a concentration (0.1-100 ng/ml)-, time (5-15 min)-, and Ca2+-dependent manner. IL-18 directly increased cytosolic Ca2+ concentration. IL-18 activation of PMNs was blocked by inhibition of p38 MAP kinase activity (SB203580) or by inhibition of p38 MAP kinase activation by chelation of cytosolic Ca2+. We conclude that IL-18, at physiologic concentrations, is an effective PMN priming agent that requires p38 MAP kinase activity.
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PMID:Physiological levels of interleukin-18 stimulate multiple neutrophil functions through p38 MAP kinase activation. 1214 32


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