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)

During vascular injury, such as observed in atherosclerosis, restenosis, vasculitides, transplantation, or sepsis, vascular smooth muscle cells (SMC) can be exposed to platelets or platelet products. Under these conditions proliferation or cytokine production of SMC stimulated by platelets or platelet products may contribute to regulation of vascular pathogenesis. Thus, we investigated interleukin-6 (IL-6) and IL-8 production as well as proliferation of SMC in response to platelets or platelet lysates. Platelets not already preactivated by thrombin induced IL-6 (10- to 50-fold) or IL-8 production of unstimulated SMC in a cell number dependent fashion. Preactivation of platelets with thrombin potently increased the platelet-mediated IL-6 (50- to 1,000-fold) and IL-8 production of SMC. Hirudin specifically inhibited the activation of platelets with thrombin. Isolated platelets cultured in the absence of SMC did not contain detectable IL-6 or IL-8. Prestimulation (4 hours) of SMC with pathophysiologically relevant substances (lipopolysaccharide [LPS], tumor necrosis factor-alpha [TNF-alpha], or IL-1alpha) further increased the platelet-induced cytokine production. The platelet-derived SMC stimulatory activity was IL-1, since IL-1 receptor antagonist (IL-1-Ra) inhibited the platelet-induced cytokine production of SMC. Anti-platelet-derived growth factor (PDGF)-antibody did not further reduce this activity. Thrombin itself stimulated expression of IL-6 and IL-8 to some degree and induced IL-6 production of SMC synergistically with IL-1. Platelets also induced proliferation of SMC, however, anti-PDGF antibodies, rather than IL-1-Ra blocked this response. These data show that platelet-derived IL-1 stimulates cytokine production of vascular smooth muscle cells, indicating that platelet-derived IL-1 may contribute to regulation of local pathogenesis in the vessel wall by activation of the cytokine regulatory network.
 ...
PMID:Platelet-derived interleukin-1 induces cytokine production, but not proliferation of human vascular smooth muscle cells. 941 77

We measured the plasma levels of anti-inflammatory cytokines, including interleukin 1 receptor antagonist (IL-1ra), IL-4 and IL-10; inflammatory cytokines, including IL-2, IL-6, IL-8 and tumor necrosis factor receptor I and II (TNFR I and TNFR II); and endotoxin in 11 patients with septic shock associated with gram-negative bacteria and 12 patients with sepsis not associated with shock. The plasma levels of IL-1ra and IL-10 were elevated in the septic shock group compared with the sepsis group. TNFR I and TNFR II levels tend to be higher in the septic shock group. The plasma level of TRNF-alpha was significantly correlated with levels of IL-1ra, IL-4, IL-10, TNFR I, and TNFR II. The elevated levels of the anti-inflammatory cytokines, TNFR I, and TNFR II, appeared to reflect an attempt to suppress the shock syndrome.
 ...
PMID:Anti-inflammatory cytokine levels in patients with septic shock. 943 13

Monocytes (MO) and macrophages (MAC) are important producers of cytokines involved in the pathophysiology of bacterial sepsis. Most studies concentrate on the effects of bacterial lipopolysaccharides (LPS) regarding the induction of cytokine gene expression and secretion in MO/MAC. Here we report that besides LPS, the synthetic lipoprotein analogue lipopeptide N-palmitoyl-S-(2,3-bis(palmitoyl)-(2RS)-propyl)-(R)-cysteinyl-alanyl- glycine (Pam3-Cys-Ala-Gly), another component of the outer membrane of Gram-negative bacteria, as well as heat-killed Staphyloccocus aureus (S. aureus/SAC) are potent stimuli for cytokines in human MO. For all three investigated stimuli we found an individual pattern of cytokine induction: LPS was most potent in inducing interleukin-6 (IL-6) synthesis, whereas for tumour necrosis factor-alpha (TNF-alpha) secretion SAC was the best stimulus. Comparable amounts of IL-8 were induced by either LPS or Pam3-Cys-Ala-Gly, with SAC being less effective even at higher concentrations. The addition of serum led to an increase in LPS-, SAC- and Pam3-Cys-Ala-Gly-stimulated TNF-alpha secretion, indicating that the presence of serum is critical not just for LPS stimulation. Furthermore, as is known for LPS, Pam3-Cys-Ala-Gly and SAC rendered MO refractory to a second bacterial stimulus. Pam3-Cys-Ala-Gly and SAC induced tolerance for itself, but LPS could partially overcome this effect. As the CD14 molecule is discussed as a common receptor for different bacterial components, we investigated whether the TNF-alpha response of MO could be blocked by anti-CD14 antibodies. MY4, a CD14 antibody, selectively blocked the TNF-alpha secretion induced by LPS but not by Pam3-Cys-Ala-Gly or SAC. In summary, we conclude that besides LPS, lipopeptide Pam3-Cys-Ala-Gly and SAC are potent stimuli for human MO, while the mechanisms of activation seem to be partially different from LPS.
 ...
PMID:A comparative analysis of cytokine production and tolerance induction by bacterial lipopeptides, lipopolysaccharides and Staphyloccous aureus in human monocytes. 948 14

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.
 ...
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

We evaluated the effect of C1 inhibitor (C1-inh), an inhibitor of the classical pathway of complement and the contact system, on the physiologic and inflammatory response in baboons suffering from lethal Escherichia coli sepsis. Five animals pretreated with 500 U/kg C1-inh (treatment group; n = 5), followed by a 9-h continuous infusion of 200 U/kg C1-inh subsequent to bacterial challenge, were compared with five controls receiving E. coli alone. Of the treatment group, one animal survived and another lived beyond 48 h, whereas all control animals died within 27 h. In four of five treated animals, less severe pathology was observed in various target organs. C1-inh administration did not prevent the hemodynamic or hematologic changes observed upon E. coli infusion. The activation of fibrinolysis and the development of disseminated intravascular coagulation were essentially unaffected by C1-inh. However, C1-inh supplementation significantly reduced decreases in plasma levels of factor XII and prekallikrein and abrogated the systemic appearance of C4b/c, indicating substantial inhibition of activation of the contact system and the classical complement pathway, respectively. Furthermore, treated animals displayed a reduced elaboration of various cytokines including TNF, IL-10, IL-6, and IL-8. Thus, the administration of C1-inh may have a beneficial but modest effect on the clinical course and outcome of severe sepsis in nonhuman primates. We suggest that activated complement and/or contact system proteases may, at least in part, contribute to the attendant manifestations of septic shock through an augmentation of the cytokine response.
 ...
PMID:Effect of C1 inhibitor on inflammatory and physiologic response patterns in primates suffering from lethal septic shock. 955 6

Interleukin (i.l.)-8 levels in serial serum samples of 10 burned patients were analysed. The total body surface areas (TBSAs) of the burn injury ranged 30 to 85 per cent. Of these ten patients, five recovered and the other five, who were septic, died. On admission at about 5-13 h postburn, one of the five survivors and two of the non-survivors had serum IL-8 levels higher than 18.1 pg/ml, which is the detection limit of the IL-8 assay kit. The serum IL-8 values of six healthy laboratory personnel included in the present study were all less than 18.1 pg/ml. Afterwards, an initial peak serum IL-8 response was detected within 2-4.5 days postburn. Significant differences in the peak serum IL-8 levels were not found between patients with TBSAs of greater or less than 50 per cent and patients who survived or expired from burn injury. In the survivors, serum IL-8 remained low, whereas IL-8 increased markedly, starting at about one week postburn in four of the five non-survivors with confirmed sepsis. Significant differences in the maximum serum IL-8 levels were detected between patients who recovered vs. those who died from the thermal injury. In conclusion, the results showed that there was an increase in serum IL-8 postburn. Serum IL-8 was significantly higher in the septic patients, who all died. This cytokine may play a significant role in the pathophysiology of sepsis in burned patients.
 ...
PMID:Changes in levels of serum IL-8 in burned patients. 956 23

An in vitro system composed of a plasma separation membrane coupled with natural (charcoal) or synthetic (Amberlite, Amberchrome) types of sorbents was evaluated for the simultaneous removal of proinflammatory cytokines (TNF-alpha, IL-1 beta and IL-8) and cytokine antagonists [interleukin (IL)-1 receptor antagonist (IL-1Ra), soluble tumor necrosis factor-alpha (TNF-alpha) receptor I and II (sTNFR I and II)] in whole blood spiked with bacterial lipopolysaccharide (LPS). These studies showed that plasma filtration rather than ultrafiltration significantly increased the clearance of all cytokines, particularly TNF-alpha, and the synthetic (Amberlite-type of resin) but not natural (uncoated charcoal) membrane could extensively absorb almost 100% of plasma filtered IL-Ra, IL-1 beta and IL-8, but only 40% of TNF-alpha. Other synthetic (Amberchrome) membranes could also effectively (80%) remove TNF-alpha. In the complex scenario of sepsis, the simultaneous removal of excess proinflammatory and/or immunomodulatory mediators may play a role in reducing the hemodynamic alterations, thus resulting in enhanced patient survival. Whether this occurs in the human setting awaits the results of an ongoing clinical investigation.
 ...
PMID:Continuous plasma filtration coupled with sorbents. 957 1

An in vitro model for the study of sepsis mediators was used to investigate the effects of two different lipopolysaccharides (LPS), a smooth (LPS-S) and a rough (LPS-R) type, on the release of chemokines (IL-8 and MIP-1 alpha) and cytokines (TNF alpha, IL-1 beta, IL-1ra and IL-10) from human whole blood samples. TNF alpha level increased significantly vs. control, at 4 h and 8 h after the challenge with smooth and rough type of LPS respectively. Concentrations of the two chemokines studied, IL-8 and MIP-1 alpha, were significantly elevated following stimulation by both LPS, and reached concentrations significantly different from controls at 4, 8 and 24 h. After 24 h of incubation both LPS produced a significant IL-10 increase, although such change was more substantial with the rough type. Present data suggest an early and maintained release of chemokines regardless of the type of LPS used and often in absence of a significant increase in primary pro-inflammatory cytokines.
 ...
PMID:Kinetics of IL-8, MIP-1 alpha, TNF alpha, IL-1 beta, IL-1ra and IL-10 in human whole blood samples triggered by smooth and rough LPS. 957 36

We have previously shown that an anticoagulant could attenuate inflammation in animal models of sepsis with disseminated intravascular coagulation (DIC) and that coagulation activation of human whole blood ex vivo results in a proinflammatory cytokine response. The current studies were performed to better understand mechanisms for the blood cell cytokine response and extend the investigation of such a response to endothelial cells as likely contributors to a vascular inflammatory response. Utilizing cell separation techniques, it was determined that the whole blood IL-8 response to coagulation activation or thrombin, specifically, was mediated by CD14+ monocytes. Moreover, thrombin was observed to stimulate both IL-8 and IL-6 production in cultured mononuclear cells. Analyses of the effects of coagulation activation and thrombin were extended to cultured human endothelial cells, and a similar cytokine response was observed. Thrombin catalytic activity appeared essential, since hirudin reduced thrombin-stimulated proinflammatory cytokine production in cultured monocytes and endothelial cells and prothrombin only weakly mimicked the thrombin response. The endothelial cell IL-8 and IL-6 response to thrombin could be mimicked by the thrombin receptor agonist peptide (TRAP), implicating a functional role of the classic thrombin receptor. Altogether, the results facilitate a better understanding of potential proinflammatory vascular responses to coagulation activation.
 ...
PMID:Potential mechanisms for a proinflammatory vascular cytokine response to coagulation activation. 959 Feb 65

Enzymes and other factors secreted by degranulating neutrophils (polymorphonuclear leukocytes, PMNs) mediate endothelial injury, thrombosis, and vascular remodeling. In bacteremia and sepsis syndrome and their consequent complications (including acute respiratory distress syndrome and systemic ischemia-reperfusion resulting from septic shock), neutrophil degranulation is an important mechanism of injury. In related studies, we found that human endothelial cells regulate neutrophil degranulation and that inflammatory cytokines induce synthesis of degranulating factors by human endothelial cells. Here we show that lipopolysaccharides (LPS) from gram-negative bacteria were the most potent agonists for release of degranulating activity by endothelial cells when compared to several cytokines and stimulatory factors. LPS also induced the release of degranulating signals for PMNs from a human endothelial cell line, EA.hy 926. Interleukin 8 (IL-8) is synthesized by endothelial and EA.hy 926 cells in response to LPS and induces neutrophil degranulation. However, complementary strategies using receptor desensitization, translation of messenger RNA by Xenopus laevis oocytes, and purification and analysis of factors from conditioned supernatants demonstrated that degranulating factors distinct from IL8 are generated in response to LPS. The characteristics of a partially purified degranulating factor isolated from conditioned supernatants distinguished it from known chemokines and other factors that induce PMN degranulation and are generated by endothelial cells in response to LPS. Thus, cultured human endothelial cells and endothelial cell lines synthesize several unique signaling molecules that can trigger neutrophil granular secretion. If produced in vivo in response to LPS or other pathologic agonists, these degranulating signals may activate PMNs in combination or in sequence, initiating or propagating vascular damage.
 ...
PMID:Bacterial lipopolysaccharide induces endothelial cells to synthesize a degranulating factor for neutrophils. 961 46


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