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)

Phospholipase A2 (PLA2) regulates eicosanoid and platelet-activating factor production. It also plays an important role in the regulation of critical mediators in inflammatory diseases in which PLA2 activity is significantly enhanced during sepsis and multiple organ failure. Therefore, inhibitors of PLA2 activity offer themselves as target substances in the development of anti-inflammatory drugs. We identified 2 biflavonoids, bilobetin and ginkgetin, that can inhibit PLA2 activity. In experiments using 2-linol-[1-14C]PE as substrate both substances potently inhibited several kinds of type II 14-kDa PLA2 while inhibiting type I 14-kDa PLA2 to a lesser extent. We tested these PLA2 inhibitors for their ability to inhibit the production of tumor necrosis factor alpha (TNFalpha) and 2 enzymes, inducible nitric oxide synthase (iNOS) and inducible cyclooxygenase (COX-2) in an assay system using lipopolysaccharide (LPS)-stimulated Raw264.7 macrophages. In Raw264.7cells, bacterial LPS induced the production of COX-2 and iNOS proteins as well as TNFalpha. The inhibitors consistently inhibited the production of TNFalpha in a dose-dependent manner. Moreover, treatment of the macrophages with bilobetin and ginkgetin shut down the production of nitrite, one of the stable end products of NO released into the culture supernatant. The decrease in NO products was accompanied by a decrease in iNOS protein level as assessed by Western blot probed with specific anti-iNOS antibody. Both inhibitors also reduced the expression of COX-2 protein in the LPS-stimulated cells, which coincided with the reduction in iNOS protein. These results, therefore, suggest that these two sPLA2 inhibitors may be useful for inhibiting the production of inflammatory cytokine and NO production in inflammatory diseases.
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PMID:The effects of two new antagonists of secretory PLA2 on TNF, iNOS, and COX-2 expression in activated macrophages. 1058 17

Prostaglandin E2 production by tissue-fixed macrophages (Mphi) after severe injury contributes to an enhanced susceptibility to infection and sepsis. The purpose of this study was to investigate the effect of cyclic adenosine monophosphate (cAMP) on prostaglandin (PGE2) production and cyclooxygenase II (COX-2) gene activation in LPS-stimulated macrophages (Mphi). RAW264.7 cells, a mouse Mphi cell line, were exposed to various concentrations of dibutyryl cAMP +/- lipopolysaccharide (10 microg/mL) stimulation. Total Mphi ribonucleic acid (RNA) was harvested for the determination of COX-2 messenger RNA (mRNA) with mouse complementary deoxyribonucleic acid (cDNA) by Northern blot assay. Mphi supernatant was collected for the measurement of tumor necrosis factor (TNF) by L929 bioassay and PGE2 by enzyme-linked immunosorbent assay (ELISA), respectively. Mphi NFkappaB activity was determined by electrophoretic mobility shift assays (EMSA). Dibutyryl cAMP significantly inhibited TNF production by LPS-stimulated Mphi. Dibutyryl cAMP (1 mM) alone induced PGE2 production. Dibutyryl cAMP (100 microM and 1 mM) also augmented PGE2 production by LPS-stimulated Mphi. Dibutyryl cAMP had similar effect on Mphi COX-2 mRNA expression and NFkappaB activity. Our data demonstrate that cAMP modulates Mphi TNF production and upregulates COX-2 gene and PGE2 production.
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PMID:Cyclooxygenase 2 (COX-2) gene activation is regulated by cyclic adenosine monophosphate. 1063 68

We studied the hemodynamic responses of 29 anesthetized and mechanically ventilated piglets to acute hypoxia [reduction of Pao2 from 130 to 38 mm Hg induced by inhalation of 7% fraction of inspired oxygen (Fio2) for 7.5 min] before and during group B beta-hemolytic streptococci (GBS) sepsis. During hypoxia, nonseptic piglets maintained stable systemic blood pressure [105+/-9 (SD) to 97+/-14 mm Hg] and cardiac output (CO) (667+/-72 to 685+/-113 mL/min). However, during GBS/hypoxia, systemic blood pressure fell from 94+/-17 to 49+/-25 mm Hg, CO fell from 397+/-146 to 223+/-142 mL/min (both p < 0.001 versus pre-GBS), and cardiac arrest often ensued. We tested three hypotheses that might underlie GBS-induced intolerance to systemic hypoxia: 1) GBS-induced reduction of systemic CO/systemic oxygen delivery (QO2) below a critical QO2 beyond which the superimposition of hypoxia becomes intolerable; this mechanism is unlikely as nonseptic piglets with comparable reductions in CO/QO2 (induced by inflation of a left atrial balloon) tolerated hypoxia well; 2) GBS-induced inhibition of nitric oxide (NO) synthesis that is vital to tolerance of hypoxia; this mechanism is unlikely as infusion of the NO substrate L-arginine did not restore tolerance to hypoxia during GBS infusion (as it did after inhibition of NO synthesis during infusion of N-nitro-L-arginine in nonseptic piglets); and 3) GBS-induced production of pathologic prostaglandins that impaired the piglet's capacity to tolerate hypoxia; this mechanism finds support in the observation that inhibition of prostaglandins with the cyclooxygenase inhibitor indomethacin completely restored the ability of septic piglets to tolerate hypoxia. Further evaluation of GBS-induced intolerance to systemic hypoxia may provide insight into the incompletely understood mechanisms by which sepsis induces circulatory collapse in experimental animals and in humans.
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PMID:Hemodynamic homeostasis during acute hypoxia in septic and nonseptic piglets: differential role of prostaglandins and nitric oxide. 1075 60

Enhanced prostanoid generation has been implicated in vascular abnormalities occurring during endotoxemia and sepsis, and the lung is particularly prone to such events. Prostanoids are generated from arachidonic acid (AA) via cyclooxygenase (COX)-1 or -2, both isoenzymes recently demonstrated to be expressed in different lung cell types. Upregulation of COX may underlie the phenomenon that endotoxin [lipopolysaccharide (LPS)]-exposed lungs show markedly enhanced vasoconstrictor responses to secondarily applied stimuli (priming). Isolated rat lungs were perfused with a physiological salt buffer solution in the absence and presence of 1.5% rat plasma and exposed to different concentrations of LPS (1,000 or 10,000 ng/ml) during a 2-h priming period. No change in physiological variables was noted during this period, although enhanced baseline liberation of both thromboxane (Tx) A(2) and PGI(2) as well as of tumor necrosis factor (TNF)-alpha was evident compared with that in control lungs in the absence of LPS. LPS priming caused a significant elevation in AA-induced pulmonary arterial pressure, ventilation pressure, and lung weight gain. Concomitant increased levels of TxA(2) were found in the buffer perfusate. All changes were largely suppressed by three selective, structurally unrelated COX-2 inhibitors (NS-398, DUP-697, and SC-236) in both buffer- and buffer-plasma-perfused lungs. Anti-TNF-alpha neutralizing antibodies were ineffective under conditions of buffer perfusion. In the presence of plasma components, manyfold augmented TNF-alpha generation was noted, and anti-TNF-alpha antibodies significantly suppressed the increase in ventilation pressure but not in the vascular pressor response and lung edema formation. We conclude that the propensity of LPS-primed lungs to respond with enhanced vasoconstriction, edema formation, and bronchoconstriction to a secondarily applied stimulus proceeds nearly exclusively via COX-2 and increased Tx formation, with TNF-alpha generation being involved in the change in bronchomotor reactivity in the presence of plasma constituents. In context with recent immunohistological investigations, LPS-induced upregulation of the COX-2-thromboxane synthase axis in vascular and bronchial smooth muscle cells is suggested to underlie these events.
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PMID:Endotoxin priming of the cyclooxygenase-2-thromboxane axis in isolated rat lungs. 1083 25

Monocytes play a pivotal role in various human infectious and inflammatory diseases. To reveal a whole picture of pathophysiologic function of activated human monocytes, this study used the serial analysis of gene expression (SAGE) procedure in lipopolysaccharide (LPS)-stimulated human monocytes. A total of 35 874 tags corresponding to more than 12 000 different transcripts were sequenced. Comparison of gene expression profile with that of resting monocytes revealed the LPS-inducible gene expression profile. Many cytokines and chemokines, including interleukin (IL)-6, IL-1alpha, IL-1beta, tumor necrosis factor (TNF)-alpha, macrophage inflammatory protein (MIP)-1beta, MIP-2beta, MIP-2alpha, liver and activation-regulated chemokine (LARC), MIP-1alpha, thymus and activation-regulated chemokine (TARC), macrophage-derived chemokine (MDC), regulated on activation, normal T cell expressed and secreted (RANTES), growth-regulated oncogene (GRO) alpha, and IL-8, were observed in the highest inducible transcripts. Other genes encoding plasminogen activator inhibitor type 2 (PAI-2), Hc-gp39, apolipoproteins, malate dehydrogenase, matrix metalloproteinase-9 (MMP-9), and cyclooxygenase (COX2) were also highly elevated in LPS-stimulated monocytes. Moreover, up-regulation of Naf1beta, IL-7 receptor, adenosine receptor A2a, and many novel genes was newly identified. These results suggest that the LPS-inducible gene products may be involved in cell activation and migration, angiogenesis, tissue remodeling, and metabolism, and thus may orchestrate the inflammatory reactions. On the other hand, the expression of numerous sets of novel genes was discovered to be down-regulated on LPS stimulation. This study represents the first comprehensive analysis of LPS-inducible gene expression in human monocytes and provides tremendous novel information for the function of LPS-activated monocytes and targets for diagnosing, monitoring, and treating sepsis and various human infectious and inflammatory diseases.
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PMID:Comprehensive gene expression profile of LPS-stimulated human monocytes by SAGE. 1100 15

Prostaglandins of the E series are believed to act as important mediators of several pathophysiological events that occur in sepsis. Studies were performed to evaluate the effect of cyclooxygenase (COX)-2-specific inhibition on the outcome in murine endotoxemia and cecal ligation and puncture (CLP). We observed a significant time-dependent upregulation of PGE(2) production in both blood and lung homogenates of mice administered lipopolysaccharide intraperitoneally, which was nearly completely suppressed by the administration of the COX-2 inhibitor NS-398. Treatment with NS-398 significantly improved early but not late survival in lipopolysaccharide-challenged mice. On the contrary, elevated PGE(2) levels were found in bronchoalveolar lavage fluid but not in plasma of mice subjected to CLP (21 gauge). Pretreatment with NS-398 failed to significantly improve survival in CLP mice. No significant differences were noted in plasma or lung homogenate proinflammatory cytokine levels or lung neutrophil sequestration between the NS-398-treated and control groups. These results demonstrate that selective COX-2 inhibition confers early but not long-term benefits without affecting the expression of proinflammatory cytokines or the development of lung inflammation.
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PMID:Selective inhibition of COX-2 improves early survival in murine endotoxemia but not in bacterial peritonitis. 1150 77

Sepsis, resistant to therapy, results in the development of septic (endotoxin) shock. The latter is caused by the endotoxins of different Gram-negative bacteria. Endotoxin (bacterial lipopdisacharide--LPS) interacts with cells through specific membrane or plasma soluble endotoxin receptors (sCD14, mlD14, LBP, CD13/CD14, CD16, CD116/CD18, L-selectin, etc.). Endotoxin interaction with the mCD14 receptor of the monocytes, macrophages and the neutrophils results in the production of a number of proinflammatory cytokines--tumor necrosis factor alpha (TNF alpha), interleukines 1 and 6 (IL-1 and IL-6, etc), antiinflammatory cytokines--interleukines 10 and 12 (IL-10 and IL-12), cell adhesion molecules (P-selectin, E-selectin, ICAM-1, VCAM-1, etc.) and inducible enzymes: inducible NO synthase (iNOS), inducible phospholipase A2 (cPL-A2), inducible cyclooxygenase (COX-2). All pathologic processes in the structure and function of human body during endotoxin shock are a result of the disbalance of a number of mediators with a proinflammatory and antiinflammatory effects.
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PMID:[The role of bacterial endotoxins, receptors and cytokines in the pathogenesis of septic (endotoxin) shock]. 1168 28

Studies indicate that trauma-hemorrhage results in activation of Kupffer cells to release inflammatory mediators and it leads to immunosuppression and increased susceptibility to subsequent sepsis. The cyclooxygenase (COX) product prostaglandin (PG) E2 appears to be central to this process, however, non-selective inhibition of COX activity with non-steroidal anti-inflammatory agents that block both the constitutive (COX-1) and inducible (COX-2) isoforms of cyclooxygenase has not yielded promising results in trauma patients. Nonetheless, it remains unknown whether selective inhibition of COX-2 activity has any salutary effect following trauma-hemorrhage and subsequent induction of sepsis. To study this, male C3H/HeN mice were subjected to laparotomy (i.e., soft-tissue trauma) and hemorrhagic shock (35 +/- 5 mmHg for 90 min, then resuscitated) or to sham operation. Twenty-four hours later, the mice were subjected to sepsis by cecal ligation and puncture (CLP) or to sham CLP. The mice were treated with the COX-2 inhibitor NS-398 (10 mg/kg body weight, intraperitoneally) or vehicle immediately after trauma-hemorrhage or sham operation, 12 h thereafter, and following CLP or sham CLP. At 5 h after CLP, plasma PGE2, Interleukin-(IL) 6, and TNF-alpha levels were determined along with Kupffer cell IL-6 and TNF-alpha production in vitro. NS-398 treatment markedly suppressed the elevation in plasma PGE2 levels following CLP. The increase in plasma IL-6 levels after CLP were also significantly attenuated by NS-398 treatment. In vitro Kupffer cell IL-6 production after CLP was significantly reduced by in vivo NS-398 treatment. However, NS-398 had no effect on TNF-alpha levels, in vivo and in vitro. These findings indicate that activation of COX-2 following trauma-hemorrhage and subsequent sepsis up-regulates Kupffer cell IL-6 production. Thus, selective inhibition of COX-2 activity may reduce the deleterious consequences of sepsis under such conditions.
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PMID:Cyclooxygenase-2-mediated regulation of Kupffer cell interleukin-6 production following trauma-hemorrhage and subsequent sepsis. 1177 48

Macrophage (Mphi) prostaglandin (PG)E(2) production has been implicated in immunosuppression and increased susceptibility to sepsis after thermal injury. Deficient interleukin (IL)-12 production has also been implicated in these postburn complications. The present study examined the relationship between Mphi cyclooxygenase (COX)-2 activity and IL-12 production after thermal injury. C57BL/6 female mice were subjected to a 25% total body surface area full-thickness burn. Mphi were isolated 7 days later, or the mice were subjected to sepsis by cecal ligation and puncture (CLP). IL-12 production by Mphi from injured mice was suppressed by >50%, whereas COX-2 expression and PGE(2) production were increased twofold. The COX-2 inhibitor NS-398 suppressed PGE(2) production and normalized IL-12 production in the injury group, whereas it had no effect on IL-10 production. Injured mice subjected to CLP had lower IL-12 plasma levels compared with sham-treated mice subjected to CLP. NS-398 treatment prevented the suppression in plasma IL-12 levels in the injury group. Thus elevated Mphi COX-2 activity, independent of IL-10, suppresses Mphi IL-12 production after thermal injury and may play an important role in the observed immunosuppression under such conditions.
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PMID:Cyclooxygenase 2-mediated suppression of macrophage interleukin-12 production after thermal injury. 1178 37

The activation of a pro-inflammatory cascade after burn injury appears to be important in the development of subsequent immune dysfunction, susceptibility to sepsis and multiple organ failure. Macrophages are major producers of pro-inflammatory mediators and their productive capacity for these mediators is markedly enhanced following thermal injury. Thus, macrophage hyperactivity (as defined by increased productive capacity for pro-inflammatory mediators) appears to be of critical importance in the development of post-burn immune dysfunction. This review will focus on the current state of knowledge with regards to the role of macrophages in the development of post-burn immune dysfunction. Particular areas of discussion include: nitric oxide synthase (NOS) and cyclooxygenase (COX) enzyme systems, macrophages and the T-helper (Th)-1/Th-2 cytokine responses, alterations in macrophages signal transduction and a potential role for gamma/delta T-cells in the development of macrophage hyperactivity following thermal injury. A more comprehensive understanding of the relationship between macrophage activity and post-burn immune dysfunction will hopefully provide the basis for improved therapeutic regimes in the treatment of burn patients.
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PMID:Macrophages and post-burn immune dysfunction. 1254 39

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