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1.
Role of nitric oxide in the expression of hepatic vascular stress genes in response to sepsis 总被引:1,自引:0,他引:1
This study examined the role of nitric oxide (NO) on the expression of the hepatic vasoregulatory gene during polymicrobial sepsis. Aminoguanidine (AG, 100 mg/kg) or Nomega-nitro-L-arginine methyl ester (L-NAME, 100 mg/kg) was injected intraperitoneally at 0, 3, 6, 10, and 20 h after a cecal ligation and puncture (CLP). The heart rate increased 24 h after the CLP, and this increase was attenuated by L-NAME and further attenuated by AG. The mean arterial pressure in the CLP animals did not change significantly 24 h after the onset of sepsis but was increased after the L-NAME injection. Sepsis increased the serum aminotransferase levels, which were attenuated by AG but augmented by L-NAME. CLP increased the mRNA level of the ET-1 and ETB receptors in the liver. This increase was prevented by AG but augmented by L-NAME. The level of iNOS and HO-1 mRNA expression were increased by CLP, which was prevented by both AG and L-NAME. The level of TNF-alpha and COX-2 mRNA expression increased after CLP, and was attenuated by AG. These results show that iNOS and eNOS are regulated differently in sepsis. While eNOS appears to have a protective role in liver microcirculation, the strong upregulation of iNOS might contribute to a microvascular dysfunction and hepatic injury. 相似文献
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Kaplan JM Nowell M Lahni P O'Connor MP Hake PW Zingarelli B 《Obesity (Silver Spring, Md.)》2012,20(10):1995-2002
The purpose of this study was to examine the effect of short-term high fat feeding on the inflammatory response in polymicrobial sepsis. Male C57BL/6 mice at 6 weeks of age were randomized to a high-fat diet (HFD) (60% kcal fat) or control diet (CD) (16% kcal fat) for 3 weeks. After 3 weeks of feeding, sepsis was induced by cecal ligation and puncture (CLP) and animals were monitored for survival. In a separate experiment, after 3 weeks of feeding mice underwent CLP and were sacrificed at various time points thereafter. Tissue was collected for biochemical studies. Mice fed a HFD gained more weight and had a greater fat mass compared to CD-fed mice. Mice on a HFD had a lower probability of survival and more severe lung injury compared with CD-fed mice following sepsis. Myeloperoxidase (MPO) activity, an indicator of neutrophil infiltration, was increased in the lung and liver after CLP in HFD-fed mice compared with CD (P < 0.05). The plasma cytokines tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 were increased in both groups after CLP, however, TNF-α and IL-6 levels were lower in HFD mice at 3 h after CLP compared with CD and consistent with lung, but not liver, messenger RNA (mRNA) expression. Leptin levels were higher in HFD-fed mice at 18 h after sepsis compared to baseline levels (P < 0.05). Polymicrobial sepsis increased hepatic nuclear factor-κB (NF-κB) activation in HFD-fed mice after CLP vs. CD-fed mice. Short duration high fat feeding increases mortality and organ injury following polymicrobial sepsis. These effects correspond to changes in NF-κB. 相似文献
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Isabela Casagrande Jeremias Giselli Scaini Larissa Constantino Francieli Vuolo Andreia Kurek Ferreira Emilene Barros Silva Scherer Janaina Kolling Arethuza da Silva Dornelles Angela Terezinha de Souza Wyse Maurício Reis Bogo Felipe Dal-Pizzol Emilio Luiz Streck 《Molecular neurobiology》2012,46(2):467-474
In the present study, we investigated whether sepsis induced by cecal ligation and puncture (CLP) modifies Na+, K+-ATPase activity, mRNA expression, and cerebral edema in hippocampus and cerebral cortex of rats and if antioxidant (ATX) treatment prevented the alterations induced by sepsis. Rats were subjected to CLP and were divided into three groups: sham; CLP??rats were subjected to CLP without any further treatment; and ATX?CCLP plus administration of N-acetylcysteine plus deferoxamine. Several times (6, 12, and 24) after CLP or sham operation, the rats were killed and hippocampus and cerebral cortex were isolated. Na+, K+-ATPase activity was inhibited in the hippocampus 24?h after sepsis, and ATX treatment was not able to prevent this inhibition. The Na+, K+-ATPase activity also was inhibited in cerebral cortex 6, 12, and 24?h after sepsis. No differences on Na+, K+-ATPase catalytic subunit mRNA levels were found in the hippocampus and cerebral cortex after sepsis. ATX treatment prevents Na+, K+-ATPase inhibition only in the cerebral cortex. Na+, K+-ATPase inhibition was not associated to increase brain water content. In conclusion, the present study demonstrated that sepsis induced by CLP inhibits Na+, K+-ATPase activity in a mechanism dependent on oxidative stress, but this is not associated to increase brain water content. 相似文献
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The present study aimed to determine the role of Kupffer cells (KCs) in cytochrome P450 (CYP) isozyme activity and the expression of its gene during polymicrobial sepsis. For ablation of KCs, rats were pretreated with gadolinium chloride (GdCl(3)) at 48 and 24 h before cecal ligation and puncture (CLP). The depletion of KCs was confirmed by measuring the mRNA level of the KC marker gene CD163. Serum aminotransferase levels and lipid peroxidation showed an increase and hepatic glutathione content showed a decrease at 24 h after CLP. These changes were prevented by GdCl(3) pretreatment. Catalytic activities of CYP1A1, 1A2 and 2E1 showed a significant reduction at 24 h after CLP but were prevented by GdCl(3). A reduction in the levels of CYP2E1 protein and CYP2B1 and CYP2E1 mRNA expression was prevented by GdCl(3). Phosphorylation of CYP1A1/1A2 markedly increased 24 h after CLP, which was prevented by GdCl(3). The increased serum level of high mobility group box 1, hepatic level of Toll-like receptors 2 and 4, and inducible nitric oxide synthase protein expression were prevented by GdCl(3). In addition, elevated serum concentrations of tumor necrosis factor-α and interleukin-6, and increased hepatic mRNA levels of tumor necrosis factor-α and interleukin-6 were decreased by depletion of KCs. Our findings suggest that ablation of KCs protects against hepatic drug-metabolizing dysfunction by modulation of the inflammatory response. 相似文献
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《The Journal of nutritional biochemistry》2014,25(1):19-25
This study investigated the effect of dietary fish oil on systemic inflammation and hepatic injury in mice with polymicrobial sepsis. Male ICR mice were assigned to a control group (C, n=30) and a fish oil group (FO, n=30). Mice in the C group were fed a semi-purified diet with 10% soybean oil, and those in the FO group were fed a fish oil diet (2.5% fish oil+7.5% soybean oil; w/w). Three weeks later, sepsis was induced by cecal ligation and puncture (CLP), and mice were sacrificed at 0, 6 and 24 h after CLP, respectively. Results showed that compared with C group, the FO group had lower plasma levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, and nitrite at 6 and 24 h after CLP. Also, peritoneal lavage fluid concentrations of TNF-α and prostaglandin (PG) E2 were significantly lower at 24 h in the FO than in the C group. The FO group had lower myeloperoxidase activities at 6 h after CLP in various organs. Plasma aminotransferase and alanine aminotransferase activities revealed significantly decreased in the FO group. The DNA-binding activity of peroxisome proliferators-activated receptor gamma (PPARγ) and mRNA expression of I kappaB alpha (IκBα) were up-regulated while nuclear factor (NF)-κB p65 DNA-binding activity, inducible nitric oxide synthase protein expression and the concentration of nitrotyrosine were significantly decreased in the FO group in liver after CLP. These results indicate that dietary fish oil administration may attenuate systemic inflammation and up-regulate hepatic PPARγ DNA-binding activity, which may consequently have ameliorated liver injury in these septic mice. 相似文献
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MAPK p38 antagonism as a novel method of inhibiting lymphoid immune suppression in polymicrobial sepsis 总被引:3,自引:0,他引:3
Song Grace Y.; Chung Chun-Shiang; Chaudry Irshad H.; Ayala Alfred 《American journal of physiology. Cell physiology》2001,281(2):C662
Although studies indicatethat a shift from a Th1 to a Th2 response contributes to a markedsuppression of cell-mediated immunity during sepsis, the mechanism bywhich this occurs remains unknown. Given that the mitogen-activatedprotein kinase (MAPK) p38 plays a critical role in the activation andfunction of immune cells, the aim of this study was to determine thecontribution of MAPK p38 activation to the immune dysfunction seen inpolymicrobial sepsis. To study this, polymicrobial sepsis was inducedin C3H/HeN male mice by cecal ligation and puncture (CLP). Spleniclymphocytes and purified T cells were harvested 24 h post-CLP,pretreated with the specific MAPK p38 inhibitor SB-203580, and thenstimulated with a monoclonal antibody against the T cell marker CD3.The results indicate that interleukin (IL)-2 release is markedlydepressed while the release of the immunosuppressive mediator, IL-10,as well as mRNA levels of IL-10 and IL-4, are augmented after CLP. Inhibition of MAPK p38 suppressed in vitro IL-10 levels as well asIL-10 and IL-4 gene expression while restoring the release of IL-2. Todetermine whether these in vitro findings could be translated to an invivo setting, mice were given 100 mg of SB-203580/kg body wt or salinevehicle (intraperitoneal) at 12 h post-CLP. Examination of ex vivolymphocyte responsiveness indicated that, as with the in vitro finding,septic mouse Th1 responsiveness was restored. In light of our recentfinding that delayed in vivo SB-203580 treatment also improved survivalafter CLP, we believe that these results not only illustrate the roleof MAPK p38 in the induction of immunosuppressive agents in sepsis butdemonstrate that SB-203580 administration after the initialproinflammatory state of sepsis significantly prevents the morbidityfrom sepsis. 相似文献
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Is gut the major source of proinflammatory cytokine release during polymicrobial sepsis? 总被引:4,自引:0,他引:4
D J Koo M Zhou D Jackman W G Cioffi K I Bland I H Chaudry P Wang 《Biochimica et biophysica acta》1999,1454(3):289-295
Although studies have shown that the gut is capable of being a cytokine-producing organ and that the proinflammatory cytokines TNF-alpha, IL-1beta, and IL-6 are upregulated following the onset of sepsis, it remains unknown whether the gut is indeed the major source of the increased cytokine production under such conditions. To determine this, male rats were subjected to cecal ligation and puncture (CLP, a model of polymicrobial sepsis) or sham operation followed by the administration of normal saline solution subcutaneously (i.e., fluid resuscitation). Systemic and portal blood samples were taken simultaneously at 2, 5, 10, or 20 h after CLP or sham operation. Plasma levels of TNF-alpha, IL-1beta, and IL-6 were determined using an enzyme-linked immunosorbent assay. In additional animals, the small intestine was harvested at 10 h after CLP or sham operation and examined for TNF-alpha, IL-1beta, and IL-6 gene expression by RT-PCR. The results indicate that the levels of TNF-alpha, IL-1beta, and IL-6 in both systemic and portal blood samples were significantly elevated during sepsis with the exception that the increase in IL-1beta was not significant at 2 h after CLP. However, there were no significant differences in the levels of those proinflammatory cytokines between systemic and portal blood at any points after the onset of sepsis. Moreover, there were no significant alterations in the proinflammatory cytokine gene expression in the small intestine at 10 h after CLP. Since the levels of TNF-alpha, IL-1beta, and IL-6 were not significantly increased in portal blood as compared to systemic blood and since there was no upregulation of gene expression for these cytokines, it appears that organs other than the gut are responsible for the upregulated proinflammatory cytokines during polymicrobial sepsis. 相似文献
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B I Sikic E G Mimnaugh C L Litterst T E Gram 《Archives of biochemistry and biophysics》1977,179(2):663-671
The effects of ascorbic acid (AA) deficiency on microsomal and soluble (postmicrosomal supernatant) enzymes which catalyze drug metabolism were studied in the guinea pig liver, lung, and kidney, (i) Twenty-one days of AA depletion produced a 50–60% decrease in hepatic cytochrome P-450 levels, 20–30% decreases in renal levels, but no significant changes in pulmonary cytochrome P-450 content. Upon repletion of ascorbic acid, recovery to control levels occurred within 7 days. (ii) The decreases in hepatic cytochrome P-450 in scurvy were not accompanied by a corresponding increase in cytochrome P-420. (iii) Aminopyrine N-demethylation decreased by 40% in livers of deficient animals, and recovered within 3 days, but there were no corresponding changes in lungs and kidneys. (iv) There were no significant alterations of NADPH-cytochrome c reductase activity in scorbutic animals in any of the three organs. (v) Activity of “native” UDP-glucuronyl transferase was increased in liver microsomes after 21 days of deficiency, but this apparent increase was not observed when the enzyme was fully activated in vitro with UDP N-acetylglucosamine. “Native” UDP-glucuronyl transferase was increased in kidneys of deficient animals and unchanged in lungs. (vi) In the postmicrosomal supernatant, glutathione S-aryl transferase activity in deficient livers decreased tc 50% of control and did not fully recover after 14 days of ascorbic acid repletion. These changes were not seen in kidney and lung. (vii) Also in the postmicrosomal supernatant, p-aminobenzoic acid (PABA) N-acetyl transferase activity increased in the kidneys of deficient animals, but was unchanged in liver and lungs. (viii) Addition of ascorbic acid in vitro to hepatic microsomes prepared from scorbutic animals had no effect on activities of aminopyrine N-demethylase, NADPH-cytochrome c reductase, PABA N-acetyl transferase, and glutathione S-aryl transferase. 相似文献
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Protective effects of IL-6 blockade in sepsis are linked to reduced C5a receptor expression 总被引:11,自引:0,他引:11
Riedemann NC Neff TA Guo RF Bernacki KD Laudes IJ Sarma JV Lambris JD Ward PA 《Journal of immunology (Baltimore, Md. : 1950)》2003,170(1):503-507
IL-6 is known to be an important pro- and anti-inflammatory cytokine, which is up-regulated during sepsis. Our previous work has suggested a role for IL-6 in the up-regulation of C5aR in sepsis. We reported earlier that interception of C5a or C5aR results in improved outcomes in experimental sepsis. Using the cecal ligation/puncture (CLP) model in mice, we now demonstrate that treatment with anti-IL-6 Ab (anti-IL-6) results in significantly improved survival, dependent on the amount of Ab infused. CLP animals showed significantly increased binding of 125I-labeled anti-C5aR to organs when compared to either control mice at 0 h or CLP animals infused with normal rabbit 125I-labeled IgG. Binding of 125I-labeled anti-C5aR to lung, liver, kidney, and heart was significantly decreased in anti-IL-6-treated animals 6 h after CLP. RT-PCR experiments with mRNA isolated from various organs obtained 3, 6, and 12 h after CLP demonstrated increased C5aR mRNA expression during the onset of sepsis, which was greatly suppressed in CLP mice treated with anti-IL-6. These data suggest that IL-6 plays an important role in the increased expression of C5aR in lung, liver, kidney, and heart during the development of sepsis in mice and that interception of IL-6 leads to reduced expression of C5aR and improved survival. 相似文献
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Zhou M Arthur AJ Ba ZF Chaudry IH Wang P 《American journal of physiology. Regulatory, integrative and comparative physiology》2001,280(2):R382-R388
Although studies have indicated that calcitonin gene-related peptide (CGRP), a potent vasodilatory peptide, is upregulated after endotoxic shock, it remains controversial whether this peptide increases during sepsis and, if so, whether the gut is a significant source of CGRP under such conditions. To study this, polymicrobial sepsis was induced by cecal ligation and puncture (CLP) followed by fluid resuscitation. Plasma levels of CGRP were measured at 2, 5, and 10 h after CLP (i.e., early, hyperdynamic sepsis) and at 20 h after CLP (late, hypodynamic sepsis). The results indicate that plasma CGRP did not increase at 2--5 h but increased by 177% at 10 h after CLP (P < 0.05). At 20 h after the onset of sepsis, however, the elevated plasma CGRP returned to the sham level. To determine the source of the increased plasma CGRP, the liver, spleen, small intestine, lungs, and heart were harvested, and tissue CGRP was assayed at 10 h after CLP in additional animals. Only the small intestine showed a significant increase in tissue levels of CGRP (by 129%, P < 0.05). Determination of portal vs. systemic levels of CGRP indicates that portal CGRP was 65.7 +/- 22.7% higher than the systemic level at 10 h after CLP, whereas portal CGRP in sham-operated rats was only 4.9 +/- 2.1% higher. Immunohistochemistry examination revealed that CGRP-positive stainings increased in the intestinal tissue but not in the liver at 10 h after the onset of sepsis. The distribution of CGRP stainings was associated with intestinal nerve fibers. These results, taken together, demonstrate that upregulation of CGRP occurs transiently during the progression of sepsis (at the late phase of the hyperdynamic sepsis), and the gut appears to be a major source of such an increase in circulating levels of this peptide. 相似文献
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The effects of dietary supplemental magnesium oxide (MgO), magnesium-L-aspartate (MgAsp) and monomagnesium-di-L-aspartate (MgdiAsp) on hepatic catalase (CAT) activity and its mRNA expression were investigated. A total of 360 one-day-old male Abor Acre broiler chickens were allocated to ten treatments, i.e. control plus 9 treatments from 3 x 3 factorial arrangement (Mg source, Mg level), each treatment with six replicates of 6 chickens. The birds were fed with the basal diet alone or supplemented with magnesium (Mg) at 0.9, 1.8, 2.7 g/kg of the diet from MgO, MgAsp or MgdiAsp. Results showed that hepatic Mg concentration increased quadratically as MgO or MgAsp supplementation increased (p < 0.01). Hepatic CAT activity increased linearly in birds fed with MgAsp or MgdiAsp (p < 0.01) and quadratically in birds fed with MgO (p < 0.05) as dietary Mg supplementation level increased. Hepatic CAT mRNA was linearly correlated with the dietary Mg supplementation level (p < 0.01). There were positive correlations among hepatic CAT activity, its mRNA expression level and hepatic Mg concentration (p < 0.01). No effect of Mg2+ on the purified CAT activity was detected in vitro enzymatic reaction system (p > 0.05). Supplemental MgAsp or MgdiAsp was more efficient to increase hepatic Mg concentrations, enhance hepatic CAT activity and its mRNA expression than MgO (p < 0.01). It can be concluded that dietary Mg supplementation could increase hepatic Mg concentration, enhance CAT mRNA expression and consequently enhance CAT activity, and the organic Mg (MgAsp or MgdiAsp) is much more efficient than the inorganic form (MgO). 相似文献
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《Redox report : communications in free radical research》2013,18(1):36-46
AbstractObjectiveTo investigate the efficacy of combined administration of alpha-tocopherol (AT) and ascorbic acid (AA) in reducing ethanol-induced hepatotoxicity.MethodsRats were maintained for 90 days and grouped as follows: I – control rats, II – ethanol, III – alpha-tocopherol, IV – ethanol + alpha-tocopherol, V – AA, VI – ethanol + ascorbic acid, VII – alpha-tocopherol + ascorbic acid, VIII – ethanol + alpha-tocopherol + ascorbic acid. At the end of the experimental period, markers of hepatic function, oxidative stress, and the expression of markers of inflammation and fibrosis were assayed.ResultsThe markers of hepatic function, lipid peroxidation products, protein carbonyls, and the expression of nuclear factor kappa B, tumor necrosis factor alpha, transforming growth factor beta 1, cytochrome P4502E1, and collagen Type I were elevated after ethanol administration. All these parameters were reduced in the ethanol group administered AT and AA in combination. The activities of antioxidant enzymes which were reduced by ethanol administration were enhanced on combined administration of AT and AA. The reduction in hepatic fibrosis was almost 20% more in AT and AA co-administered group compared with AT and AA alone treated groups.DiscussionCombined administration of fat soluble AT and water soluble AA was beneficial against ethanol-induced hepatotoxicity. This may be due to their different subcellular localizations. 相似文献
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Saia RS Oliveira-Pelegrin GR da Silva ME Aguila FA Antunes-Rodrigues J Rocha MJ Cárnio EC 《Regulatory peptides》2011,169(1-3):21-30
Our aim was to investigate whether neonatal LPS challenge may improve hormonal, cardiovascular response and mortality, this being a beneficial adaptation when adult rats are submitted to polymicrobial sepsis by cecal ligation and puncture (CLP). Fourteen days after birth, pups received an intraperitoneal injection of lipopolysaccharide (LPS; 100μg/kg) or saline. After 8-12 weeks, they were submitted to CLP, decapitated 4, 6 or 24h after surgery and blood was collected for vasopressin (AVP), corticosterone and nitrate measurement, while AVP contents were measured in neurohypophysis, supra-optic (SON) and paraventricular (PVN) nuclei. Moreover, rats had their mean arterial pressure (MAP) and heart rate (HR) evaluated, and mortality and bacteremia were determined at 24h. Septic animals with neonatal LPS exposure had higher plasma AVP and corticosterone levels, and higher c-Fos expression in SON and PVN at 24h after surgery when compared to saline treated rats. The LPS pretreated group showed increased AVP content in SON and PVN at 6h, while we did not observe any change in neurohypophyseal AVP content. The nitrate levels were significantly reduced in plasma at 6 and 24h after surgery, and in both hypothalamic nuclei only at 6h. Septic animals with neonatal LPS exposure showed increase in MAP during the initial phase of sepsis, but HR was not different from the neonatal saline group. Furthermore, neonatally LPS exposed rats showed a significant decrease in mortality rate as well as in bacteremia. These data suggest that neonatal LPS challenge is able to promote beneficial effects on neuroendocrine and cardiovascular responses to polymicrobial sepsis in adulthood. 相似文献
17.
Padmalaya Das Mani Chopra Avadhesh C. Sharma 《Molecular and cellular biochemistry》2009,323(1-2):61-68
This study was designed to test whether increased sympathetic stimulation during polymicrobial sepsis modulates the profile of the syntaxin1A and norepinephrine transporter (NET) in the heart. Sepsis of mild and severe intensity was induced in male Sprague-Dawley rats (275–350 g) using the cecal inoculum (CI) and cecal ligation and puncture (CLP) methods, respectively. The heart samples were isolated from sham, 1, 3, and 7 day post-sepsis in the CI model and at 2 and 20 h post-sepsis in the CLP model. In the CI model, the plasma concentration of norepinephrine (NE) significantly increased at 1, 3, and 7 days post-CI compared to the sham group. The myocardial syntaxin1A mRNA and protein expression also significantly increased at 1 day post-CI compared to the sham group. However, the sepsis-induced increase in syntaxin1A returned to the baseline values at 3 and 7 days post-CI. The expressions of myocardial NET mRNA and protein were not altered at 1 day post-CI but significantly decreased at 3 days post-CI compared to the sham and 1 day post-CI groups. The immunohistochemical analyses revealed an increased localization of NET and syntaxin1A in the heart tissue sections of the 1 day post-CI group. In the CLP model of severe sepsis, the myocardial syntaxin1A mRNA protein expressions significantly increased at 2 h post-CLP, but remained unchanged at 20 h post-CLP compared to the sham group. In contrast, the myocardial expressions of NET mRNA and protein significantly decreased at both 2 and 20 h post-CLP compared to the sham group. It appears that during severe sepsis (CLP model), both the upregulation of syntaxin1A and the downregulation of NET contribute to increased concentrations of NE during the early and late stages of sepsis. 相似文献
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Zhou M Wu R Dong W Jacob A Wang P 《American journal of physiology. Regulatory, integrative and comparative physiology》2008,294(1):R84-R92
The nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is anti-inflammatory in a cell-based system and in animal models of endotoxemia. We have shown that PPAR-gamma gene expression is downregulated in macrophages after lipopolysaccharide (LPS) stimulation. However, it remains unknown whether hepatic PPAR-gamma is altered in sepsis and, if so, whether LPS directly downregulates PPAR-gamma. To study this, rats were subjected to sepsis by cecal ligation and puncture (CLP). Hepatic tissues were harvested at 5, 10, and 20 h after CLP. PPAR-gamma gene expression and protein levels were determined by RT-PCR and Western blot analysis, respectively. The results showed that PPAR-gamma gene expression decreased at 10 and 20 h and that its proteins levels were reduced at 20 h after CLP. PPAR-gamma levels were also decreased in animals that were administered LPS. To determine the direct effects of LPS on PPAR-gamma downregulation, LPS binding agent polymyxin B (PMB) was administered intramuscularly after CLP. The administration of PMB significantly reduced plasma levels of endotoxin, but it did not prevent the downregulation of PPAR-gamma expression. We found that circulating levels of TNF-alpha still remained significantly elevated in PMB-treated septic animals. We, therefore, hypothesize that the decrease of PPAR-gamma expression is TNF-alpha dependent. To investigate this, Kupffer cells (KCs) were isolated from normal rats and stimulated with LPS or TNF-alpha. TNF-alpha significantly attenuated PPAR-gamma gene expression in KCs. Although LPS decreased PPAR-gamma in KCs, the downregulatory effect of LPS was blocked by the addition of TNF-alpha-neutralizing antibodies. Furthermore, the administration of TNF-alpha-neutralizing antibodies to animals before the onset of sepsis prevented the downregulation of PPAR-gamma in sepsis. We, therefore, conclude that LPS downregulates PPAR-gamma expression during sepsis via an increase in TNF-alpha release. 相似文献
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Previous studies have shown that adrenomedullin (AM), a potent vasodilatory peptide, is upregulated during sepsis. However, it remains unknown whether the increased AM observed under such conditions is solely due to the elevated levels of circulating lipopolysaccharide (LPS). To determine this, an Alzet micro-osmotic pump, containing a low dose of Escherichia coli LPS or vehicle (sterile normal saline), was implanted in the peritoneal cavity of the normal male adult rat. At 10 h after the pump implantation, samples of blood and small intestine were harvested for the determination of AM by radioimmunoassay. In additional groups, rats were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP). LPS binding agent polymyxin B was administrated intramuscularly at 1 h prior to as well as 5 h after the onset of sepsis. At 10 h after CLP or sham-operation, blood and intestinal samples were harvested and levels of AM were then determined. Plasma levels of LPS were also measured by Limulus amebocyte lysate assay. The results indicate that administration of a low dose of LPS via the peritoneal cavity in normal animals (which did not significantly alter cardiac output, blood pressure or heart rate) markedly increased plasma and intestinal levels of AM. In addition, plasma and tissue levels of AM increased significantly at 10 h after CLP. Administration of polymyxin B, however, attenuated the increase in AM levels under such conditions. Similarly, the increased plasma levels of LPS was significantly reduced by polymyxin B during sepsis. These results, taken together, suggest that the upregulated AM observed during polymicrobial sepsis is at least in part due to the increase in circulating levels of endotoxin. 相似文献