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ABSTRACT: BACKGROUND: Gut barrier failure caused by endotoxemia is a life-threatening problem. The present study aimed to determine whether any specific intestinal site is highly correlated with gut barrier failure, and whether recombinant human growth hormone (rhGH) can ameliorate gut barrier failure in a rat model of endotoxemia. METHODS: Enterostomy tubes were surgically placed in adult male Sprague-Dawley rats three days before induction of endotoxemia by lipopolysaccharide (LPS) injection. Controls received no LPS. Rats were then randomly assigned to receive subcutaneous injections of rhGH (experimental, n = 30) or 0.9 % saline (control, n = 15) at 24, 48, or 72 h after LPS injection. Escherichia coli labeled with green fluorescent protein (GFP) were injected into the intestinal segment of all rats through the enterostomy tubes. The number of GFP-labeled E. coli detected in mesenteric lymph nodes was examined after 96 h. Apoptosis and proliferation rates of intestinal epithelial cells, and intestinal permeability were measured. RESULTS: Endotoxemia led to high mortality, compared with the control group, and rhGH treatment did not improve survival. Intestinal permeability, reflected by translocation rates of GFP-labeled E. coli, and apoptosis rates in the LPS-induced endotoxemia group were higher than those in the non-endotoxemia control group, and the endotoxemia ileum group had the highest rates of both bacterial translocation and apoptosis. The LPS+GH group had less bacterial translocation and apoptosis than the LPS-induced endotoxemia group. In contrast, the proliferation rates were lower in the LPS group compared to the LPS+GH group. CONCLUSIONS: Endotoxemia can induce gut barrier failure in rats, and the ileum is the site of greatest risk. The GH can reduce the incidence of endotoxemia-induced gut barrier failure, but not the associated mortality.
Agents and Actions 01/2013; · 1.59 Impact Factor
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ABSTRACT: Berberine hydrochloride (BBR), a plant alkaloid, has been used to treat intestinal inflammation or infection for years. Cyclooxygenase-2 (COX-2) is pro-inflammatory mediator and involved in the induction of gut inflammation. The expression of COX-2 in small bowel mucosa was determined and the mechanism by which BBR modulated COX-2 expression was explored in a rat model of endotoxemia induced by lipopolysaccharide (LPS). The results showed that without LPS stimulation COX-2 was constitutively expressed at low levels in control rats. LPS challenge rapidly induced COX-2 gene transcription resulting in high levels of inducible COX-2 expression in endotoxemic rats. BBR pre- and post-treatment had no marked effect on constitutive COX-2 expression but inhibited inducible COX-2 overexpression. LPS challenge increased the expression and phosphorylation of peroxisome proliferator-activated receptor gamma (PPARγ), p38 and activating transcription factor 2 and 3 (ATF2, ATF3), but the effects of LPS were inhibited by BBR treatment. GW9662 did not influence constitutive COX-2 expression but enhanced inducible COX-2 overproduction. Besides, GW9662 abolished the inhibitory effect of BBR on inducible COX-2, p38, ATF2, 3 expression and phosphorylation. Collectively, these results indicated that BBR gavage could attenuate the overexpression of inducible COX-2, not constitutive COX-2, in ileal mucosa during acute endotoxemia in part via activation of PPARγ pathway, which negatively interfered with p38/ATFs cascade.
International immunopharmacology 12/2011; 12(1):182-8. · 2.21 Impact Factor
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ABSTRACT: The effect of berberine hydrochloride (BBR) on inducible cyclooxygenase-2 (COX-2) in small intestinal mucosa and related mechanisms was investigated in a rat model of acute endotoxemia. The results showed that lipopolysaccharide (LPS) increased COX-2 expression, whereas SB202190 and BBR curtailed it. LPS increased phosphorylation of mucosal p38 MAPK and ATF2 as well as production of ATF2, whereas BBR attenuated these effects. LPS upregulated mucosal peroxisome proliferator-activated receptor gamma (PPARγ), but BBR reduced this receptor. GW9662 aggravated LPS-induced and reversed BBR-attenuated COX-2 expression. The findings showed that BBR ameliorated COX-2 overexpression partially via modulation of p38 and PPARγ pathways during acute endotoxemia.
Fitoterapia 05/2011; 82(7):976-82. · 1.85 Impact Factor
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ABSTRACT: It is known that the loss of DC plays an important role for immune suppression during endotoxemia or sepsis. To verify our hypothesis that pre-enrichment of the lamina propria (LP) DC pool may improve protective immunity to bacterial translocation and outcome in endotoxemic mice, we pre-treated mice with Flt3L or normal saline, and then challenged them with or without LPS. Twelve hours later the population size and maturity of DC in the LP and circulation were analyzed by flow cytometry. Bacterial translocation to distant organs, inflammatory responses in the intestine and the survival rate of mice were evaluated. We observed that pretreatment of Flt3L significantly expanded DC in the LP and blood, but did not alter their maturation. However, exacerbation of DC growth induced by Flt3L-pretreatment aggravated intestinal inflammation and increased the mortality of endotoxemic mice rather than enhancing their resistance to bacterial translocation.
Inflammation 10/2009; 33(1):34-45. · 1.75 Impact Factor
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ABSTRACT: To investigate the effects of nuclear factor kappa B (NF-kappaB) on insulin signaling in skeletal muscle cells of rat with sepsis.
SD rats were randomly divided into two groups: control group and sepsis group.Sepsis model was reproduced by cecal ligation and puncture in sepsis group. At 8, 16, 24, 48 and 72 h after operation, the gastrocnemius was harvested. Conventional HE staining was used to observe the morphology of skeletal muscle cells. IRS-1 protein and tyrosine phosphorylation of IRS-1 and Ser(307) phosphorylation of IRS-1 were detected by Western Blotting and immuno-precipitation. Activities of NF-kappaB in skeletal muscle cells were detected by electrophoretic mobility shift assay.
Tyrosine phosphorylation of IRS-1 in sepsis group was significantly lower than in control group (P < 0.01), while Ser(307) phosphorylation of IRS-1 in sepsis group was significantly higher than in control group (P < 0.01). In sepsis group, NF-kappaB activity in skeletal muscle cells was significantly higher than in control group (P < 0.01). There was significant negative correlation between activity of NF-kappaB and tyrosine phosphorylation of IRS-1 (r = 0.972, P < 0.01). There was significant positive correlation between activities of NF-kappaB and Ser(307) phosphorylation of IRS-1 (r = 0.969, P < 0.01).
There is no inflammatory cell infiltrate in skeletal muscle cells with sepsis. But the activity of NF-kappaB in skeletal muscle cells is obviously enhanced, and it is closely related with disorder of insulin signaling in skeletal muscle cells of rat with sepsis.
Zhonghua wai ke za zhi [Chinese journal of surgery] 08/2009; 47(16):1257-60.
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ABSTRACT: The omega-3 polyunsaturated fatty acids (PUFAs) play a key role as immune response modulators and suppressors of immunologic functions, such as lymphocyte proliferation, cytokine production, and cell surface molecular expression in T lymphocytes, monocytes, and natural killer cells. However, little is known about the effect of omega-3 PUFAs on dendritic cells (DCs). We studied the effect of omega-3 PUFAs on DCs and the related intracellular signal transduction pathway.
Dendritic cells were generated from human peripheral blood monocytes in the presence of granulocyte-macrophage colony-stimulating factors and interleukin (IL)-4 and treated with eicosapentaenoic acid (EPA), docosahexanoic acid (DHA), and stearic acid for 24 h. Lipopolysaccharide (LPS) was used for maturation of the DCs. The expressions of CD40, CD80, CD86, and human leukocyte antigen-DR (HLA-DR) were analyzed by flow cytometry; production of IL-12 and tumor necrosis factor-alpha were detected by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay. The proliferative ability of allogeneic T cells stimulated by DCs was evaluated by tritiated thymidine ((3)H-TdR). Western blot analysis of p38 mitogen-activated protein kinase was conducted.
The omega-3 PUFAs reduced expression levels of costimulatory molecules CD80 and CD86 and major histocompatibility complex HLA-DR. IL-12 and tumor necrosis factor-alpha levels decreased significantly in the EPA and DHA groups. EPA and DHA also significantly reduced the proliferative ability of allogeneic T cells stimulated by DCs. The omega-3 PUFAs significantly inhibited LPS-induced p38 phosphorylation.
The omega-3 PUFAs may inhibit LPS-induced DC maturation and upregulate cytokine production. Impaired p38 mitogen-activated protein kinase activity is a potential critical intracellular signaling transduction mechanism.
Nutrition 07/2007; 23(6):474-82. · 3.03 Impact Factor
