The role of PGE2 in intestinal inflammation and tumorigenesis.
The role of PGE2 in intestinal inflammation and tumorigenesis.
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DOI：
10.1016/j.prostaglandins.2014.10.002
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发表时间：
2015-01
影响因子：
2.9
通讯作者：
Rosenberg DW
中科院分区：
文献类型：
--
作者：
Montrose DC;Nakanishi M;Murphy RC;Zarini S;McAleer JP;Vella AT;Rosenberg DW
胞质磷脂酶A2 （cPLA2）释放游离脂肪酸花生四烯酸（AA），随后由环加氧酶和脂加氧酶代谢产生广泛的类二十烷酸，包括前列腺素（pg）。本研究旨在探讨这些介质在炎症和炎症相关肠道肿瘤发生的实验模型中的作用。利用实验性结肠炎的葡聚糖硫酸钠（DSS）模型，我们首先利用cPLA2敲除小鼠研究了类二十烷酸产生的整体减少如何影响肠道损伤。cPLA2缺失增强了结肠损伤，表现为粘膜溃疡和促炎细胞因子表达增加。疾病严重程度的增加与几种类二十烷酸代谢物（包括PGE2）水平的显著降低有关。我们进一步评估了PGE2合成在粘膜损伤和修复中的精确作用，利用小鼠微粒体PGE合成酶-1 （mPGES-1）基因缺失，这是诱导PGE2形成的末端合成酶。与野生型小鼠相比，DSS暴露导致基因敲除小鼠更广泛的急性损伤和恢复受损。肠道损伤的增加与PGE2水平的降低以及包括PGD2在内的其他二十烷类物质水平的改变有关。为了确定这种代谢重定向是否影响炎症相关的肠道肿瘤发生，ApcMin/+和ApcMin/+:mPGES-1 - / -小鼠暴露于DSS。DSS仅在ApcMin/+:mPGES-1−/−小鼠中引起肠息肉数量的减少。这些结果证明了肠道中前列腺素平衡对维持肠道稳态和影响肿瘤发展的重要性。
Release of the free fatty acid arachidonic acid (AA) by cytoplasmic phospholipase A2 (cPLA2) and its subsequent metabolism by the cyclooxygenase and lipoxygenase enzymes produces a broad panel of eicosanoids including prostaglandins (PGs). This study sought to investigate the roles of these mediators in experimental models of inflammation and inflammation-associated intestinal tumorigenesis. Using the dextran sodium sulfate (DSS) model of experimental colitis, we first investigated how a global reduction in eicosanoid production would impact intestinal injury by utilizing cPLA2 knockout mice. cPLA2 deletion enhanced colonic injury, reflected by increased mucosal ulceration and pro-inflammatory cytokine expression. Increased disease severity was associated with a significant reduction in the levels of several eicosanoid metabolites, including PGE2. We further assessed the precise role of PGE2 synthesis on mucosal injury and repair by utilizing mice with a genetic deletion of microsomal PGE synthase-1 (mPGES-1), the terminal synthase in the formation of inducible PGE2. DSS exposure caused more extensive acute injury as well as impaired recovery in knockout mice compared to wild-type littermates. Increased intestinal damage was associated with both reduced PGE2 levels as well as altered levels of other eicosanoids including PGD2. To determine whether this metabolic redirection impacted inflammation-associated intestinal tumorigenesis, ApcMin/+ and ApcMin/+:mPGES-1−/− mice were exposed to DSS. DSS administration caused a reduction in the number of intestinal polyps only in ApcMin/+:mPGES-1−/− mice. These results demonstrate the importance of the balance of prostaglandins produced in the intestinal tract for maintaining intestinal homeostasis and impacting tumor development.
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影响因子：
2.4
作者：
Hernandez, Yasmin;Sotolongo, John;Fukata, Masayuki
通讯作者：
Fukata, Masayuki
DOI：
10.1158/1940-6207.capr-09-0005
发表时间：
2009-04
期刊：
Cancer prevention research (Philadelphia, Pa.)
影响因子：
--
作者：
Duffield-Lillico AJ;Boyle JO;Zhou XK;Ghosh A;Butala GS;Subbaramaiah K;Newman RA;Morrow JD;Milne GL;Dannenberg AJ
通讯作者：
Dannenberg AJ
影响因子：
3.7
作者：
Masoodi, Mojgan;Pearl, Daniel S.;Trebble, Timothy M.
通讯作者：
Trebble, Timothy M.
影响因子：
15.9
作者：
Morteau, O;Morham, SG;Sartor, RB
通讯作者：
Sartor, RB
影响因子：
4.7
作者：
Ishikawa, Tomo-o;Herschman, Harvey R.
通讯作者：
Herschman, Harvey R.