魚油對敗血症小鼠發炎反應及粒線體功能之影響

敗血症 (sepsis)為臨床上常見因感染所引發之病症，其死亡率高達30-70 %。敗血症晚期發生敗血性休克，主要的死亡原因為多重器官衰竭，而促發炎物質的過度產生及粒線體功能異常被認為在多重器官衰竭的病理過程中扮演重要的角色。本實驗是探討在飲食中補充魚油對敗血症小鼠發炎反應及粒線體功能之影響。將雄性ICR小鼠分成兩組 (n=60)，分別為給予含10 %大豆油的控制組 (C)、2.5 %魚油混合7.5 %大豆油組 (FO)，在FO組飼料中n-3:n-6脂肪酸的比例為1:2。餵養三週後進行盲腸結紮穿刺手術 (cecal ligation and puncture, CLP)引致敗血症，並於第0、6、及24小時犧牲動物，取其血液、腹腔沖洗液 (peritoneal lavage fluid, PLF)、肝、肺、及腎進行分析。結果顯示FO組在PLF中 prostaglandin (PG) E2及tumor nercrosis factor (TNF)-α濃度及在敗血症後第6和24小時血漿中FO組之TNF-α及亞硝酸鹽 (nitrite)濃度皆顯著低於C組。CLP後第6小時FO組器官中骨髓過氧化酶 (myeloperoxidas, MPO)活性顯著低於C組。敗血症後FO組肝臟中PPAR-γ轉錄活性顯著高於C組，而FO組p65 (NF-κB subunit) 、 inducible nitric oxides synthase (iNOS)蛋白質表現量及nitrotyrosine的濃度則皆顯著低於C組。C組肝臟粒線體酵素活性在敗血症早期顯著降低，而FO組NADH cytochrome c reductase (NCCR)、succinate cytochrome c reductase (SCCR)及cytochrome c oxidase (CCO)活性皆顯著高於C組。本實驗結果顯示飲食中補充魚油可增加敗血症小鼠PPAR-γ轉錄活性並降低體內促發炎激素之濃度，且維持肝臟粒線體電子傳遞鏈之酵素活性。

關鍵字

敗血症；魚油； PPAR-γ ；骨髓過氧化酶粒線體； nitrotyrosine

並列摘要

Sepsis is a common clinical disease induced by infection and multiple organ dysfunction syndrome (MODS) is the main cause of death in the late phase of septic shock. Overproduction of pro-inflammatory mediators and mitochondrial dysfunction are thought to play important roles in pathogenesis of MODS. This study investigated the effects of dietary fish oil on inflammatory response and hepatic mitochondrial function in a cecal ligation and puncture (CLP)-induced septic mice model. Male ICR mice were assigned to a control group (C) and the fish oil group (FO) (n=60). Mice in the C group were fed with a semi-purified diet with 10% soybean oil, and those in the FO group was fed with a fish oil diet (2.5% fish oil+ 7.5% soybean oil; w/w). The ratio of n-3/n-6 fatty acid was 1:2 in FO group. Three weeks later, blood, peritoneal lavage fluid (PLF), livers, lung, kidney, and intestine were harvested at 0, 6 and 24 h after CLP, respectively. Compared with C group, the FO group showed a lower prostaglandin (PG) E2 and tumor necrosis factor (TNF)-α in PLF. Also, plasma levels of TNF-α and nitrite were lower at 6 and 24 h after CLP. The FO group had lower organs myeloperoxidase (MPO) activities at 6 h after CLP. The transcriptional activity of peroxisome proliferators-activated receptor (PPAR)-γ was up-regulated while NF-κB p65 subunit, iNOS protein expression and the concentration of nitrotyrosine were significantly decreased in FO group than C group in liver homogenate after CLP. Hepatic mitochondrial respiratory chain enzyme activities were suppressed during early stage of sepsis in C group. The rotenone-sensitive NADH cytochrome c reductase, succinate cytochrome c reductase and the cytochrome c oxidase activities were higher in the FO group at 6h after CLP. The morphology showed enlargement of hepatic mitochondria during early stage of sepsis. These results suggest that mice fed with fish oil up-regulate the transcriptional activity of PPAR-γ, reduce pro-inflammatory mediator levels and maintain hepatic mitochondrial electron-transport chain enzyme activities in septic mice.

並列關鍵字

sepsis ； fish oil ； PPAR-γ ； myeloperoxidase ； mitochondria ； nitrotyrosine

參考文獻

Adrie C, Bachelet M, Vayssier-Taussat M, Russo-Marie F, Bouchaert I, Adib-Conquym M, Cavaillon JM, Pinsky MR, Dhainaut JF, Polla B. Mitochondrial membrane potential and apoptosis peripheral blood monocytes in severe human sepsis. Am J Respir Crit Care Med 2001; 164: 389-395.

Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001; 29: 1303-1310.

Abdelrahman M, Sivarajah A, Thiemermann C. Beneficial effects of PPAR- ligands in ischemia–reperfusion injury, inflammation and shock. Cardiovasc Res 2005; 65: 772-781.

Avontuur JA, Stam TC, Jongen-Lavrencic M, van Amsterdam JG, Eggermont AM, Bruining HA. Effect of L-NAME, an inhibitor of nitric oxide synthesis, on plasma levels of IL-6, IL-8, TNF alpha and nitrite/nitrate in human septic shock. Intensive Care Med 1998; 24: 673-679.

Bone RC, Grodzin CJ, and Balk RA. Sepsis: a new hypothesis for pathogenesis of the disease process. Chest 1997; 112: 235-243.

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魚油對敗血症小鼠發炎反應及粒線體功能之影響

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