系統性發炎在病理上為關鍵性的症狀，其與多重器官衰竭和敗血症等多種人類疾病高度相關，但臨床上對於系統性發炎仍缺乏明確的治療策略。生理與飲食上的代謝物具有調控發炎與發炎相關疾病之功能，我們認為生理與飲食代謝物可能可控制發炎反應並抵抗系統性發炎疾病。甘油二酯(Diacylglycerol, DAG)為飲食中常見的脂肪酸之一，其具有三種不同立體化學結構，分別為sn-1,2-DAG、sn-2,3-DAG與sn-1,3-DAG。儘管文獻指出飲食中的DAG可調控慢性發炎相關疾病，但其參與的調控機制目前仍未被詳細研究。本篇論文中，我們發現sn-1,2-DAG可抑制脂多醣(Lipopolysaccharide, LPS)在RAW 264.7細胞與腹腔巨噬細胞(peritoneal macrophage)中誘導的COX-2表現與細胞素(cytokine)生成。而在小鼠模式實驗中，sn-1,2-DAG亦可抑制LPS在小鼠中造成的細胞素風暴(cytokine storm)與趨化因子(chemokine)生成，進而保護小鼠免於受到LPS產生的系統性發炎反應而死亡。此外，sn-1,2-DAG可藉由抑制LPS所誘導的Akt與p38活化，進而調控NF-κB，以減少COX-2與發炎相關細胞素的生成。因此，我們認為sn-1,2-DAG可調控LPS誘導的發炎反應能力，並具控制系統性發炎反應之潛力。除了飲食，生理的代謝產物也可能具有調控系統性發炎反應的功能，內皮組織對於調節發炎反應恆定、控制系統性發炎反應與啟動發炎反應上扮演重要角色，我們猜測內皮細胞可能藉由釋放可溶性小分子來調控發炎反應的恆定。實驗結果指出，內皮細胞的條件培養基 (endothelial cells conditioned medium)可抑制LPS在巨噬細胞所誘導的COX-2與細胞素生成。利用代謝質譜分析後發現一具有潛力的分子，5-甲氧基色胺酸(5-methoxytryptophan, 5-MTP)。值得注意的是，LPS所誘發的發炎反應會降低內皮細胞、小鼠、以及敗血症病患體內的5-MTP生成，而在利用腹腔注射給予小鼠5-MTP後，會提高小鼠血液中的5-MTP濃度以產生保護作用，減輕LPS或CLP手術所誘發之敗血症狀，並降低小鼠的死亡率。因此，我們認為內皮細胞會藉由釋放5-MTP來控制發炎反應，以維持免疫反應的恆定性。總結而言，本篇論文證實外生性的sn-1,2-DAG與內皮細胞所產生的5-MTP可用於調控、對抗過度發炎反應，除可作為營養補給以預防系統性發炎反應外，亦具有治療系統性發炎相關疾病的潛力。

Systemic inflammation has emerged as a key pathophysiological process that induces multi-organ injury and causes many diseases such as sepsis. Unfortunately, specific clinical treatment of controlling systemic inflammation is still lacking. Physiological metabolites and dietary metabolites are thought to play an important role in modulating inflammation and inflammatory diseases. We postulated that physiological and dietary metabolites might modulate inflammatory responses and protect against systemic inflammation. Diacylglycerols (or "diglycerides", DAGs) are natural components of vegetable oils and are extensively used in food oil as an emulsifier. They exist in three stereochemical forms, sn-1,2- and sn-2,3-diacylglycerols and sn-1,3-diacylglycerols. Despite substantial evidence supports the role of exogenous DAG in modulating chronic inflammation and chronic diseases, the potential mechanisms of it in metabolic inflammation modulation remains to be investigated. We find that sn-1,2-DAGs pretreatment suppresses LPS/TLR4-induced cyclooxygenase-2 (COX-2) expression and cytokines production in macrophages, but has no significant effect on other TLRs. Furthermore, sn-1,2-DAGs treatment improves the survival rate in LPS-induced lethal endotoxemic mice by suppressing proinflammatory cytokines and chemokines production. sn-1,2-diacylglycerols alleviate systemic inflammation by inhibiting LPS-induced p38 MAPK- and PI3K/AKT- mediated NF-κB activation in macrophages. Collectively, exogenous sn-1,2-diacylglycerol protects mice against LPS-induced lethal endotoxemia by suppressing TLR4-driven inflammatory responses. As dietary metabolites, endogenous physiological metabolite may have the ability to control systemic inflammation. Endothelium is critical in maintaining inflammatory homeostasis, controlling systemic inflammation, and progression of inflammatory diseases. We postulated that endothelium produces and releases endogenous soluble factors to modulate inflammatory responses and protect against systemic inflammation. The results indicate endothelial cells conditioned medium suppressed LPS-induced proinflammatory cytokines and COX-2 expression in macrophages. Using metabolic approach, we identified that the potential effective molecule is 5-methoxytryptophan (5-MTP). Furthermore, endothelial cells-derived 5-MTP suppressed LPS-induced inflammatory response in macrophages and endotoxemic lung tissues. Notably, LPS depressed 5-MTP production in endothelial cells and reduced serum 5-MTP level in the endotoxemic mice and patient with sepsis. Intraperitoneal injection of 5-MTP increased the serum level of 5-MTP and rescued mice from LPS- and CLP-mediated lethal systemic inflammation. These results suggest that endothelial cells produce 5-MTP to control the homeostasis of the inflammatory response. In summary, this study demonstrated that exogenous sn-1,2-diacylglycerol and endothelium-derived 5-MTP are capable of defending against excessive systemic inflammatory responses and may be useful as a dietary health supplements for prevention or therapy of systemic inflammatory diseases.

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