急性腎臟傷害在臨床上是重症病患最常遇到的嚴重併發症，因此常會有較高的死亡率，甚至在加護病房中的死亡率高達50%以上；臨床上如使用腎毒性藥物、橫紋肌溶解、鐵中毒以及敗血症等都是引起嚴重急性腎臟傷害的重要原因；目前對於急性腎臟傷害的治療主要仰賴支持性療法與藥物處理，不僅仍效果有限，更可能會產生藥物腎毒性等副作用。天然物主要是由自然界有機生物體取得的化合物或物質，如芝麻油、芝麻酚或蠅蕈醇等；已有許多研究嘗試利用天然物來做為預防或治療發炎性疾病如全身性發炎與敗血症，以及保護器官傷害，目前已知保護機制主要為透過降低氧化壓力、促使細胞自噬或細胞凋亡；此外，神經免疫系統也被認為在抗發炎反應中扮演重要的角色，然而，天然物對全身性發炎反應以及器官傷害的作用及其機制仍然不清楚。因此，本研究目的為：一、探討芝麻油對小鼠鐵中毒所引起急性腎臟傷害的影響；二、探討芝麻酚對大鼠經多種微生物感染所引起全身性發炎反應及其急性腎臟傷害的作用；三、探討蠅蕈醇對敗血症小鼠所引起急性腎臟傷害以及全身性發炎反應的影響及其調控機制。研究第一部份，主要利用胺三醋酸鐵(ferric nitrilotriacetate)誘導小鼠產生急性腎臟傷害；小鼠經誘導後一小時，血中尿素氮與肌酸酐含量明顯被增加，而芝麻油在第三與第六小時均可明顯降低血中尿素氮與肌酸酐含量，本研究總結為芝麻油可保護小鼠經鐵中毒所引起的急性腎臟傷害。研究第二部分，主要利用盲腸結紮穿刺術誘導大鼠產生多種微生物感染；芝麻酚可明顯降低血中尿素氮、肌酸酐與嗜中性白血球明膠相關性脂質運載蛋白含量，抑制腫瘤壞死因子-a(tumor necrosis factor-a, TNF-a)、介白素-1b (interleukin-1b, IL-1b)與IL-6含量；芝麻酚亦可明顯抑制髓過氧化物酶活性；此外，芝麻酚也可明顯增加大鼠經盲腸結紮穿刺術誘導感染後的存活率；總結本研究，芝麻酚可藉由抑制嗜中性球所引起的全身性發炎反應，進而減緩大鼠經多種微生物感染後所產生的急性腎臟傷害並進一步增加存活率。研究第三部分，蠅蕈醇可明顯增加敗血症大鼠存活率、降低尿素氮與肌酸酐含量、降低腎臟與血液中發炎物質TNF-a、IL-1b、IL-12與一氧化氮含量、並增加抗發炎物質IL-10生成；此外，蠅蕈醇可明顯降低NF-kB (nuclear factor kappa B)活性，增加IkB (inhibitor of NF-kB)與降低磷酸化IKK (inhibitor of IkB kinase)的蛋白質表現；在r-氨基丁酸(gamma-aminobutyric acid, GABA)調控路徑，以GABAA受體拮抗劑處理後，會增加IL-1b, IL-12以及IL-10含量；而在給予GABAA受體協同劑處理後，會抑制經蠅蕈醇處理的敗血症小鼠血中發炎物質的含量；而不論給予GABAC受體之拮抗劑或是協同劑處理，均會增加血中TNF-a、IL-1b、以及IL-10含量；在膽鹼性抗發炎調控路徑，給予尼古丁乙醯膽鹼受體(nicotinic acetylcholine receptors, nAChRs)拮抗劑處理後，會明顯降低TNF-a、IL-1b、IL-12以及IL-10含量，但給予nAChRs協同劑處理則沒有任何影響。總結本研究，蠅蕈醇可能藉由調控尼古丁乙醯膽鹼受體以及刺激氨基丁酸A受體來抑制全身性發炎反應，進而減緩急性腎臟傷害並增加存活率。綜合以上結果，本研究結論為，天然物如芝麻油、芝麻酚及蠅蕈醇，可減緩因鐵中毒、多種微生物感染以及內毒素所引起的急性腎臟傷害，而神經免疫反應的調控可能參與在天然物的抗發炎作用中。

Acute kidney injury (AKI) is the most serious complications in critically ill patients in ICU in which mortality rate is more than 50%. Nephrotoxic drugs, rhadomyolysis, iron intoxication and sepsis are the common risk factors in the pathogenesis of AKI. Supportive therapy and medications are major treatments in AKI patients; however, the side-effects have been reported. Natural products, such as sesame oil, sesamol, and muscimol, have been demonstrated that can prevent and treat inflammatory diseases, as well as protect organ injury. Alothough oxidative stress, autophagy, and apoptosis are included in the protective effects of natural products. The exact mechanism of natural products on inflammatory response and organ injury is still unclear. The purposes of present study were (i) to examine the effect of sesame oil on AKI in iron-intoxicated mice; (ii) to examine the effect of sesamol on systemic inflammatory response-associated AKI in polymicrobial infectious rats; and (iii) to examine the effect and possible mechanisms of muscimol on renal injury and systemic inflammatory response in septic mice. In the part I of this study, mice AKI was induced by ferric nitrilotriacetate (FeNTA). One hour after the FeNTA injection, serum blood urea nitrogen (BUN), creatinine (CRE) levels were significantly increased in FeNTA-treated mice. Sesame oil significantly decreased BUN and CRE levels 3 and 6 hours after the FeNTA injection. We suggested that a single dose of subcutaneous sesame oil injection may have therapeutic effects against iron-induced AKI in mice. In the part II of this study, rats polymicrobial infection was induced by cecal ligation and puncture (CLP). Sesamol significantly decreased the levels of BUN, CRE, neutrophil gelatinase-associated lipocalin, myeloperoxidease activity, and pro-inflammatory cytokines including tumor necrosis factor (TNF)-a, interleukin (IL)-1b, and IL-6. In addition, sesamol significantly increased the survival rate in CLP-induced polymicrobial infectious rats. We suggested that sesamol may increase survival rate and attenuate AKI by inhibiting neutrophil-initiated systemic inflammation in polymicrobial infectious rats. In the part III of this study, experimental sepsis was induced by lipopolysaccharide (LPS) and CLP. Muscimol significantly increased survival rate in both LPS- and CLP-induced mice. Muscimol decreased the levels of BUN, CRE, TNF-a, IL-1b, IL-12, and nitrite, but increased IL-10 levels in kidney tissue and serum. Muscimol decreased NF-kB activity and pIKK protein expression, as well as increased the expression of IB. Blockage of gamma-aminobutyric acid A receptors (GABAARs) increased IL-1b, IL-12, and IL-10 levels in muscimol-treated septic mice. While the stimulation of GABAARs showed a synergistically inhibition of inflammatory mediators. The levels of TNF-a, IL-1b and IL-10 were increased after GABACRs antagonist or agonist treatment. In addition, nicotinic acetylcholine receptors (nAChRs) antagonist decreased serum TNF-a, IL-1b, IL-12, and IL-10 levels, while nAChRs agonist failed to affect the levels of circulating inflammatory cytokines in endotoxemic mice. We suggested that muscimol may attenuate AKI and increased survival rate by inhibiting systemic inflammatory response in septic mice, which may be modulated by nAChRs and GABAA receptors. In conclusion, natural products, including sesame oil, sesamol, and muscimol, could attenuate AKI induced by iron intoxicity, polymicrobial infection, and LPS. Further, regulating neuroimmune response may be involved in the anti-inflammatory effects exerted by natural products.

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