鉛為環境中的污染物，會增強脂多醣所引發的發炎反應，並造成實驗動物肝臟嚴重傷害。本研究的目的在探討鉛增強脂多醣所誘發之瘤壞死因子-α及肝臟傷害的機制。以尾靜脈注射方式，單獨投予大鼠不同劑量的醋酸鉛(0、5、10、15 mg/kg)或合併投予脂多醣(100 µg/kg)，量測其血液中腫瘤壞死因子-α的濃度、一氧化氮產量、脂質過氧化程度和肝功能受損指標天門冬酸轉胺以及氨基丙酸轉胺，建立鉛增強脂多醣腫瘤壞死因子的活性及肝臟傷害的機制，並以抑制劑阻斷的方式，來探討醋酸鉛合併脂多醣所誘導的訊息傳遞路徑。結果顯示，單獨給予不同劑量的鉛，對各項量測指標並無顯著的影響；在合併脂多醣後，大鼠血中瘤壞死因子-α、一氧化氮產量、脂質過氧化程度及肝臟傷害明顯增加。投予1400W (5 mg/kg)來抑制一氧化氮的產生後，鉛合併脂多醣所造成的腫瘤壞死因子-α 、脂質過氧化和肝臟傷害均會減緩。Pentoxifylline (100 mg/kg)可顯著降低腫瘤壞死因子-α並減緩肝臟傷害。然而，無法有效降低一氧化氮生成和脂質過氧化程度。以gadolinium chloride (10
mg/kg)抑制巨嗜細胞後，則會減緩血液中一氧化氮產量、腫瘤壞死因子-α的濃度、脂質過氧化和肝臟傷害。大鼠於共同暴露前分別投予chelerythrine chloride(5 mg/kg)和U0126 (50 µg/kg)，抑制活化PKC和MEK的訊息傳導，均可減緩血液中腫瘤壞死因子-α的濃度、一氧化氮產量、脂質過氧化和肝臟傷害。總之，在大鼠實驗的結果顯示，高鉛暴露具有加成性地增強脂多醣所誘導的肝臟傷害，可能是經由刺激巨嗜細胞的作用，循著PKC和ERK的訊息途徑，來促進腫
瘤壞死因子的過度表現和一氧化氮的增加所致，其中一氧化氮的增加會造成脂質過氧化作用。

　　Lead (Pb) increases lipopolysaccharide (LPS)-induced tumor necrosis factor-α (TNF-α) over-expression and liver damage. In this study, the effects of TNF-α over-expression and liver damage induced by co-exposure of Pb/LPS in the rat model were investigated. Co-exposure of Pb (0, 5, 10 and 15 mg/kg; i.v.) and LPS (100 µg/kg; i.v.)-stimulated TNF-α, nitric oxide (NO), lipid peroxidation (LPO), aspartate aminotransferase (AST), and alanine
aminotransferase (ALT) were determined in vivo. The levels of TNF-α, NO, LPO, AST, and ALT level were synergistically increased upon Pb/LPS co-exposure in rats. Several inhibitors were used to examine the possible factors involved in TNF-α over-expression and liver damage in the Pb (10 mg/kg)/LPS (100 µg/kg)-treated rats. Pretreatment with the iNOS inhibitor 1400W (5 mg/kg) reduced NO, TNF-α, LPO, AST, and ALT in Pb/LPS-exposed rats. Pentoxifylline (a TNF-α inhibitor100 mg/kg) significantly decreased TNF-α, AST, and ALT, but not NO and LPO. GdCl3 (a macrophage inhibitor, 10 mg/kg) significantly decreased TNF-α, NO, LPO, AST, and ALT. Chelerythrine chloride (a protein kinase C inhibitor, 5 mg/kg) and U0126 (a mitogen-activated protein or extracellular signal-regulated kinase inhibitor, 50 µg/kg) decreased the TNF-α, NO, LPO, ALT, and AST in Pb/LPS-treated rats. These in vivo experiments indicate that Pb-enhanced hepatotoxicity induced by LPS may be due to stimulation of macrophages through PKC and ERK which lead to over-expression of TNF-α and NO; furthermore, increased NO results to LPO.

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