巨噬細胞及 TNF-α 在受損細胞引起的無菌發炎反應中扮演的角色

在發炎反應中，組織中的巨噬細胞常負責辨識外來病原菌或物質，活化後能夠釋出發炎相關細胞激素 (cytokine) 進一步引起發炎反應。本篇研究中，我們首先研究 C5aR (C5a receptor) 在受損細胞引起腹膜炎的無菌發炎模式中扮演的角色。結果顯示 C5aR 缺陷小鼠，腹腔中嗜中性白血球滲入 (neutrophil infiltration) 的情形與野生型小鼠 (wild-type) 無異。接著我們以包覆 clodronate 的微脂體 (liposome) 去除小鼠腹腔中巨噬細胞，觀察巨噬細胞是否參與在受損細胞引起小鼠的腹膜炎中。結果顯示，將受損細胞以腹腔注射引起小鼠腹膜炎後，去除腹腔中巨噬細胞的小鼠其腹腔中嗜中性白血球聚集的情形有顯著降低。　　另外，我們也利用 AAP (acetaminophen) 造成的肝臟細胞壞死，作為體內組織受損模式，來研究 TNF-α 在受損細胞引起發炎反應中扮演的角色。在這個體內組織受損模式中，TNFR1 (TNF-α receptor 1) 缺陷小鼠中以腹腔注射給予過量 AAP 後，不管是血清中肝功能指數 (ALT activity)、嗜中性球聚集情形、及發炎相關細胞激素的釋放 (TNF-α, IL-1α, IL-1β, IL-6, and KC) 的情形都有顯著降低。而 TNF-α 缺陷小鼠對於 AAP 引起的肝細胞壞死及發炎反應也都有明顯的保護效果。在注射入 AAP 的前一天，若給予小鼠阻斷 TNF-α 訊息傳遞的藥物 “ Enbrel ”，則能有效降低 AAP 引起的肝細胞壞死及其引起的發炎反應。由以上結果可知，TNF-α 參與在由 AAP 引起的肝臟損傷中。而阻斷 TNF-α 的訊息傳遞可能成為有效治療 AAP 引起肝細胞受損的策略。

關鍵字

細胞受損；發炎；巨噬細胞； clodronate ；腫瘤壞死因子-α ； acetaminophen

並列摘要

Cell death in vivo provokes a severe sterile inflammatory response. The rising inflammatory response is necessary to remove cell debris, but neutrophil accumulation in inflamed tissue also causes harm to adjacent normal cells and tissues. We first examined the effect of C5aR on necrosis-induced peritonitis. However, there was no difference in the number of neutrophil infiltration in the peritoneal cavity between C5aR-deficient and WT mice. Since resident macrophages are considered to play a key role in initiating inflammatory responses, we also investigated the involvement of resident macrophage in the peritonitis model. By directly depleting macrophages using clodronate liposome, we found that resident macrophages have an important role in the acute neutrophilic inflammatory response to cell injury. In mice pretreated with clodronate-liposome, the neutrophilic inflammatory response to necrotic cells was significantly attenuated. In this study, we also investigated the role of TNF-α in an in vivo model of necrosis-induced inflammation performed by AAP administration. Mice lacking TNFR1 or TNF-α were resistant to AAP-induced liver injury and showed a markedly reduced neutrophilic inflammatory response. Moreover, pretreatment with Enbrel (soluble TNFR2 fusion protein) would also prevent AAP-induced hepatotoxicity. These results demonstrated that the inflammatory mediator TNF-α participated in AAP-induced liver failure and the TNF-α blocker Enbrel was suggest to have the therapeutic potential in treating AAP overdose induced hepatitis.

並列關鍵字

Cell injury ； inflammation ； macrophage ； clodronate-liposome ； TNF-α ； acetaminophen (AAP) ； Enbrel (etanercept)

參考文獻

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巨噬細胞及 TNF-α 在受損細胞引起的無菌發炎反應中扮演的角色

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