細胞受損引起發炎反應機轉之研究

Mechanism of sterile inflammation triggered by cell injury

李威霆(Wei-Ting Li)

指導教授 ： 陳俊任

國立臺灣大學/生命科學院/微生物與生化學研究所/碩士(2009年)

https://doi.org/10.6342/NTU.2009.02058

摘要

細胞受損是引起發炎反應的原因之一，同時也是一些疾病的致病原因，其中的機制到目前為止還尚未十分明瞭，我們在這裡針對此發炎反應，探討1) IL-1α 產生的機制、2) 肥大細胞 (mast cell) 在發炎反應中的角色、3) tumor necrosis factor (TNF)-α 的功能 及 4) 嗜中性白血球 (neutrophil) 活化的機制。研究中發現 IL-1α 很可能是由壞死細胞 (necrotic cell) 中釋放出來的 damage-associated molecular pattern (DAMP)。另外，在藉由藥物 compound 48/80 使腹腔中肥大細胞缺失後，以壞死細胞誘導產生腹膜炎 (peritonitis)的模式中，發現肥大細胞缺失顯著降低腹腔中嗜中性白血球的滲入(neutrophil infiltration)，但對於單核白血球 (monocytes) 的滲入卻沒有顯著影響。另一方面，TNFR1 (TNF receptor 1) 缺陷小鼠以 acetaminophen (AAP) 誘導的肝臟損傷模式 (liver injury model) 中，結果顯示 TNFR1 缺陷小鼠相較於野生型 (wild-type)，組織損傷程度有明顯減輕，而肝組織中嗜中性白血球滲入的情形也有下降的趨勢。最後，以壞死細胞直接或間接刺激嗜中性白血球，結果顯示壞死細胞能夠直接或間接活化嗜中性白血球釋放 O2− ，這也許與壞死細胞所釋放的 IL-1α 有關。這些結果顯示了 IL-1α、肥大細胞、TNF 及嗜中性白血球的活化在細胞受損引起發炎反應的機制中，各自扮演相當重要的角色，但其中的關聯性尚需更進一步實驗證實。

關鍵字

細胞損傷 ； 發炎反應 ； 肥大細胞 ； 嗜中性白血球

並列摘要

Cell injury is one of the principal stimuli of inflammation, which leads to the pathogenesis of many diseases. Here our research aimed to further delineate the mechanisms behind this type of sterile inflammation. Our experiments were designed to address four aspects including 1) the source of interleukin-1α (IL-1α) generation, 2) the role of mast cells in inflammation, 3) the function of tumor necrosis factor (TNF)-α in sterile inflammation, and 4) the mechanisms of neutrophil activation. We found that IL-1α is potentially a damage-associated molecular pattern (DAMP) released from necrotic cells. In a cell injury-induced peritonitis model, we showed that neutrophil infiltration was markedly reduced in mice depleted of mast cells with compound 48/80. In the acetaminophen (AAP)-induced liver injury model, our data revealed that the level of injury was markedly reduced in TNFR1-deficient mice, and leukocyte infiltration was also affected. We also analyzed whether neutrophils could be stimulated by necrotic cells directly and/or indirectly, and our results showed that necrotic cells could both directly and indirectly activate neutrophils to release O2−, which might be associated with the IL-1α released from necrotic cells. Overall our findings provide new insights on how interleukin-1α (IL-1α), mast cells, and TNF-α, may play their roles in regulating the sterile inflammation induced by cell injury, and how neutrophils are activated once they are recruited to the injured site. Further studies will be carried out to support our models of how these factors link each other in the sterile inflammatory response.

並列關鍵字

cell injury ； inflammation ； interleukin-1α ； tumor necrosis factor (TNF)-α ； mast cell ； neutrophil

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