- 學位論文
肥大細胞在細胞受損引起之無菌發炎反應中所扮演的角色
Identification of the role of mast cell in sterile inflammation induced by necrotic cell
摘要
細胞壞死後會釋出的許多物質會引起體內的急性發炎反應，這種類型的發炎反應稱為無菌發炎反應，所引起的發炎反應其目的為移除細胞殘骸，避免造成周圍組織持續性的傷害，以及恢復組織內恆定。但是過多的白血球聚集到發炎反應部位卻反而對周圍正常細胞組織造成傷害，並引起許多相關疾病產生。而目前對於無菌發炎反應的機制並未能完全了解，在本研究中，我們使用三種無菌發炎反應模式來探討肥大細胞於發炎反應中的影響。 首先在壞死細胞引發的腹膜炎模式中，實驗結果顯示嗜中性球和單核球浸潤至腹膜中的數量在肥大細胞缺陷WBB6F1(KitW/KitW-v)小鼠中有明顯的減少，但若將由正常小鼠骨髓分化出之肥大細胞移植入此缺陷小鼠，則使嗜中性球和單核球的數量則有明顯的提升。 另外，在acetaminophen(AAP)和concanavalin A(ConA)所誘導的肝炎反應中，肥大細胞缺陷小鼠肝受損的程度以及發炎反應上都有明顯的下降，且在移植入正常之肥大細胞後，肝受損和發炎反應程度都較原本缺陷小鼠來的嚴重。在體外試驗中，壞死細胞可以活化由骨髓分化之肥大細胞，使之釋放細胞激素和及進行去顆粒化作用。 由本研究結果顯示，肥大細胞在細胞壞死所引起的發炎反應中佔有重要地位，因此如能對於肥大細胞的功能進行調節，也許可以應用於治療無菌性之發炎疾病上。
並列摘要
Cell death in vivo releases intracellular components which induce an acute sterile inflammatory response. The physiological function of the sterile inflammatory response is to eliminate cell debris and restore tissue homeostasis; however the leukocytes accumulated in inflammed tissues may cause harm to healthy cells. Detailed mechanisms for causing the sterile inflammatory response are not fully elucidated. In this study, we used three sterile inflammatory mouse models to examine the role of mast cell in necrosis-induced inflammation. In the necrotic cell-induced peritonitis model, the number of neutrophils and monocytes infiltrated was remarkably reduced in mast cell deficient mice (W-/V-) compared to in the wild-type mice (WBB6F1), and the inflammatory response could be restored in in W-/V- mice receiving bone marrow-derived mast cells (BMMCs) (mast cell knockin mice). In addition, we investigated the effect of mast cell on hepatitis induced by acetaminophen (AAP) and concanavalin A (ConA). In both AAP and ConA models, mast cell deficient mice showed attenuated liver injury and neutrophil infiltration into liver, which were recovered in the mast cell knockin mice. We also found that necrotic cells could activate BMMCs to degranulate and release cytokines in vitro. Our results indicate that mast cells play a key role in regulating the inflammatory responses to cell death and therapeutic strategies targeting mast cells could be considering for treating diseases associated with sterile inflammation.