Abstract
摘要:組織及細胞受損時會引起急性之發炎反應(可稱作無菌性發炎反應)。雖然組織細胞受損所誘發之發炎反應具有對抗可能存在之微生物感染,清除死亡細胞以及促進組織之修復等功能,進入發炎組織中之白血球也會釋放出有毒物質,而對正常細胞造成傷害,進而導致許多疾病之發生。受損細胞如何引起發炎反應之機轉仍不清楚,本計畫的目標是探討細胞受損時引起發炎反應之機轉,並根據我們的研究結果,對發炎反應進行調節,以期減低發炎反應對組織造成之傷害與發炎疾病之惡化。
我們認為當細胞受損死亡時,會發生以下三個步驟而促使發炎反應進行。首先,死亡細胞會釋出一些能刺激發炎反應之物質(或稱作damage-associated molecular patterns, DAMPs) ,接著DAMPs將刺激組織中的一些先天免疫細胞活化,而被這些被活化的細胞可進一步釋放出能促進發炎反應之細胞激素及趨化激素,進而活化血管內皮細胞,使得血液中之白血球能進入到受損組織中。我們先前的研究發現尿酸 (uric acid)在細胞死亡時濃度會上升,並可扮演DAMP的角色而引起發炎反應(Journal of Clinical Investigation, 2010, 120: 1939-49)。另外我們過去的研究也指出,IL-1α之產生及IL-1受體之活化在發炎反應過程中,對於嗜中性球進入發炎組織,扮演著相當重要的角色 (Nature Medicine 13:851-856)。
在本研究計畫中,我們繼續探討細胞受損所引起之發炎反應及發炎疾病之機轉。我們將針對下以下三個方向進行探討。(一) 探討肥大細胞與巨噬細胞在無菌性發炎反應中扮演的角色。(二) 探討腫瘤壞死因子-α (TNF-α)在無菌性發炎反應中扮演之角色。(三) 探討TREM-1及C5a在無菌性發炎反應中扮演之功能。
Abstract: Tissue and cell injury stimulate acute inflammation and this response is thought to contribute to the pathogenesis of many diseases. The inflammatory response to dying tissues is thought to promote several functions, such as alerting the immune system to a potential infection and recruiting leukocytes to remove the dead cells and stimulate tissue repair. While these aspects of the inflammatory response are beneficial, the recruited leukocytes can also damage healthy cells. Although it has been known for a long time that tissue and cell injury can trigger sterile inflammation, the underlying mechanism has just begun to be understood. Our long-term goal is to elucidate the mechanisms of sterile inflammation triggered by cell injury, and hopefully based on our research finding, we will be able to design therapeutic strategies to modulate the response and to reduce tissue damage.
We hypothesize that when cells receive injury and undergo necrosis, three major stages are followed to trigger the inflammatory response. First, dying cells must express or release proinflammatory molecules (also called damage-associated molecular patterns; DAMPs). Upon the release of DAMPs, the next stage involves the sensing of DAMPs by cellular sensors in the local tissue. For the sterile inflammatory response to ensue, the activated cellular sensors need to produce proinflammatory mediators including cytokines and chemokines, which then act on the vascular endothelium and recruit the blood leukocytes into the injured tissue. Our previous data indicate that uric acid is a DAMP released from dying cells and contributes significantly to the cell death-induced inflammatory response (Journal of Clinical Investigation, 2010, 120: 1939-49). We have also identified that IL-1α production and IL-1 receptor 1 (IL-1RI) activation play pivotal roles in mediating the neutrophilic inflammatory response (Nature Medicine, 2007, 13:851-856).
In this project, we will continue to explore the mechanisms underlying the sterile inflammatory response and the diseases associated with it. To achieve our goals, three Specific Aims are proposed in this project: (1) To characterize the role of macrophages and mast cells in sensing the mediating sterile inflammation, (2) To determine the role of TNF-α in mediating the sterile inflammatory response, and (3) To investigate the role of TREM-1 and C5a in sterile inflammation.
Keyword(s)
細胞受損
發炎反應
肥大細胞
巨噬細胞
腫瘤壞死因子
cell injury
inflammation
mast cell
macrophage
Tumor necrosis factor