Interleukin-1（IL-1）為一種自發性免疫反應中產生的促發炎因子，IL-1會與其特有的受體結合並誘導一連串的發炎反應。本研究探討此第一型IL-1受體（type-1 IL-1R）在小鼠由綠膿桿菌引發肺炎時所扮演的角色，將綠膿桿菌注入正常（WT）和第一型IL-1受體缺失（IL1R-/-）小鼠的氣管後，於8小時至24小時觀察其肺部微血管滲漏、MPO活性、NF-κB的表現、iNOS、IL-1β以及其他前促炎因子的表現。結果顯示在注入菌8小時後，WT小鼠所誘發的發炎反應皆比IL1R1-/-小鼠高，但IL1R1-/-小鼠在24小時後的存活率卻比WT小鼠低。當研究IL1R1-/-小鼠高死亡率的原因時，發現IL1R1-/-小鼠肺部及血中的含菌量均較WT小鼠有明顯的增加，而由PMN吞噬活性的實驗顯示WT與IL1R1-/-小鼠的PMN的噬菌活性沒有差異。進一步利用基因嵌合小鼠證實引發IL1R1-/-小鼠肺炎的細菌轉移至血液並無法由PMN清除。同樣的，在24小時時，IL1R1-/-小鼠肺部微血管的滲漏情形也較WT嚴重，當在小鼠引發肺炎後8小時給予iNOS抑制劑SMT時，可減少IL1R1-/-小鼠在引發肺炎後24小時的肺部通透性、死亡率、肺部和血中的含菌量，證實IL1R1-/-小鼠的肺部iNOS表現並造成肺部通透性上升係造成高死亡率的主因，同時顯示此實驗模式下所引發的菌血症及死亡可藉由調控iNOS的活性而改善。

IL-1 is an essential pro-inflammatory factor in inflammation response. The effect of IL-1 is through binding to the IL-1 receptor that triggers the following signal transduction pathway. To study the role of IL-1 receptor-mediated signal pathway in inflammatory response, injecting P. aeruginosa into trachea of wild-type (WT) and type-1 IL-1 receptor knock-out (IL-1R1-/-) mice was used as the experimental model. Injecting bacterium into trachea of mice will induce pneumonia which increases accumulation of neutrophils, production of nitric oxide, expression of intercellular adhesion molecule-1 as well as many kinds of cytokines and causes the lung damage. The pneumonia-induced lung damage and inflammation at 24 hr after injecting P. aeruginosa into trachea were more severe in knock-out than in WT mice, as demonstrated by increases in extravasations of Evans blue dye (EBD), myeloperoxidase (MPO) activity, expression of iNOS, IL-1 beta and ICAM-1, and higher mortality of knock-out mice. The cause of the high mortality in knock-out mice was further investigated by culturing the lung and blood samples for bacterial counts. The bacterial counts of lung and blood of IL-1R1-/- mice were all higher than that of WT mice in 8 to 24 hr after injection of bacterium. Finally, chimeric mice (WT → WT, IL1R1-/- →IL1R1-/-, WT → IL1R1-/-, IL1R1-/- → WT) were generated and used to determine the role of PMN cells of blood. Suggesting that increased amounts of bacteria in lung and blood is related to the higher mortality in knock-out mice and the type-1 IL-1 receptor is essential for mice to against pneumonia in this model.

Abstract in Chinese .......................................................................... 3
Abstract in English ........................................................................... 4
Introduction ...................................................................................... 5
Materials and Methods ..................................................................... 12
Results .............................................................................................. 20
Discussion ......................................................................................... 25
Figures .............................................................................................. 31
References ........................................................................................ 42

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