燒燙會引起發炎反應進而使小腸屏蔽功能失常，而導致多重器官衰竭。 之前的研究報告指出，燙傷之後的器官損傷，與iNOS的表現量有密切相關，而iNOS的表現受到NF-κB的活化所調控，而NF-κB的活化由上游的MAPKs所調控，發炎反應的產生與促發炎細胞素的作用有密切相關，藉由細胞素與其接受器的結合而開啟訊息傳遞路徑，進而影響MAPKs的活化，接著影響NF-κB 的活性，再促使iNOS的基因表現。本研究探討其中一種促炎細胞素Interleukin-1的接受器 (IL-1R) 在老鼠受燙傷後經由訊息傳遞路徑的影響，而造成器官損傷的過程中所扮演的角色。實驗中，藉由將老鼠背部進行體表面積30~35 % 的燙傷，觀察其小腸黏膜通透性的變化，另外取小腸黏膜進行實驗分析，利用Immunoblotting 偵測MAPKs 活化的情形及iNOS的表現量，用EMSA 偵測NF-κB活化的情形，在wild type (WT)的老鼠在燙傷後，受到活化的MAPKs中，ERK及p38扮演主要的調控角色，它們的磷酸化現象伴隨NF-κB活化情形的增加，iNOS的表現量跟著增加，而腸道通透性跟著增加。但卻發現在缺乏IL-1 R 的老鼠受燙傷之後，腸道通透性沒有改變， 其ERK、p38與NF-κB活化的情形減少，iNOS的表現量也較WT少，而WT在利用U0126 阻斷MEK1/2對ERK的活化之後，腸道損傷的情形、ERK的活化與iNOS的表現明顯減少，因此由實驗結果推論，IL-1 R 在老鼠燙傷後，扮演一個經由活化MAPK 而調控NF-κB，促使iNOS增加而導致腸道通透性增加，進而引起器官損傷的角色。

Burn induces the inflammation response, and causes the intestinal barrier failure. The failure of intestinal barrier may cause organ damage. Pervious studies have shown that the increase of iNOS activity is closely related to the organ damage after burn. The expression of iNOS is regulated by the activation of NF-κB, and that is regulated by MAPKs. The pro-inflammatory cytokines play important roles to promote the inflammation through activating a series of signal transduction cascade, via binding to their receptors on cell membrane. The signal transduction cascades are turn on, MAPKs and NF-κB are activated and the expression of iNOS is promoted. In this study, the role of pro-inflammatory cytokine interleukin-1 receptor (IL-1R) in burn induced intestinal damage was focused on. In experiments, the animals (C57BL/6 mice) were undergone 30~35 % total body surface area (TBSA) burn. The change of intestinal permeability was examined, and intestinal mucosa was assayed for the activation of iNOS and MAPKs by immunoblotting, and the activation of NF-κB was detected by EMSA. The results reveal that activation of NF-κB, intestinal permeability and expression of iNOS were increased after burn in wild type mice (WT). ERK MAPK plays an important role to regulate the activation of NF-κB and expression of iNOS. Surprisingly, the permeability had no change after burn in IL-1R knock out mice (KO). The activation of ERK, NF-κB and the expression of iNOS were also measured in KO. The levels of p-ERK, NF-κB activation and iNOS expression were low in KO. When WT mice were treated with U0126 (5 mg/kg i.p.) right after burn to block the activation of ERK, the activation of ERK and NF-κB, the expression of iNOS, and the intestinal permeability were all decreased significantly. To sum up, the changes in iNOS expression, NF-κB activation, and intestinal permeability increase are mostly related to the activation of ERK after burn. IL-1 R plays a promotion role in ERK, NF-κB activation, and iNOS expression that lead to the increase in intestinal permeability and promote damage in intestine.

Contents


Abstract in Chinese………………………………………………1

Abstract in English……………………………………………….2

Introduction………………………………………………………3

Material and Methods…………………………………………….8

Results…………………………………………………………...12

Discussion……………………………………………………….14

Figures…………………………………………………………...17

References……………………………………………………….28

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