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研究生:黃彥智
研究生(外文):Evan YT Huang
論文名稱:綠膿桿菌外毒素A對大鼠腹腔巨噬細胞形態學及功能的影響
論文名稱(外文):The effect of Pseudomonas aeruginosa exotoxin A on morphology and functions of rat peritoneal macrophages
指導教授:龐飛龐飛引用關係鄭謙仁
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:獸醫學研究所
學門:獸醫學門
學類:獸醫學類
論文種類:學術論文
論文出版年:2001
畢業學年度:89
語文別:中文
論文頁數:196
中文關鍵詞:綠膿桿菌外毒素A大鼠巨噬細胞形態學功能細胞素 -1
外文關鍵詞:Pseudomonas aeruginosaexotoxin Aratmacrophagemorphologyfunctioninterleukin-1IL-1
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  • 被引用被引用:4
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摘要:
過去的研究指出外毒素A(exotoxin A, ETA)為綠膿桿菌(Pseudomonas aeruginosa)所產生最多的毒物,對宿主細胞的致害主要是因蛋白質合成之受抑制。ETA亦被證實會干擾免疫細胞的功能,巨噬細胞是炎症反應及免疫系統中的重要成員,然而有關ETA對巨噬細胞影響的相關研究卻極為有限,其中更缺乏大鼠的資料,因此在本研究中進行一系列的實驗以探討ETA對大鼠原住腹腔巨噬細胞(rat resident peritoneal macrophages, RPM)的可能免疫毒性。將RPM與0, 1, 10, 50及100 ng/ml ETA於體外共同培養 3 至 60 小時後,分別檢測其細胞存活率、MTT代謝率、大分子(含DNA、RNA及蛋白質)合成能力、細胞形態、吞菌力、殺菌力、移行能力,以及自由基、炎症介質及細胞素產生能力的變化情形。以trypan blue 色素排除法進行檢測,發現RPM的細胞存活率隨ETA劑量和培養時間的增加而下降。當就總量進行比較時,類似的下降情形也出現於MTT代謝率和DNA、RNA及蛋白質合成能力,雖然在1-50 ng/ml ETA處理組於攻毒24-36小時間,於RNA及蛋白質合成能力上有短暫的提升現象。然而就存活細胞的平均值而言,在以10-100 ng/ml 劑量攻毒12-24小時以後,其MTT代謝率和DNA、RNA及蛋白質合成能力均呈現較對照組顯著為高的現象。於形態學上,在以50 或 100 ng/ml劑量攻毒 24 小時之後,大多數的RPM均已呈現壞死或凋亡(apoptosis)。在以10 ng/ml 攻毒 24 小時後細胞存活率雖亦明顯下降,但在存活細胞的質內出現大量大小不一的顆粒。經穿透式電顯檢查,發現這些顆粒是源自於粗糙內質網的擴張與融合而成的泡狀物,其內並蓄積有具電子密度的物質,而有些細胞因內容物的排出呈空洞狀;此外偽足亦出現可逆性的塌陷和重疊。雖然1 ng/ml ETA對RPM並無明顯的形態學影響,但其蛋白質合成能力仍是隨ETA攻毒時間的延長而明顯的受到抑制。
在吞菌力及殺菌力方面,係使用念珠菌及acridine orange/crystal violet染色法來進行測定,在ETA處理組,具吞菌力的細胞數及所吞的念珠菌芽胞總數均隨攻毒劑量的增加及作用時間的延長而有明顯的減少,其中以50 及100 ng/ml ETA處理組最為顯著,且在攻毒後12-24小時間幾乎已完全喪失吞菌力,殺菌力的喪失似乎較吞菌力稍早些,兩組於攻毒12小時後殺菌力即已完全喪失;就存活細胞的實際吞菌力及殺菌力而言,除了在100 ng/ml ETA處理組於攻毒初期其吞菌力在殺菌力受影響前已下降外,於各劑量及作用時間下,殺菌力普遍較吞菌力所受的影響為明顯。在移行力方面,是以通過5 m孔徑transwell培養盤的細胞數來檢測移行力的變化,具通過培養盤能力的細胞數隨著ETA劑量的增加及作用時間的延長而逐漸減少,其中亦以50 及100 ng/ml ETA處理組的降幅最大,於攻毒後3小時已大幅降低,至12小時則完全喪失;反之,在1 ng/ml ETA處理組,於攻毒後48小時其移行力卻有短暫的提升。在炎症介質的產生方面,是以ELISA試劑組進行檢測;LTB4無論在ETA處理組或對照組均因產量過低而偵測不到;至於PGE2的產生量則大致上亦隨ETA劑量的增加及作用時間的延長而減少,但在50 ng/ml ETA處理組攻毒3小時後,其總產生量有短暫的提升現象,約為對照組的1.8倍,若就存活細胞的平均值而言,在100 ng/ml ETA處理組攻毒12小時後,其產生量甚至比對照組高出5.7倍。在自由基方面,係採用化學呈色法進行分析,其產量亦隨ETA劑量的增加及作用時間的延長而逐漸減少;在50 及100 ng/ml ETA處理組,於攻毒24-48小時後,幾乎已測不到H2O2及OH˙,NO3-則於攻毒24小時後即測不到,而O2-似乎更為敏感,於12-24小時間即完全測不到;在1 ng/ml ETA處理組,於攻毒60小時後NO3-的產生量有短暫的提升。由於ETA可誘發RPM產生大量富含醣蛋白之質內顆粒,因此選擇10 ng/ml劑量及36和48小時的攻毒時間來觀察細胞素產生能力的變化情形,使用ELISA試劑組進行檢測;於對照組能自發性分泌大量的MCP-1及少量IL-8;在10 ng/ml ETA處理組,MCP-1的產生受到明顯抑制,IL-8的產生量亦減少,而IL-6及TNF-的產生量卻呈短暫的增加,但上清液中並無法偵測到IL-1。
為探討由ETA誘發RPM所產生質內顆粒的成份,而進行一系列的組織化學染色,結果顯示該等質內顆粒對hemocolor、PAS及alcian blue皆呈陽性反應,但對oil red、OsO4及Sudan III卻呈陰性,初步推斷其成份可能為醣蛋白。進而選用數種巨噬細胞所分泌的主要細胞素,含IL-1、IL-1、IL-1 receptor antagonist (IL-1ra)、IL-6及TNF-,進行免疫螢光染色以及前包埋、後包埋及銀增染超小金粒等免疫電顯,以確認該醣蛋白的種類及其在細胞內的分佈位置。在免疫螢光染色上,雖然有散發的點狀IL-1ra及IL-6陽性反應出現於少數細胞的質內顆粒中,但所有的質內顆粒均呈現全面性的IL-1強陽性反應,免疫電顯亦證實IL-1主要是存於質內顆粒中,而銀增染超小金粒免疫金染色更進一步證實ETA處理組所產生的顆粒細胞為富含IL-1的細胞。另以ELISA來定量RPM分泌於上清液中及存在細胞內的IL-1含量,並用對IL-1具感受性之A375.S2細胞株來分別測定細胞內、外IL-1之生物活性,結果發現上清液中並無法偵測到IL-1和IL-1活性,而細胞內容物中亦僅有少許的IL-1和IL-1活性。當再用lipopolysaccharide (LPS)進行刺激,結果上述的存活細胞可產生大量並具有活性之IL-1,經以抗大鼠IL-1抗體進行中和作用後,可極顯著地降低其對A375.S2細胞株的毒殺作用,而抗大鼠IL-1或TNF-抗體以及抗ETA抗體的添加則無此效果,因此推測質內顆粒所含的IL-1可能主要為不具活性的IL-1前驅物。進一步以ELISA針對RPM細胞內容物和上清液中所含巨噬細胞產生的主要細胞素,包括IL-1、IL-1、IL-6、IL-8、TNF-及MCP-1,進行分析,結果發現富含質內顆粒的RPM的細胞內容物中IL-6含量增加,但卻僅有少量的IL-1存在;在單純的LPS刺激組,細胞內容物和上清液中除了IL-1的含量明顯較各組多及MCP-1含量明顯較對照組少外,其他細胞素的含量僅較對照組及ETA處理組稍高些,其中IL-1含量亦極低。反之,若將富含質內顆粒的RPM以LPS再行刺激,在細胞內容物和上清液中除了可偵測到大量的IL-1,同時也有較LPS處理組稍高的TNF-、IL-6、IL-8及MCP-1含量,但均完全測不到IL-1。
綜合上述結果可見,ETA不僅會造成RPM的死亡,也會干擾存活細胞的多重功能,並選擇性的誘發富含低活性IL-1前驅物的質內顆粒產生,此低活性的IL-1前驅物可藉LPS的協同作用而成熟具生物活性並能分泌至細胞外。由於巨噬細胞在炎症及免疫反應中均扮演著重要的角色,因此推測ETA對巨噬細胞所產生的各種干擾均會影響宿主整體防禦體系的正常運作。
Abstract:
Previous studies have shown that exotoxin A (ETA) is the toxic substance produced in the largest amount by Pseudomonas aeruginosa. Its cytotoxicity is primarily caused by protein synthesis inhibition. ETA has also been demonstrated to be capable of interfering with the functions of various immune cells. Macrophages are essential in both inflammation and immune regulation. Because there is only limited information in the effects of ETA on macrophages within which no data of rats are available, a series of studies were therefore conducted to study the immunotoxic potential of ETA in rat resident peritoneal macrophages (RPM). Changes in the viability, MTT metabolic rate, large molecule synthesis (DNA, RNA, protein), morphology, phagocytosis, killing, migration, and free radical, inflammatory mediator, and cytokine production were evaluated in vitro following incubation with ETA at concentrations of 0, 1, 10, 50, and 100 ng/ml for 3 to 60 hours. A dose and time-dependent decrease in the viability was revealed in the ETA-treated RPM as measured by trypan blue dye exclusion. When compared at the total level, a similar trend of dose and time-dependent decrease was also seen in the MTT metabolic rate and DNA, RNA, and protein synthesis, although a transient but significant elevation in the RNA and/or protein synthesis appeared at 24-36 hours post-incubation (HPI) in 1-50 ng/ml ETA-treated groups. However, when compared at the level of per viable cell, the MTT metabolic rate and DNA, RNA, and protein synthesis became enhanced at 10-100 ng/ml ETA after 12-24 HPI. The majority of 50-100 ng/ml ETA-treated RPM became necrotic and apoptotic before 24 HPI. By 36 HPI, 31% of 10 ng/ml ETA-treated RPM were still viable but became full of cytoplasmic granules. Sequential transmission electron microscopic studies revealed that these granules were actually vesicles and vacuoles formed from segmentally dilated rough endoplasmic reticula with accumulation of an electron dense content; these vesicles and vacuoles were eventually fused and some of the cells became vacuolated because of excretion of the content from these vacuoles; additionally, there was also a reversible collapse and folding of the pseudopodia. Although no evident morphological alterations were revealed in 1 ng/ml ETA-treated group, there was still a significant dose and time-dependent reduction in its protein synthesis.
Candida albicans and acridine orange/crystal violet stain were used for the phagocytosis and killing measurement. The number of RPM capable of engulfing C. albicans and the total number of yeast engulfed by each cell were both significantly reduced in a dose and time-dependent manner. The 50 and 100 ng/ml ETA-treated groups were affected the most with the complete loss of phagocytic and killing abilities at 12-24 and 12 HPI, respectively. Except for the early stage of exposure to 100 ng/ml, the killing ability of RPM was generally affected prior to the phagocytosis in other ETA-treated groups. The migration ability was evaluated by counting the number of RPM that could emigrate through the 5 m transwell. A dose and time-dependent reduction in the number of RPM crossing the well was seen in the ETA-treated groups. A complete loss of the migration ability occurred in the 50 and 100 ng/ml ETA-treated groups at 12 HPI; however, there was a transient elevation in the 1 ng/ml ETA-treated group at 48 HPI. A commercial ELISA kit was used for the measurement of inflammatory mediators, PGE2 and LTB4. A trend of dose and time-dependent reduction in the production of PGE2 also appeared in the ETA-treated groups, although there was a transient elevation in the 50 ng/ml ETA-treated group at 3 HPI. If compared at the level of per viable cell, a 5.7-fold increase was present in the 100 ng/ml ETA-treated group at 12 HPI. However, no LTB4 could be detected in any of the groups. Chemical colorimetric assays were used for free radical analyses. A trend of dose and time-dependent reduction in the production of O2-, OH, H2O2 and NO3- was also revealed in the ETA-treated groups, although there was a transient elevation in NO3- in the 1 ng/ml ETA-treated group at 60 HPI. In the 50 and 100 ng/ml ETA-treated groups, no H2O2 and OH, NO3-, and O2- could be detected by24-48, 24, and 12-24 HPI, respectively. Because ETA could induce the formation of glycoprotein-rich cytoplasmic granules in RPM, changes in cytokine production were evaluated in RPM treated with 10 ng/ml ETA for 36 and 48 hours by commercial ELISA kits. It was revealed that the control group could secrete a significant amount of MCP-1 and some IL-8 in culture supernatant spontaneously. In the 10 ng/ml ETA-treated group, there was a marked and slight reduction in the amount of MCP-1 and IL-8, respectively, and also a transient elevation in IL-6 and TNF-, but no detectable IL-1/IL-1.
To further elucidate the possible component of the ETA-induced cytoplasmic granules in RPM, a serial of histochemical staining and immunofleuorescent, and pre-embedding, post-embedding, and ultra-small gold with silver enhancement immunogold staining for IL-1, IL-1, IL-1 receptor antagonist (IL-1ra), IL-6, and TNF- were performed. The result of histochemical staining of the cytoplasmic granules was positive for hemocolor, alcian blue, and periodic acid Schiff but negative for oil red、OsO4, and Sudan III, and this suggested that the granular content might be a glycoprotein. Immunofluorescent staining revealed that the granules were strongly IL-1 positive but there was only infrequent weak spotted intragranular reaction for IL-1ra, and IL-6 and no signal for TNF-. The immunogold staining confirmed that IL-1 was primarily present in the granules and the ultra-small gold with silver enhancement immunogold staining further proved that the granule-containing cells were IL-1-rich cells. The quantity of IL-1 and IL-1 bioactivity in the supernatant and cell lysate of ETA-treated RPM were analyzed with commercial ELISA kits and IL-1 sensitive A375.S2 cell line. No detectable IL-1 and IL-1 bioactivity was seen in the supernatant and there was only a small amount of IL-1 and low level of IL-1 bioactivity in the cell lysate. However, when the ETA-treated RPM were further stimulated with LPS, a large amount of bioactive IL-1 was produced; its cytotoxicity to A375.S2 cells could be neutralized by the addition of anti-rat IL-1 antibody but not anti-rat IL-1, anti-rat TNF-, and anti-ETA antibodies. Thus, it was speculated that the granule-associated IL-1 could mainly be a low-activity IL-1 precursor. Further analysis of various cytokines present in the culture supernatant and cell lysate of different treatment groups revealed that the lysate of the ETA-treated group with granule formation had a significant increase in IL-6 but contained only a small amount of IL-1; the simple LPS-treated group was the only group had a large amount of IL-1 in both supernatant and cell lysate, had less MCP-1 than the control group, and had very little IL-1; when the RPM with cytoplasmic granules were further stimulated with LPS, in addition to a large amount of IL-1 detected in the supernatant and cell lysate there was more TNF-, IL-6, IL-8, and MCP-1 than the LPS-treated group but still no IL-1 was detected.
The results indicated that ETA could not only cause death in RPM and interfere with various functions in the remaining viable RPM but also selectively induce a low-bioactivity IL-1 precursor-rich cytoplasmic granule formation in RPM and the IL-1 precursor could become mature and secretable with the help of LPS. Since macrophages play an important role in both inflammation and immune regulation, it is reasonable to speculate that these ETA-induced effects on macrophages may certainly interfere with the normal operation of the host defense system.
封面
目次
摘要
前言
第一章、研究計畫之背景、目的、重要性及國內外有關研究之近況
一、綠膿桿菌感染對宿主的影響
二、綠膿桿菌對生物醫學研究的影響
三、巨噬細胞在宿主免疫反應中所扮演的角色
四、研究計劃之目的及實驗設計
五、參考文獻
第二章、綠膿桿菌外毒素A對大鼠腹腔巨噬細胞的影響 (I) 形態學變化、質內顆粒的形成及DNA、RNA及蛋白質合成能力的改變
一、摘要
二、緒言
三、材料與方法
四、結果
五、討論
六、參考文獻
第三章、綠膿桿菌外毒素A對大鼠腹腔巨噬細胞的影響 (II)吞菌力、殺菌力、移行力以及炎症物質、自由基及細胞素產生能力的變化
一、摘要
二、緒言
三、材料與方法
四、結果
五、討論
六、參考文獻
第四章、綠膿桿菌外毒素A對大鼠腹腔巨噬細胞的影響 (III) 質內顆粒成份分析、生物活性測定及抗體中和作用之檢測
一、摘要
二、緒言
三、材料與方法
四、結果
五、討論
六、參考文獻
第五章、綜合討論及結論
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