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研究生:李振婷
研究生(外文):Chen-Ting Lee
論文名稱:一氧化氮、前列腺素E2和活性氧化物在家塵蟎致敏小鼠過程中的角色
論文名稱(外文):Role of nitric oxide, prostaglandin E2 and reactive oxygen species in allergic sensitization in mice
指導教授:余俊強
指導教授(外文):Chun-Keung Yu
學位類別:碩士
校院名稱:國立成功大學
系所名稱:微生物及免疫學研究所
學門:生命科學學門
學類:微生物學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:中文
論文頁數:81
中文關鍵詞:小鼠氣喘活性氧化物一氧化氮前列腺素E2
外文關鍵詞:PGE2nitric oxideROSasthmamice
相關次數:
  • 被引用被引用:3
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  • 下載下載:123
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氣喘是一種第二型輔助T細胞媒介的慢性呼吸道發炎反應,然而對於氣喘的致病機轉及發展過程中牽涉的分子和細胞機制仍未明瞭。目前有證據顯示抗原呈現細胞所產生的發炎中介物質,譬如發炎前細胞激素、一氧化氮、前列腺素E2和活性氧化物對於影響原始T細胞分化扮演重要的角色,因此極有可能參與致敏的過程。我們利用兩種塵蟎所誘發的氣喘動物模式:周邊致敏模式和經呼吸道致敏模式,探討在過敏原處理期間給予前列腺素E2、前列腺素E2的阻斷劑indomethacin、NS-398或抗氧化劑GSH、NAC對致敏過程的影響,以釐清各種發炎中介物質在其中的功能。
首先在周邊致敏模式中,Der f/IFA致敏小鼠後小鼠肺泡沖洗液細胞總數、肺泡巨噬細胞、淋巴球、嗜中性球和嗜酸性球都明顯增加,且產生大量的O2-,顯示小鼠肺部處於慢性發炎反應,小鼠血清中Der f特異性IgG1抗體也明顯增加,表示免疫反應偏向Th2型。若在致敏的過程中處理NS-398、GSH和NAC會減少肺泡沖洗液細胞產生O2-的量,且NS-398可以減弱由Der f刺激後淋巴結細胞的增生,並使這些細胞產生較高量的IFN-g,而降低IL-4的量,給予PGE2則得到相反的結果,顯示PGE2可能扮演一個促使免疫反應偏向Th2的角色。在呼吸道致敏模式中,Der f同樣也會引起小鼠肺部發炎反應、使肺泡沖洗液細胞產生大量O2-和血清中Der f特異性IgG1抗體增加。若在致敏期間給予NS-398和indomethacin可以降低肺臟lipid peroxidation,而且給予NS-398也會降低血清中NO的濃度。另外給予NAC不但可以抑制由Der f所引起的肺部發炎反應,包括降低肺泡沖洗液細胞總數及發炎細胞的浸潤,亦會抑制淋巴結細胞增生的情形,顯示PGE2和過氧化物等發炎物質確實可以影響Der f的致敏過程。
在in vitro實驗發現肺泡巨噬細胞經Der f刺激後會產生大量IL-6、TNF-α和O2-,以及NF-kB的活化。PGE2、NO阻斷劑及抗氧化劑都可以減少Der f刺激肺泡巨噬細胞所產生的IL-6,顯示肺泡巨噬細胞經過Der f刺激後所產生許多發炎物質之間可能存在互相調控的機制。由實驗結果我們相信在Der f過敏原刺激後會使肺泡巨噬細胞產生大量發炎中介物質,這些物質有利於第二型輔助T細胞的分化發育,而影響後續過敏反應的形成。
Asthma is a chronic airway inflammatory disease mediated by the type 2 helper T cells. However the pathogenesis mechanism is still unknown. A variety of antigen-presenting cell-derived pro-inflammatory mediators including cytokines, nitric oxide (NO), prostaglandin E2 (PGE2) and reactive oxygen species(ROS) are key players in controlling T cell polarization. The objective of this study is to clarify the role of these mediators in allergic sensitization to house dust mite Dermatophagoides farinae (Der f) in mice.
Two Der f-induced asthma models have been tested: a parental sensitization model with Der f in the presence of IFA, and an airway sensitization model with repetitive Der f intratracheal challenge. BALB/c mice were treated with NS-398 (COX-2 inhibitor), indomethacin (COX inhibitor), GSH, NAC (both antioxidants) or PGE2 during Der f sensitization. The Der f-induced responses: airway inflammation and pro-inflammatory mediator production (NO, superoxide(O2-), IL-6 and TNF-a) were examined and compared with those of control mice.
In the parental sensitization model, the administration of NS-398 enhanced IFN-g and decreased IL-4 production of lymph node cells stimulated with anti-CD3, PHA or Der f. Opposite results were obtained with the administration of PGE2. Superoxide production of alveolar macrophages (AMs) was also reduced ex vivo when administration of NS-398, GSH and NAC. In the airway sensitization model, NAC treatment reduced the influx of lymphocytes and eosinophils in bronchoalveolar lavage fluid and inhibited the proliferation of lymph node cells stimulated with PHA or Der f. The administration of NS-398 could decrease lipid peroxidation of the lung tissue and NO concentration in the serum.
Our previous studies indicated AM might be a target of Der f. Therefore, we further examined the mediators production of AMs in response to Der f. We observed that AMs produced substantial amounts of IL-6, TNF-a and O2-, and had NF-kB protein expression after Der f stimulation. Treatment with NS-398, indomethacin, L-NMMA, GSH and NAC could inhibit Der f-induced IL-6 production of AMs. These results suggested that these pro-inflammatory mediators might be involved in mediating the Th1/Th2 balance during Der f sensitization.
中文摘要I
英文摘要II
目錄III
圖表目錄V
第一章 緒論 1
第一節 氣喘現況1
第二節 過敏性氣喘致病機轉 1
第三節 家塵蟎過敏原及其致敏性 2
第四節 肺泡巨噬細胞與氣喘的致病機轉 4
第五節 發炎中介物質與氣喘的關係 5
a、前列腺素(Prostaglandin) 5
b、一氧化氮(Nitric oxide)7
第六節 氧化性壓迫與氣喘的關係 8
第七節 研究動機10
第二章 實驗設計 11
第一節 整體實驗構想11
第二節 具體實驗目標 11
第三節 動物實驗的實驗設計12
第四節 體外實驗的實驗設計 15
第三章 材料與方法 16
第一節 方法16
A、萃取家塵蟎抗原(Dermatophagoids farinae)16
B、實驗動物 17
C、家塵蟎乳化抗原致敏小鼠17
D、氣管內接種(Intratracheal inoculation)17
E、支氣管肺泡沖洗液(Bronchoalveolar lavage,BAL)17
F、支氣管肺泡沖洗液中白血球分類計算 18
G、血中嗜酸性球的計數 19
H、頸部淋巴結細胞以抗CD3單株抗體、PHA及塵蟎刺激實驗19
I、脾臟細胞以抗CD3單株抗體、PHA及塵蟎刺激實驗 20
J、測定血清中家塵蟎特異性IgG1、IgG2a/2b抗體含量 20
K、測定肺泡沖洗液或巨噬細胞刺激後上清液中IL-6、TNFa的含量21
L、測定淋巴結細胞和脾臟細胞刺激後上清液中IFN-g、IL-4的含量22
M、測定血清、肺泡沖洗液或巨噬細胞刺激後上清液中NO的含量 22
N、測定全血、肺泡沖洗液細胞或巨噬細胞刺激後過氧化物(O2-)的含量 23
O、測定肺臟中lipid peroxidation的含量 23
P、阻斷劑的使用 24
Q、脾臟細胞以阻斷劑前處理再以塵蟎或LPS刺激實驗24
R、肺部巨噬細胞以阻斷劑前處理再以塵蟎或LPS刺激的細胞活性實驗 25
S、肺部巨噬細胞以阻斷劑前處理再以家塵蟎或LPS刺激實驗26
T、肺泡巨噬細胞影響T細胞的分化 26
U、製備肺泡巨噬細胞的nuclear extracts 26
V、EMSA的放射性探針(probe)之製備 27
W、EMSA的操作 27
第二節 材料 29
A、 儀器設備 29
B、 藥品 30
第四章 實驗結果 35
第五章 討論 42
參考文獻 48
圖表 59
附錄 78
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