1967年，Ashbaugh等人發表12位急性呼吸衰竭的病例，這些人原先肺部正常，而在外傷或感染後出現急性呼吸困難，低血氧，肺順應性減低，胸部X光有兩側瀰漫性浸潤，以傳統呼吸治療方法無法矯正其低血氧等現象。病理上出現肺組織明顯的充血，肺泡及間質水腫，肺泡塌陷，炎性細胞浸潤，肺泡內有透明膜 (hyaline membrane) 之形成及纖維化病變。由於此病近似新生兒之呼吸窘迫症候群，Ashbaugh與Petty於1971年將之命名為「成人呼吸窘迫症候群」 (Adult respiratory distress syndrome, ARDS)。經由醫界的努力，對於此病廣泛的研究，發現肺部的直接傷害或肺外的其它疾患，均可導致此一症候群的發生。而此種急性肺損傷 (Acute lung injury，ALI) 是有輕重之分，ARDS正是此病程最嚴重的表現。臨床上導致ARDS的原因，可分為直接肺傷害和間接肺傷害兩種。間接肺傷害，是由於肺以外的疾病或損傷，經由全身發炎反應的激活，使血中細胞激素或細胞分泌的發炎相關介質濃度增加，而間接造成肺損傷。目前雖然對於ARDS的致病機轉較有了解，但ARDS的治療仍屬支持治療為主，而其死亡率雖有下降，但是仍然維持在40%至60%的高點。臨床問題的根本解決，主要還是需從基礎醫學研究開始，因此本研究嘗試利用建立急性肺損傷動物模型，和分子生物學的方法，分別探討在肺損傷急性期高度氧化壓力存在下，對於肺上皮細胞鈉離子通道（Epithelial sodium channel, ENaC）基因調控的影響；同時也探討急性肺損傷修復期，增生之第二型肺泡細胞其細胞重塑之機轉。
(一) 氧化壓力對肺上皮細胞鈉離子通道之調控機轉
　　本研究是利用肺上皮細胞株A549細胞，暴露於外加之H2O2，以研究經由其誘發之訊息傳導路徑，以及在抑制 glucocorticoid receptor/ Dexamethasone (GR/Dex) 活化epithelial soudium channel α-subunit gene (α-ENaC) 基因表達上所扮演的角色。(1) 在A549細胞內，GR/Dex活化α-ENaC基因之表達受外加之H2O2所抑制。無論在原本或異種的啟動子（homologous and heterologous promoter）存在下，將α-ENaC glucocorticoid response element突變後，均可使H2O2的抑制作用完全被阻斷。而H2O2抑制α-ENaC基因表達的作用，並非是經由其非特異性的細胞損傷所造成，而是經由其特異性的抑制GR活化α-ENaC基因的作用。(2) A549細胞受到200 μM H2O2的作用，可以活化extracellular signal-regulated protein kinase (ERK) 和C-Jun N-terminal kinase (JNK) 二種訊息傳導路徑，但是只有活化ERK路徑，才能抑制α-ENaC GRE的功能。使用藥理學和生物學上ERK路徑抑制劑，可以減少H2O2產生的抑制作用，顯示ERK路徑的活化，參與了氧化壓力對α-ENaC GRE的抑制作用。(3) 過度表達thioredoxin (TRX) 基因，可以阻斷H2O2對α-ENaC GRE的抑制作用，顯示在A549細胞內，H2O2抑制α-ENaC基因表達的作用是經由活化ERK和另一TRX-sensitive pathway所造成。我們的研究結果顯示肺上皮細胞，在氧化壓力下是經由此雙重的路徑，而使GR/Dex活化α-ENaC基因的作用受到抑制。
(二) 急性肺損傷修復期增生之第二型肺泡細胞其細胞重塑之機轉
利用內毒素誘發急性肺損傷之大鼠模型，我們發現，在急性肺損傷後的早期，伴隨著發炎反應，第二型肺泡細胞也出現增生的現象，其增生約在第三天達到高峰。然而其細胞凋亡，大約在急性肺損傷第7天後達到最高。在內毒素誘發急性肺損傷後，表達Fas的第二型肺泡細胞的數目急遽增加，約在第1天至第5天達到高峰。同時肺組織和肺泡沖洗液內，也出現Fas ligand (FasL)，而其高峰約出現在急性肺損傷後的第一週。而表達FasL最主要的細胞是巨噬細胞和嗜中性白血球。我們的實驗結果中，Fas和FasL的表達均早於第二型肺泡細胞凋亡的時間。在急性肺損傷的急性期過後，Fas和FasL的表達減少，而第二型肺泡細胞凋亡的數目也減少。以上的這些結果與組織學上增生後的第二型肺泡細胞的消失是相關聯的。本研究的結果顯示，與Fas相關之細胞凋亡之機轉，參與了調控增生後的第二型肺泡細胞的消除。

Acute lung injury (ALI) refers to a syndrome of severe, acute respiratory failure characterized by respiratory distress, a severe impairment of oxygenation, and non-cardiogenic pulmonary edema. ALI can vary in severity, acute respiratory distress syndrome (ARDS) is a term applied to patients with more severe manifestations of ALI. Both terms are used to reflect a relative specific form of pathologic injury to the lung occurring from a wide range of causes or associated condition. ALI involves rapid disruption of the gas exchange apparatus when the lungs are exposed to noxious environmental or endogenous agents. The disease process begins with an explosive inflammatory response in the alveolar wall and results in flooding the alveolar spaces with protein-rich edema fluid. This inflammation may cause tissue destruction, extensive cellular reaction, and fibroproliferation of alveolar septa, which consist of capillaries, fibroblasts, and their connective-tissue product. This may result in severe gas exchange and lung compliance abnormalities. ARDS is a very important problem in critical care medicine. First, ARDS occurs commonly in young, previously well individuals. Second, the mortality of ARDS, though declined, remains relatively high at 40% to 60% despite improvements in drug therapy, mechanical ventilation, hemodynamic management, more potent antibiotics, better prevention of complication and better supportive care. Third, the health care costs of ARDS are considerable because patients are almost exclusively managed in an expensive ICU setting. In this investigation, we evaluated the mechanism of oxidant-mediated epithelial sodium channel a-subunit transcriptional repression and mechanism involved in the resolution of type II pneumocyte hyperplasia after acute lung injury.
Part I.
Oxidative stress disrupts glucocorticoid hormone-dependent transcription of the amiloride-sensitive epithelial sodium channel a-subunit in lung epithelial cells through ERK-dependent and thioredoxin-sensitive pathways
The amiloride-sensitive epithelial sodium channel (ENaC) plays a critical role in the maintenance of alveolar fluid balance. It is generally accepted that reactive oxygen and nitrogen species can inhibit ENaC activity and aggravate acute lung injury; however, the molecular mechanism for free radical-mediated ENaC inhibition is unclear. Previously, it has been shown that the expression of the a-subunit of ENaC, alpha-ENaC, which is indispensable for ENaC activity, is repressed by Ras activation in salivary epithelial cells. Here, we investigated whether exogenous H2O2 modulates a-ENaC gene expression in lung epithelial cells through a similar molecular mechanism. Utilizing transient transfection reporter assays and site-directed mutagenesis analyses, we found that the glucocorticoid response element (GRE), located at -1334 to -1306 base pairs of the a-ENaC 5'-flanking region, is the major enhancer for the stimulated a-ENaC expression in A549 lung epithelial cells. We further demonstrate that the presence of an intact GRE is necessary and sufficient for oxidants to repress a-ENaC expression. Consistent with our hypothesis, exogenous H2O2-mediated repression of a-ENaC GRE activity is partially blocked by either a specific inhibitor for extracellular signal-regulated kinase (ERK) pathway activation, U0126, or dominant negative ERK, suggesting that, in part, activated ERK may mediate the repressive effects of H2O2 on a-ENaC expression. In addition, overexpression of thioredoxin restored glucocorticoid receptor action on the a-ENaC GRE in the presence of exogenous H2O2. Taken together, we hypothesize that oxidative stress impairs sodium transport activity by inhibiting dexamethasone-dependent a-ENaC GRE activation via both ERK-dependent and thioredoxin-sensitive pathways. These results suggest a putative mechanism whereby cellular redox potentials modulate the glucocorticoid receptor/dexamethasone effect on alpha-ENaC expression in lung and other tight epithelia.
Part II.
Fas/Fas Ligand Pathway is Involved in the Resolution of Type II Pneumocyte Hyperplasia after Acute Lung Injury: Evidence from Rat Model
In the present study, we used a rat model of ALI to evaluate the role of apoptosis of type II pneumocytes in alveolar remodeling during the resolution phase. Sprague-Dawley rats had E. coli lipopolysaccharide instilled transtracheally for induction of ALI. Animals were sacrificed on various days after lipopolysaccharide instillation. Lung specimens from all animals were examined for the presence of apoptosis in type II pneumocytes by an in situ apoptosis assay, and for proliferative nuclear antigen, cytokeratin-18 and Fas, and Fas ligand with an immunohistochemical stain. Fas and Fas ligand expression in both lung tissue and bronchoalveolar lavage fluid was examined by Western blot analysis. Histologic examination revealed that the lungs of ALI rats showed infiltration of numerous inflammatory cells in the intra-alveolar and/or interstitial space, and hyperplasia of type II pneumocytes. Type II pneumocyte proliferation, detected by PCNA staining, developed maximally around day 3 after ALI. In the ISAA, positive signals in type II pneumocytes were obvious and were distributed diffusely in the lung parenchyma from day 1 after ALI, became maximal around day 7, then declined until day 21. DNA fragmentation analysis revealed that a DNA ladder pattern was detectable from day 3, persisted until day 10, and disappeared after day 14. The major cell types expressing FasL are macrophages and neutrophils. Western blot analysis showed Fas ligand, both membrane bound form and soluble form, was present from day 1 to day 21 after ALI, and with highest level occurring during the first week of ALI. Fas expression in type II pneumocytes reaches its maximum on day 3 to day 5, then gradually declined till day 21. Fas and FasL expression appeared to proceed type II pneumocyte apoptosis. After acute stage, Fas and FasL expression declined, type II pneumocyte apoptosis also decreased. These findings correlate with histologic resolution of type II pneumocyte hyperplasia. Our results confirm that type II pneumocyte proliferation in response to ALI is mainly a reparative phenomenon. During the resolution phase of ALI, extensive apoptosis of type II pneumocytes is the main cellular mechanism that accounts for the disappearance of these cells, and Fas/Fas ligand is involved in the resolution of type II pneumocytes. Our model provides a useful tool for studying the mechanisms of tissue remodeling after ALI.

論文目錄
第一章　中文摘要 6
第二章　緒　　論 8
　　一、研究背景及文獻回顧 8
　　二、研究動機及目的 10
第三章　研究方法及材料 16
第四章　結果 23
　　第一部份　氧化壓力對肺上皮細胞鈉離子通道之調控機轉 23
　　第二部份　急性肺損傷在修復期增生之第二型肺泡細胞其細胞
重塑之機轉 36
第五章　討論 46
第六章　展望 55
第七章　英文摘要 60
第八章　參考文獻 64
附錄　發表之相關論文 73
圖 目 錄
圖1-1 Dexamethasone可促進A549肺上皮細胞株α-ENaC mRNA的表達。-- 24
圖1-2 Dex可促進而Ras/ H2O2可抑制α-ENaC基因的表達是經由對GRE
的調控而達成。 24
圖1-3 外加之H2O2可活化A549細胞之ERK和JNK訊息傳導路徑。 28
圖1-4 H2O2對a-ENaC GRE的抑制作用可以經U0126處理後而回復。 31
圖1-5 Dex對a-ENaC GRE的活化作用，不受JNK訊息傳導路徑所影響。 31
圖1-6 過度表達TRX基因對受H2O2和Ras抑制之a-ENaC基因的影響。 34
圖1-7 TRX可以增強受GR/Dex活化的基因之表達，同時對H2O2媒介
之抑制a-ENaC mRNA表達的現象有保護作用。 37
圖1-8 氧化物對肺上皮細胞鈉離子通道調控機轉之推斷圖。 37
圖2-1 大鼠以氣管內滴注大腸桿菌內毒素，誘發急性肺損傷之組織顯微
圖片，H & E染色（A至C）；以原位凋亡檢測法來偵測肺組織凋
亡的現象（D至E）。 38
圖2-2 利用氣管內滴注內毒素而誘發肺損傷之鼠肺，在不同的時間點抽
取其DNA，所做的電泳分析圖。 39
圖2-3A 急性肺損傷後在不同的時間點，第二型肺泡細胞PCNA染色陽性
的百分比。 39
圖2-3B 急性肺損傷後，在不同的時間點，第二型肺泡細胞其原位凋亡檢
檢陽性之百分比。 40
圖2-4 為了要標定，何種細胞產生細胞凋亡的現象，以CK-18染色合併
原位凋亡檢測之雙重組織免疫染色法。 40
圖2-5 急性肺損傷後，在不同的時間點，第二型肺泡細胞，Fas染色呈陽
性的百分比。 43
圖2-6 急性肺損傷後，不同的時間點之肺組織，表達Fas之西方墨點分析
結果。 43
圖2-7 急性肺損傷後，不同的時間點之肺組織，表達細胞膜連結型Fas
ligane之西方墨點分析結果。 44
圖2-8 急性肺損傷後，不同的時間點之肺組織，表達游離型Fas ligand之
西方墨點分析結果。 44
圖2-9 FasL之組織免疫染色結果。 45
表 目 錄
表0-1　造成急性呼吸窘迫症候群的臨床疾病 10
表1-1　肺損傷後，不同時間點之間，肺泡發炎的嚴重度與肺溼重／
體重之比較 41

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