臺灣博碩士論文加值系統

每年有10%-20%原發性肺纖維化患者發生急性惡化，多數患者需住院接受治療且預後差，可能在急性惡化後3-4個月死亡。南義大利倫巴底地區為一工業大城，長期暴露在空氣汙染中，此地區原發性肺纖維化盛行率及惡化發生率高，在本次COVID-19大流行亦為確診率高且死亡率高的地區。儘管SARS-CoV-2病毒傳染途徑首要經由飛沫、氣溶膠及接觸傳播，但公衛證據仍見空氣污染濃度與確診率具高度相關性，空氣汙染與肺纖維化在COVID-19的角色尚不明確。我們在人體肺組織和動物模式發現，肺纖維化表現高的組織，其ACE2(angiotensin-converting enzyme 2)與TMPRSS2(transmembrane serine protease 2)表現量也升高；懸浮微粒與博來黴素誘發肺纖維化的動物模式得知，可透過阻斷IL-8(interlukin 8)/ CXCR1/2途徑降低ACE2與TMPRSS2表現，在此次COVID-19疫情中，可能可以解釋因肺纖維化母細胞的ACE2與TMPRSS2表現量升高，使其更具病毒SARS-CoV-2易感染性，且較有機會發展成為重症患者。再者，原發性肺纖維化急性惡化隨病程發展成急性呼吸窘迫症候群，使用呼吸器除了是一項支持，亦會造成傷害，卻鮮少文獻探究。我們利用急性呼吸窘迫症候群病患的病理切片，探討呼吸器參數設定與臨床參數之相關性。在回溯臨床與病理切片結果發現，瀰漫性肺泡損傷合併肺纖維化或原發性肺纖維化急性惡化，其呼吸器參數(動態機械力、動態驅動壓力、最大吸氣壓力)設定皆高且預後差，顯示不管病程中何時發展肺纖維化，一旦呼吸衰竭使用機械通氣輔助，都會面臨呼吸器引發肺損傷。因此，原發性肺纖維化患者應避免急性惡化，若呼吸衰竭使用呼吸器，應小心其呼吸器參數設定，但目前針對原發性肺纖維化患者的呼吸器參數設定建議仍未有定論，
有待未來大型研究探討。

Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) has been defined as an acute, clinical respiratory deterioration superimposed on fibrotic lung. Air pollution characterized high prevalence of AE-IPF, and lead a poor prognosis after SARS-CoV-2 infection, but the underlying mechanisms are not well explored. Angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) are the keys to the entry of SARS-CoV-2. We measured ACE2 and TMPRSS2 expression levels in lung tissues of control non-IPF and IPF patients, and used murine animal models to establish pulmonary fibrosis by bleomycin and particulate matter (PM). The severity of pulmonary fibrosis and the expression of ACE2 and TMPRSS2 were caused by PM exposure and blocked by deletion of KC (keratinocyte chemoattractant) or treatment with Reparixin. It can be mediated through upregulating ACE2 and TMPRSS2 in pulmonary fibroblasts, and prevented by blocking the IL-8/CXCR1/2 pathway. However, AE-IPF commonly lead to acute hypoxemia respiratory failure requiring mechanical ventilation, which can lead to pulmonary fibrosis. We performed a retrospective analysis of acute respiratory distress syndrome (ARDS) patients who received open lung biopsy to examine the impact of histological fibrosis on clinical outcomes and mortality. A total of 68 ARDS patients who had diffuse alveolar damage (DAD) were analyzed and stratified into fibrosis or not. Airway pressures at the time of ARDS diagnosis and on the day of biopsy were not significantly different between DAD with fibrosis group and AE-IPF. The overall 90-d hospital mortality and duration of ventilator usage also had no significance. However, these two groups had high injurious ventilator settings and it may contribute to the progression of fibrosis. The protective strategy of ventilator settings is still controversial for fibrosis lung even acute or chronic phase. Pending further studies to define the optimal strategy to ventilate these fibrotic lungs, regardless of the underlying etiology.

目錄

中文摘要 i
英文摘要 iii
目錄 iv
圖目錄 vii
表目錄 viii
第一章 緒論 1
第一節、 研究背景 2
一、 肺纖維化（pulmonary fibrosis） 2
二、 急性呼吸窘迫症候群 5
三、 新型冠狀肺炎 7
四、 空氣汙染 10
第二節、 研究假說與目的 12
第二章 實驗材料與方法 15
第一節、 人體肺組織取得 16
一、 間質性肺炎病理切片 16
二、 開放活體組織切片 16
第二節、 病患資料來源 16
一、 病歷回溯 16
二、 參數定義 17
三、 預後定義 17
第三節、 動物實驗 18
一、 懸浮微粒 18
二、 動物模式 19
三、 基因剔除鼠 19
第四節、 病理組織染色 20
一、 蘇木素-伊紅染色 20
二、 免疫組織染色法與定量 20
三、 免疫螢光染色法 21
四、 Picro Sirius Red, Masson’s trichrome, elastin stain染色法與定量 22
第五節、 統計方法 23
一、 統計方式 23
二、 存活分析 23
第三章 結果 24
第一節、 間質性肺炎患者肺組織染色表現 25
一、 ACE2、TMPRSS2在正常人體組織表現 25
二、 人體組織肺纖維化程度表現 25
三、 肺纖維化程度與ACE2、TMPRSS2在人體組織表現 25
第二節、 動物模式肺組織染色表現 26
一、 懸浮微粒與博來黴素誘發肺纖維化動物模式 26
二、 Keratinocyte chemoattractant（KC）基因剔除鼠與Reparixin治療組別 27
第三節、 瀰漫性肺泡損傷合併肺纖維化與原發性肺纖維化急性惡化病歷回溯 28
一、 病理切片結果 28
二、 臨床與呼吸器參數比較 29
三、 預後比較 29
第四章 討論 31
一、 ACE2與TMPRSS2在人體肺組織的表現量 32
二、 懸浮微粒與肺纖維化提高肺組織ACE2與TMPRSS2表現量 33
三、 IL-8途徑阻斷肺組織ACE2與TMPRSS2表現量且降低肺纖維化嚴重度 34
四、 原發性肺纖維化急性惡化與急性呼吸窘迫症候群之異同 35
五、 肺纖維化之呼吸器設定策略 37
第五章 結論 39
參考文獻 41
圖與表 51
附錄 74

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