| 摘要: | 急性肺損傷(Acute lung injury; ALI)以及急性呼吸窘迫症(Acute respiratory distress syndrome; ARDS)是造成急重症患者的多器官衰竭甚至死亡的主要原因，至今仍未有特殊的治療藥物。本研究目的是探討具有活血化瘀功能的牡丹皮(Moutan Cortex Radicis; MCR)以及其主要的成分-丹皮酚(Paeonol)是否能改善由高劑量內毒素所誘發急性大鼠肺損傷模型，並探討其治療效果與發炎反應以及凝血功能紊亂之間的關聯性。
首先，我們模擬人類在肺炎所致急性肺損傷之病理生理反應，建立了實驗動物模型，並進行時序性的研究，包括肺泡液細胞計數、肺泡液細胞激素的分析及肺部病理組織切片之肺損傷程度的判定等，以作為選擇誘發肺損傷後第16小時為觀測時間點的依據；第二：進行活血化瘀藥—牡丹皮之療效評估，比較“誘發前”以及“誘發後”給藥的效果。我們發現在“誘發肺損傷前”給予口服牡丹皮，具有保護作用，其作用可能與抑制肺部發炎反應細胞激素如IL-6、IL-1β及MIP-2的表現量有關。不論是誘發前或誘發後給藥，牡丹皮均有調節體溫、抑制MPO表現量的作用；第三：丹皮酚為牡丹皮的主要有效化學物質，具有良好的抗發炎作用。在LPS誘發急性肺損傷後，給予大鼠經腹腔注射丹皮酚，具有顯著抑制肺部發炎反應的效果，其機轉可能與抑制TNF-?恁BIL-1?牷BIL-6以及MPO和iNOS的表現量有關。丹皮酚注射也可以抑制大鼠肺泡液中PAI-1的表現量，以降低凝血功能紊亂。這個實驗顯示，丹皮酚具有顯著的抗發炎以及部份的抗凝血作用；第四個部分，使用不同濃度的丹皮酚與大鼠中性球作用，結果發現丹皮酚具有顯著抑制中性球移行的能力，同時促進中性球的吞噬能力。
本研究為選擇一目前現代醫學治療上有瓶頸之臨床疾病，經由實驗動物模型的建立，來進行篩選及驗證潛在具有治療效果之中草藥，並探討其可能的作用機轉。本研究結果，後續可深入探討：關於活血化瘀類中草藥是否均可透過抑制發炎和凝血功能紊亂來改善急性肺損傷，及可能涉及的治療靶點，以此做為中西醫臨床理論結合及應用的依據，及新藥開發、臨床試驗的起點。
Moutan Cortex Radicis (MCR) is a Chinese herbal medicine that was widely used over a long period as an analgesic, antipyretic, and anti-inflammatory agent in China. Paeonol is a major active component of Moutan Cortex Radicis. Lipopolysaccharide (LPS)-induced acute lung injury (ALI) in rat models is considered similar to adult respiratory distress syndrome (ARDS) in humans. Therefore, the present study investigates the effect of MCR and Paeonol on ALI. The ALI model was developed through the intra-tracheal (IT) administration of LPS (16 mg/kg) to Sprague-Dawley (SD) rats, which formed the LPS group. MCR was orally administered before and after LPS was introduced into rats (MCR-LPS group and LPS-MCR group, respectively). In the MCR-LPS group, rats received MCR 2 g/kg/times 3 times before LPS challenge; the LPS-MCR group received MCR 2 g/kg/times 3 times after LPS challenge. The results of this experiment indicate that the number of total cells and neutrophils and the concentration of protein exudation in bronchoalveolar lavage fluid (BALF) significantly decreased in the MCR-LPS group. Cytokine levels, including IL-1β, MIP-2, IL-6, and IL-10, in BALF were also significantly inhibited at 16 h after LPS administration in the MCR-LPS group. Myeloperoxidase (MPO) activity in lung tissue was reduced in the MCR-LPS and LPS-MCR groups at 16 h after LPS administration. Furthermore, leukocyte infiltration and protein exudation in the alveolar space were less severe in the MCR-LPS group than in the LPS group. Therefore, the findings of this study suggest that the administration of MCR prior to LPS improves ALI, possibly mediating ALI through antiinflammation.
The intraperitoneal administration of paeonol successfully reduced histopathological scores and attenuated myeloperoxidase-reactive cells as an index of polymorphonuclear neutrophils infiltration and also reduces inducible nitric oxide synthase expression in the lung tissue, at 16 h after LPS administration. In addition, paeonol reduced proinflammatory cytokines in bronchoalveolar lavage fluid, including TNF-α, IL-1β, IL-6, and PAI-1. These results indicated that paeonol successfully attenuates inflammatory and coagulation reactions to protect against ALI |
