| Abstract: | 急性肺損傷為常?且嚴重急症，當惡化後會形成急性呼吸窘迫症候群，伴有相當高的死亡率 (40~60%)。大部分病人並非死於呼吸衰竭，而死於因全身性發炎反應引發的多發性器官衰節。嗜中性球活化於細菌感染引起的急性肺損傷的病理過程中，扮演著極為重要的角色。因此若能增進對於細菌感染引起的急性肺損傷的機制認知，採用適當策略降低或抑制嗜中性球活化現象，對於疾病的預防治療應該可提供實質幫助。過去的研究結果發現嗜中性球浸潤、肺血管滲透性增加、肺水腫、肺壁透明膜形成等為細菌感染引起急性肺損傷重要的病理變化。相關研究更證實促發炎物質過度堆積、嗜中性球活化、肺血管內皮障壁喪失等傷害機制會惡化急性肺損傷。反之，則可以降低細菌所造成的急性肺損傷。不幸的，目前治療急性肺損傷只有呼吸器支持療法為主，仍無有效治療藥物可以運用。因此，若開發新的化合物以有效調控急性肺損傷的發炎現象及相關病理變化，將可有效的預防或治療急性肺損傷。?銀花(Lonicera japonica)於中醫藥已使用??千?，具有許多的藥理活性抗發炎、抗血管新生、止痛等，近?來也被當做健康食品使用。?銀花製劑的單方或複方的萃取物目前已應用於癌症、呼吸道感染、??病及風濕性關節炎，其中木犀草素 (luteolin) 為?銀花的活性成分之一。初步研究報告指出木犀草素會降低急性肺損傷，可能與抗氧化及抗發炎相關。雖然木犀草素認為是一種具潛力的急性肺損傷化合物，目前木犀草素確實的細胞及分子作用機制並不明瞭。針對這些議題，本三?期研究計畫的主要目的將藉由動物急性肺損傷實驗模式來探討木犀草素保護作用機制，及藉由體外細胞實驗模式探討木犀草素影響內皮細胞及嗜中性球的活化機制。全程的研究計畫實驗過程將依序探討下面三個議題重點來回答整體研究計畫的目標：包括一、評估木犀草素影響由氣管注射內毒素造成的急性肺部損傷的病理現象。二、評估木犀草素影響血管內皮細胞與嗜中性球間交互作用。三、評估木犀草素影響嗜中性球活化及其機制的作用。經由此計畫的結果，將有助於木犀草素成為一臨床上可用於急性肺損傷的預防或治療的化合物。
Acute lung injury (ALI) is a common clinical disorder with significant impact on quality of life and enormous social cost, with a mortality rate of approximately 40~60%. Acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS), are characterized by an acute inflammatory process in the airspaces and lung parenchyma. Respiratory failure is an uncommon cause of death in ALI patients, and a large proportion of patients with ALI died of sepsis-related multiorgan failure. Polymorphonuclear leukocytes (PMN) play an important role in the pathogenesis process of bacteria-induced ALI. It would be beneficial to the prevention and treatment of bacteria-induced ALI if the pathological mechanisms are clear. Accumulating evidence suggests that PMN infiltration, lung vascular permeability elevation, lung edema, and hyaline membrane formation are hallmarkers of bacteria-induced ALI. Among those pathological changes, proinflammatory mediators over accumulation, PMN activation, lung vascular endothelial barrier dysfunction amplified inflammatory changes leading to further tissue damage. On the contrary, reduction of these phenomenons protects against bacteria-induced ALI. Unfortunately, there is no effective therapeutic agent for the treatment of ALI. Therefore, to understand the regulatory mechanism of the inflammation and pathology phenomenon in ALI should provide more suitable targets to design and development of novel anti-ALI compounds. Honeysuckle flower, Lonicera japonica, has been used in Chinese's medicine for a long time and used as a healthy food in recent years. Honeysuckle flower is possessing several biological activities including antioxidant, anti-inflammation, analgesia, and anti-angiogenesis. Honeysuckle flower is currently used for the treatment of cancer, respiratory tract infection, diabetes, and rheumarthritis. Luteolin is an active component of honeysuckle flower. Studies show that luteolin is capable of reducing acute lung injury. The proposed protective mechanisms of luteolin include antioxidant and anti-inflammation. Although luteolin is recognized as a potential protective agent of ALI, its detailed protective mechanisms are poorly understood. To address these issues, this 3-year proposal will aim to elicit the protective mechanisms of lutelin against ALI, via acute lung injury model in rats and interaction of endothail cells and leukocytes in the cell culture system. Following three specific aims will be addressed: (1) to delineate the effect of luteolin on intratracheal injection of lipopolysaccharide (LPS) induced ALI in mice; (2) to delineate the effect of luteolin on the relationship between leukocytes and endothelial cells; (3) to delineate the effect of luteolin on the PMN activation and it’s mechanism. The results of this proposal will promote the understanding of luteolinmediated protective and therapeutic mechanisms. |
