【作者】 韦鹏；

【导师】 凌亦凌；

【作者基本信息】 河北医科大学 ， 病理学与病理生理学， 2006， 博士

【摘要】 急性肺损伤（acute lung injury, ALI）是各种肺内外因素引起的急性弥漫性肺组织损伤,其主要特点是肺部过度炎症反应和肺血管通透性增加。革兰氏阴性细菌感染是ALI的常见病因之一。细菌内毒素的主要活性成分脂多糖（lipopolysaccharide, LPS）可由其受体介导直接激活肺内炎症细胞,释放大量炎症介质,并由此引发瀑布式炎症反应,导致弥漫性肺组织损伤。ALI持续发展可导致急性呼吸窘迫综合征甚至多系统器官功能衰竭。尽管近年来各种支持疗法有了很大进展,但ALI的具体发病机制至今尚未完全阐明,病死率仍高达40%以上。内源性气体信号分子的发现为ALI发病机制的研究开辟了一个新的领域。迄今已证实的内源性气体信号分子有三种,即一氧化氮（nitric oxide, NO）、一氧化碳（carbon monoxide, CO）和硫化氢（hydrogen sulfide, H₂S）。NO和CO在ALI中的作用已得到了证实。H₂S是继NO和CO之后被确认的第三种内源性气体信号分子。关于生理和病理情况下H₂S作用的研究虽刚刚起步,但已证实H₂S参与了神经和血管等的生理功能调节,以及高血压、肺动脉高压、内毒素休克等疾病的发生。那么, H₂S在LPS所致ALI中发挥何种作用呢?这正是本研究的主要目的之一。内源性气体信号分子之间存在着相互调节的关系。已有研究证实NO与CO、NO与H₂S之间可对彼此产生的限速酶进行调节,而关于CO与H₂S之间相互关系的报道尚不多见。本实验对LPS所致ALI过程中CO与H₂S的相互作用进行了初步探讨。另外,研究表明,催化CO生成的限速酶血红素加氧酶-1（heme oxygenase-1,HO-1）是一种内源性的细胞保护蛋白,具有抗氧化应激、抗炎、抗细胞凋亡的作用。那么,在H₂S对ALI的作用中,HO-1/CO通路发挥了何种作用?这也是我们感兴趣的问题之一。肺组织中血管平滑肌细胞是HO-1和H₂S生成的关键酶胱硫醚-γ-裂解酶（cystathionineγ-lyase, CSE）的主要表达部位,由此产生的CO和H₂S均是非内皮依赖的舒血管物质。肺血管损伤后的主要表现之一是肺血管反应更多还原

【Abstract】 Acute lung injury （ALI）, the acute and diffuse injuries to lung tissues caused by various factors, is mainly characterized by inflammatory over-reaction and increased permeability of alveolar-capillary membranes. One of the most common causes of ALI is gram-negative bacterium infection. Lipopolysaccharide （LPS）, the main component of the cell wall of gram-negative bacteria, is known to induce severe lung injuries. LPS can directly activate inflammatory cells through binding to its receptors on those cells, which produce a large number of inflammatory mediators, thus causing a cascade of inflammatory reactions. ALI often develops to acute respiratory distress syndrome （ARDS） or even multiple system organ failure. Although remarkable advances have been achieved in the treatment of ARDS, the mortality associated with this syndrome still exceeds 40%, and the exact mechanism of ALI remains incompletely illustrated.Endogenous gaseous transmitters, a unique class of biomaterials in regulating homeostasis, are found to play important roles in a variety of physiological and pathological events. Up to now, three gaseous transmitters have been recognized, namely nitric oxide （NO）, carbon monoxide （CO） and hydrogen sulfide （H₂S）. Mounting evidence confirmed the important role of NO and CO in ALI. H₂S is the third to be included in the family of endogenous gaseous transmitters, following NO and CO. Researches about physiological functions and pathological effects of H₂S became frequent only recently. It was proved that H₂S participated in the regulation of neural function and vasomotion, as well as the pathogenesis of hypertension, pulmonary artery hypertension and endotoxin shock, etc. However, there were few reports about the role of H₂S in LPS-induced ALI, which was the major更多还原