组蛋白去乙酰化酶2在气管损伤后狭窄作用和调控的研究

Tracheal intubation or tracheotomy is one of the causes of tracheal stenosis. Tracheal inflammation caused by mechanical injury and compression , and tracheal infection are the mainly etiological mechanism of trachea stenosis. And interventional therapy is one of the most effective treatment methods for tracheal stenosis, but it allways resulted in tracheal re-injury, restenosis and poor curative effect.Therefore, it might be useful to study the pathogenesis of tracheal stenosis for preventing tracheal stenosis caused by trachea trauma. Histone deacetylase 2 (HDAC2) is the main factor to regulate the inflammatory response.Our previous studies showed that upexpression of HDAC2 can inhibit the inflammatory response of tracheal mucosa, even the A549 cell,s and also accelerated their apoptosis. Our preliminary results also confirmed that erythromycin or combined with hormone or other anti-inflammatory drugs can reduce the proliferation of granulation tissue caused tracheal injury.Based on this experiment results,we postulated that HDAC2 might be the cause and development in the pathogenes of tracheal stenosis by trauma.In this study, we should study the HDAC2 expression in tracheal mucosa of patients with tracheal stenosis by intubation ,and their intrinsic relationship between airway inflammation. And we also study the expression of HDAC2 and relationship between tracheal inflammation dealed with erythromycin and its combination with other anti-inflammatory drugs in experimental animal models.This research will further recognize the effect and regulation mechanism of HDAC2 in tracheal stenosis and provide theoretical basis and new ideas for the prevention and treatment of tracheal stenosis by trauma.

气管插管或气管切开是造成气管狭窄主要原因之一。机械性损伤、压迫所致的气管炎症和气管感染等因素导致其发病，而介入呼吸治疗是治疗气管狭窄主要方法，但又是造成气管再损伤、患者术后再狭窄和治疗效果欠佳原因。组蛋白去乙酰化酶2（HDAC2）能调控炎症反应，我们以往研究证实，上调HDAC2表达，可使气管黏膜细胞、甚至是A549细胞的炎症反应受到抑制、细胞凋亡加速；我们本研究的初步结果证实，红霉素或联用激素等抗炎药物能减轻气管损伤后肉芽组织增生，为此我们提出假说：HDAC2在气管损伤后狭窄发病中起重要作用。我们拟以HDAC2作为研究的切入点，研究其在气管插管后狭窄者气管黏膜表达情况以及与气管炎症的关系，观察其在动物模型中受到红霉素等抗炎药物不同组合干预下变化特点及与气管炎症关系，是否通过上调HDAC2而产生作用。研究将揭示HDAC2在气管损伤后狭窄中作用，为气管损伤后狭窄的防治提供理论基础和新思路。

气管瘢痕狭窄是临床治疗上的一大难题，炎症反应是导致损伤后气管狭窄的重要因素，而组蛋白去乙酰化酶2（HDAC2）在炎症反应中具有“开关”作用。因此，本研究以HDA2为切入点，通过临床实验得知损伤性气管狭窄HDAC2显著下调表达，TGF-β1、IL-6、IL-8促炎细胞因子明显上调表达；进一步动物实验中证实HDAC2在气管损伤后狭窄家兔模型表达下调，造成局部炎症反应失调，促使I型胶原蛋白、III型胶原蛋白堆积，促进了气管狭窄的发生发展，HDAC2抑制剂伏立诺他可逆转及上调HDAC2能减轻气管狭窄家兔模型急性炎症反应的强度，进而减轻气管狭窄的程度；在脂多糖诱导成纤维细胞体外实验中，HDAC2下调表达，VEGFA、IL-8炎症细胞因子上调表达；最后红霉素、布地奈德、尼达尼布上调HDAC2的表达，通过抗炎作用，起到防治兔气管损伤后气管狭窄的效果。以上说明HDAC2是气管狭窄炎症反应的中心环节，参与了气管损伤后狭窄的调控作用，是减轻气道炎症的靶点，为临床防治气管狭窄提供理论依据和新思路。