支气管哮喘中上皮细胞的损伤与修复

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傅恒 姚欣

南京医科大学第一附属医院  210029

   支气管哮喘是一种异质性疾病，通常以慢性气道炎症、气道重塑及气道高反应性为特征1。由于上皮细胞是外部环境和肺内部环境之间的第一道屏障，因此与支气管哮喘的发生和发展具有重要关联，也使其成为支气管哮喘研究中的一大热点。

   在正常情况下，上皮细胞通过形成紧密连接形成高度受控且几乎不可渗透的屏障2,3。而空气中的颗粒或过敏原可以水解上皮细胞连接进而破坏上皮完整性，并且增强树突细胞呈递抗原的能力4。受损的上皮细胞和周围的巨噬细胞及树突细胞会释放细胞因子对损伤作出反应，包括：EGF、TGF-β、TNF-α、白介素、基质金属蛋白酶（MMP）等5,6，并且周围的成纤维细胞和经过上皮-间质转化（EMT）的成纤维细胞会形成临时的细胞外基质促进上皮修复7。

   就上皮细胞本身而言，其受损时，留在基底层上的基底细胞8或分泌细胞9可作为支气管上皮再生的来源。就过程而言，伤口边缘的上皮细胞失去顶端-基底极性10，并且与邻近的上皮细胞失去接触抑制作用11，迅速迁移，展开并变得扁平，覆盖伤口继而增生最后重新上皮化12，EGF等因子也会形成化学梯度趋化上皮细胞迁移13。

   一般认为，哮喘中上皮细胞受损，修复能力降低，由于增殖功能反应上皮细胞自身修复能力，A Semlali等人研究发现，轻-中度哮喘患者上皮细胞增殖能力受损，上皮下成纤维细胞通过调节TGF-β1活性可以降低正常人的上皮细胞增殖能力14，Hideki Inoue等人发现哮喘患者ErbB2基因表达降低导致上皮细胞增殖能力降低，伤口愈合延迟15。在支气管哮喘中，上皮脱落被认为是其中一个重要特点，反应支气管上皮细胞损伤，在哮喘患者的肺泡灌洗液及诱导痰中发现上皮细胞数量增加16,17，且上皮脱落与气道高反应性具有相关性18。而此观点具有争议性，C Ordoñez等人通过对轻-中度哮喘患者上皮活检发现与健康人相比上皮基底膜剥脱程度相似，且与气道狭窄，气道高反应性无关19，提出上皮脱落是组织采样过程所致。

   而在重症哮喘中，上皮改变则有所不同，与上皮修复受损观点相反，LanceCohen等人通过上皮活检发现重症哮喘患者支气管上皮增殖能力增强，上皮厚度较健康对照及轻度哮喘患者增加，这可能导致其气道重塑。另一项研究也证实了轻-中度哮喘患者上皮细胞增殖能力下降，而重症哮喘患者上皮增殖增强20 ，I. Haj-Salem等人认为这种改变与TGF-β2信号通路相关21,22。这种增殖增强的现象可能是上皮细胞过度修复或无序修复的结果，目前针对重症哮喘上皮修复的研究尚少，需要进一步实验了解其机制及与临床特征的相关性。

   综上所述，哮喘患者气道上皮受刺激后屏障完整性破坏，上皮细胞受损修复能力降低，重症哮喘患者同时还发现其增殖能力增加，可能是导致哮喘发生气道重塑的重要原因。目前有关支气管哮喘中上皮细胞的损伤与修复在哮喘发生发展中的形成机制仍不十分清楚，是否可以通过抑制或逆转受损上皮细胞增殖修复过程治疗哮喘气道重塑尚需进一步探讨。

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