ALLERGY：SHP2或是哮喘患者一个潜在的新治疗目标

图4 C 示：删除气道上皮细胞内的SHP2，可防止气道平滑肌增生及支气管周围胶原沉积。该图为有代表性的显微照片，显示支气管周围胶原沉积（箭头）。马松马松三色染色检测（蓝色）。所示数据均来自两个独立的实验组，每组有试验小鼠5~6只。

支气管哮喘患者可出现气道重塑，而气道上皮细胞所产生的转化生长因子（TGF）-β1已被认为是导致这一现象的一个原因。由于蛋白酪氨酸磷酸酶SHP2已被证实能调节TGF-β1β的生成，因而其也可能对患者的气道重塑具有潜在的调节作用。

为了明确SHP2在调控气道上皮细胞的哮喘反应时所发生的信号活动。来自我国浙江大学医学院附属第二医院呼吸与危重医学科的沈华浩及其同事，利用实验性OVA诱导的气道重塑小鼠模型进行了一项研究，研究结果在线发表于2012年12月的欧洲《变态反应学》（ALLERGY）杂志上。研究结果显示：气道上皮细胞的SHP2活动似乎可以调节TGF-β1的生成，并进而调节由过敏原激发所引起的过敏性气道重塑过程。

作为变应原激发试验的一部分，该试验使用了由卵蛋白（OVA）致敏的小鼠模型，并应用卵蛋白对其进行了反复激发。研究者使用表达Cre重组酶-绿色荧光蛋白（GFP）融合蛋白的重组腺病毒载体感染了这种SHP2（flox/flox）转基因小鼠的气道。研究的终点病理指标包括气道高反应性（AHR）、肺部炎症评分、支气管周围的胶原沉积、和α平滑肌肌动蛋白（SMA）增生等，研究者对这几个指标进行了评估。在体外试验中，研究者还利用气道上皮细胞（BEAS-2B）对SHP2在肺重塑活动中的调节作用，包括胶原蛋白、α-SMA、和TGF-β1的表达等进行了研究。

该研究的主要结果为：对野生型小鼠进行慢性的OVA抗原刺激，可导致其气道重塑和肺功能障碍（例如，炎症评分增加、胶原沉积-纤维化、平滑肌增生、以及气道高反应性的显著增加）。这些终点病理指标均可因气道上皮细胞内SHP2基因的敲除而显著减轻。而使用BEAS-2B细胞进行的体外研究也证实，这些细胞所产生的TGF-β1水平与其SHP2基因的表达程度相关。

该研究结果显示：气道上皮细胞的SHP2活动似乎可以调节TGF-β1的生成，并进而调节由过敏原激发所引起的过敏性气道重塑过程。研究者认为，他们的研究结果说明：在与过敏原刺激相关的气道重塑和肺功能障碍发生过程中，SHP2的作用此前被低估了；因此，SHP2可能是哮喘患者一个潜在的新的治疗目标。

综上所述，研究者认为：气道上皮细胞蛋白酪氨酸磷酸酶SHP2似乎可以调节TGF-β1的信号活动。同时，在导致呼吸道过敏性炎症小鼠模型发生气道重塑和肺功能障碍的过程中，可能存在一个或更多的细胞调节路径，而SHP2也是这种细胞调节路径的一部分。

Protein tyrosine phosphatase SHP2 regulates TGF-β1 production in airway epithelia and asthmatic airway remodeling in mice.
BACKGROUND
Transforming growth factor (TGF)-β1 produced in airway epithelia has been suggested as a contributor to the airway remodeling observed in asthma patients. The protein tyrosine phosphatase SHP2 is a demonstrable modulator of TGF-β1 production and thus a potential regulator of airway remodeling.
OBJECTIVES
To define the signal event by which SHP2 regulates asthmatic responses in airway epithelial cells by using a mouse model of experimental OVA-induced airway remodeling.
METHODS
The airways of Shp2(flox/flox) mice were infected with recombinant adenovirus vectors expressing a Cre recombinase-green fluorescence protein (GFP) fusion protein as part of allergen provocation studies using mice sensitized with ovalbumin (OVA) and repeatedly challenged with OVA. Several endpoint pathologies were assessed, including airway hyper-responsiveness (AHR), lung inflammatory score, peribronchial collagen deposition, and α-smooth muscle actin (SMA) hyperplasia. In vitro studies using airway epithelial cells (BEAS-2B) were used to investigate the role of SHP2 in the regulation of pulmonary remodeling events, including the expression of collagen, α-SMA, and TGF-β1.
RESULTS
Chronic OVA challenges in wild-type mice resulted in airway remodeling and lung dysfunction (e.g., increased inflammatory scores, collagen deposition (fibrosis), smooth muscle hyperplasia, and a significant increase in AHR). These endpoint pathology metrics were each significantly attenuated by conditional shp2 gene knockdown in airway epithelia. In vitro studies using BEAS-2B cells also demonstrated that the level of TGF-β1 production by these cells correlated with the extent of shp2 gene expression.
CONCLUSIONS
SHP2 activities in airway epithelial cells appear to modulate TGF-β1 production and, in turn, regulate allergic airway remodeling following allergen provocation.
CLINICAL IMPLICATIONS
Our findings identify SHP2 as a previously underappreciated contributor to the airway remodeling and lung dysfunction associated with allergen challenge. As such, SHP2 represents a potentially novel therapeutic target for the treatment of asthmatics.
CAPSULE SUMMARY
Airway epithelial protein tyrosine phosphatase SHP2 appears to modulate TGF-β1 activities as part of one or more cellular pathways leading to regulating the airway remodeling and lung dysfunction occurring in mouse models of allergic respiratory inflammation.