Protein tyrosine phosphatase SHP2 regulates TGF-β1 production in airway epithelia and asthmatic airway remodeling in mice.
Protein tyrosine phosphatase SHP2 regulates TGF-β1 production in airway epithelia and asthmatic airway remodeling in mice.
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作者：
Qin XJ;Zhang GS;Zhang X;Qiu ZW;Wang PL;Li YW;Li W;Xie QM;Ke YH;Lee JJ;Shen HH
气道上皮细胞中产生的转化生长因子 (TGF)-β1 被认为是哮喘患者气道重塑的一个贡献者。蛋白酪氨酸磷酸酶 SHP2 是 TGF-β1 产生的明显调节剂，因此是气道重塑的潜在调节剂。通过使用实验性 OVA 诱导气道重塑的小鼠模型来定义 SHP2 调节气道上皮细胞哮喘反应的信号事件。作为过敏原激发研究的一部分，Shp2flox/flox 小鼠的气道被表达 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，该研究使用卵清蛋白 (OVA) 致敏并反复接受 OVA 攻击的小鼠。评估了几种终点病理学，包括气道高反应性（AHR）、肺部炎症评分、支气管周围胶原沉积和α-平滑肌肌动蛋白（SMA）增生。使用气道上皮细胞 (BEAS-2B) 的体外研究用于研究 SHP2 在肺重塑事件调节中的作用，包括胶原蛋白、α-SMA 和 TGF-β1 的表达。野生型小鼠的慢性 OVA 挑战导致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）、平滑肌增生和 AHR 显着增加）。这些终点病理学指标均因气道上皮细胞中的条件性 shp2 基因敲低而显着减弱。使用 BEAS-2B 细胞的体外研究还表明，这些细胞产生的 TGF-β1 水平与 shp2 基因表达的程度相关。气道上皮细胞中的 SHP2 活性似乎可以调节 TGF-β1 的产生，进而调节过敏原激发后的过敏性气道重塑。我们的研究结果表明，SHP2 是与过敏原挑战相关的气道重塑和肺功能障碍的一个先前被低估的贡献者。因此，SHP2 代表了治疗哮喘的潜在新治疗靶点。
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. 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. The airways of Shp2flox/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. 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. SHP2 activities in airway epithelial cells appear to modulate TGF-β1 production and, in turn, regulate allergic airway remodeling following allergen provocation. 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.
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