色氨酸代谢产物介导翻译后修饰调控PDGFRα活性在哮喘气道重塑中的作用和机制研究

既往研究表明哮喘患者肺组织色氨酸代谢关键酶IDO1活性受损；内源性硫化氢减少，补充硫化氢可抑制哮喘气道重塑，但之间的关联及硫化氢的作用机制尚不明确。已知硫化氢对蛋白质的硫巯基化可改变其生物活性。我们发现硫化氢可诱导气道平滑肌细胞内PDGFRα蛋白发生硫巯基化。因此，我们提出假设，肺组织色氨酸的代谢产物犬尿氨酸（KYN）可通过芳烃受体（AhR）调控硫化氢合成酶的表达，产生的硫化氢通过硫巯基化修饰调节PDGFRα活性，抑制细胞增殖；哮喘时，Th2型细胞因子抑制IDO1，降低肺内硫化氢水平，PDGFRα失去修饰作用，活性增强，促进平滑肌增厚和纤维增生，加重气道重塑。本研究将探索并证实：1.色氨酸代谢和硫化氢生成抑制气道重塑；2.哮喘对IDO1-KYN-AhR的抑制作用；3.AhR转录激活硫化氢合成酶；4.PDGFRα的翻译后修饰降低其酶活性；5.PDGFRα的活性增加促进哮喘气道重塑。

In lung tissue of patients with asthma, the activity of IDO1, the key enzyme of tryptophan metabolism is impaired, and the endogenous hydrogen sulfide is reduced. Supplementation of hydrogen sulfide inhibits airway remodeling in asthma, but the correlation and the targeting mechanism of hydrogen sulfide are not clear. The S-sulfhydration of protein by hydrogen sulfide changes its biological activity. We found that hydrogen sulfide induced S-sulfhydration of PDGFRα protein in airway smooth muscle cells. Therefore, we hypothesized that kynurenine, the metabolite of tryptophan in lung tissue, regulates the expression of hydrogen sulfide synthase through aryl hydrocarbon receptor, and the resulting hydrogen sulfide regulates PDGFRα activity and cell proliferation through S-sulfhydration; in asthma, TH2 cytokines inhibit IDO1, reduce the level of hydrogen sulfide in the lung, lose the modification effect of PDGFRα, enhance activity, promote smooth muscle thickening and fiber proliferation, and aggravate airway remodeling. The research will be carried out from the following aspects. 1. To prove the effects of tryptophan metabolism and hydrogen sulfide production on airway remodeling; 2. To prove the inhibitory effect of asthma on IDO1-KYN-AhR; 3. To prove that AhR transcriptively activates hydrogen sulfide synthase; 4. To prove that the post-translational modification of PDGFRα decreases its enzyme activity; 5. To prove that the change of PDGFRα activity has an effect on airway remodeling in asthma.