研究胸腺基質淋巴生成素和胸腺基質淋巴生成素接受器在氣喘相關的調控與致病機轉

Abstract

氣喘是兒童常見的發炎性呼吸道疾病。胸腺基質淋巴生成素是一種會引起免疫作用進而引起發炎反應的細胞激素。胸腺基質淋巴生成素和胸腺基質淋巴生成素接受器，目前在氣喘患者的致病機轉中扮演著重要的角色，但是否為氣喘的生物指標尚不清楚。抗胸腺基質淋巴生成素抗體在氣喘氣道重塑與對基質金屬蛋白酶、結締組織生長因子和轉化生長因子-β的影響，以及基質金屬蛋白酶和結締組織生長因子在氣喘氣道重塑中的相關性也值得研究與討論。因此在體外的研究中，我們嘗試研究氣喘和非氣喘兒童的胸腺基質淋巴生成素和胸腺基質淋巴生成素接受器的表現，我們招募了氣喘和非氣喘的兒童並記錄了臨床症狀。我們抽取血液以檢查胸腺基質淋巴生成素，並使用逆轉錄聚合鏈反應和即時聚合酶鏈鎖反應測量胸腺基質淋巴生成素接受器基因的表現。在體內的研究中，我們建立氣喘小鼠模型以評估結締組織生長因子和基質金屬蛋白酶在氣道重塑中的表現並且研究抗胸腺基質淋巴生成素抗體對氣喘氣道重塑的結構變化，同時研究抗胸腺基質淋巴生成素抗體對基質金屬蛋白酶、結締組織生長因子和轉化生長因子-β的影響。在我們對氣喘兒童的研究結果中，胸腺基質淋巴生成素和胸腺基質淋巴生成素接受器在氣喘兒童中顯著高於非氣喘的兒童。在我們對氣喘小鼠氣道重塑的研究結果中，發現結締組織生長因子有顯著的增加並且與基質金屬蛋白酶-9呈現強的正相關，也與氣道平滑肌層厚度呈現強的正相關。抗胸腺基質淋巴生成素抗體可明顯減少肺部氣道結構平滑肌層厚度，降低支氣管肺泡灌洗液中的基質金屬蛋白酶-2、基質金屬蛋白酶-9和肺部的結締組織生長因子、轉化生長因子-β。我們的總結中，胸腺基質淋巴生成素和胸腺基質淋巴生成素接受器可能是氣喘重要的生物指標。結締組織生長因子與基質金屬蛋白酶-9相關並參與氣喘氣道重塑的發病機制。抗胸腺基質淋巴生成素抗體或許對氣喘的氣道重塑具有預防作用，同時會影響基質金屬蛋白酶，結締組織生長因子、轉化生長因子-β等發炎性物質並且減少氣道結構改變。

Asthma is a common inflammatory respiratory disease in children. Thymic stromal lymphopoietin (TSLP) is a cytokine interacting with thymic stromal lymphopoietin receptor (TSLPR) that plays an important role in pathogenesis in patients with asthma. However, the role of TSLP, TSLPR as the biomarkers in asthma remains unclear. The effects of anti-thymic stromal lymphopoietin antibody (anti-TSLP antibody) on MMP, CTGF and TGF-β in airway remodeling of asthma and the correlation between CTGF and MMP in airway remodeling of asthma were still unknown and worthy of investigation. In vitro study, we tried to investigate TSLP and TSLPR levels in asthmatic and non-asthmatic children. We drew blood samples to check TSLP, and measured expression of the TSLPR genes using reverse-transcription polymeric chain reaction (RT-PCR) and real time PCR. In vivo study, we established airway remodeling of asthma in murine model and investigated CTGF expression and its correlation to MMP and airway structural changes. We also examined preventive impact of ant-TSLP antibody on airway structural changes and determine influence of MMP, CTGF and TGF-β in airway remodeling of asthma. The results in vitro study, TSLP and TSLPR were significantly higher in asthmatic than non-asthmatic children. The results in vivo study in airway remodeling of asthma in murine model, CTGF expression significantly increased. CTGF expressions positively correlated with MMP-9, and thickness of smooth muscle layer. The impact of anti-TSLP antibody on airway remodeling, MMP-2, MMP-9 in BALF and lung CTGF, TGF-β expression significantly decreased. Airway structural changes of animals’ lungs show less thickness of smooth muscle layer. In our total conclusion, TSLP and TSLPR might be a significant disease biomarker for asthma. CTGF upregulation correlates with MMP-9 involved in pathogenesis of airway remodeling of asthma. Anti-TSLP antibody had preventive effect to decrease airway structural changes and inflammatory mediators of MMP, CTGF and TGF-β in airway remodeling of asthma.