支气管上皮活化维生素D对烟曲霉暴露下肺泡巨噬细胞表型的旁分泌调节研究

Pulmonary aspergillosis has a high incidence and is extremely difficult to cure. Although in lifetime exposure to Aspergillus fumigatus conidia, airway mucosa will not produce inflammatory injury. The balance of pro- and anti-inflammatory phenotype of alveolar macrophages (AMs) plays an important role in avoiding airway inflammatory injury，however, the regulatory mechanism of which is still unclear. Our previous study found that vitamin D can prevent the pro-inflammatory phenotype polarization of AMs, so as to avoid the excessive inflammatory response of AMs in response to Aspergillus fumigatus conidia. It is known that bronchial epithelial cells constitutively express 1α-hydroxylase, the key enzyme for the activation of vitamin D. Our previous study confirmed that the stimulation of Aspergillus fumigatus conidia to bronchial epithelial cells have synergistic effect on the expression of 1α-hydroxylase and the activation of vitamin D in bronchial epithelial cells. In view of that the phenotype of AMs is affected by the micro environment in airway mucosal, we hypothesize that in lifetime exposure to Aspergillus fumigatus conidia, the phenotype of AMs may be regulated by vitamin D activated in bronchial epithelial cells in a paracrine fashion, so as to avoid excessive inflammatory response. To prove the hypothesis, we intend to interference the synthesis of active vitamin D in bronchial epithelial cells in vitro and in vivo. We hope that our study will provide basis for prevention and treatment of pulmonary aspergillosis by targeting the vitamin D signal way in airway mucosa.

肺曲霉病的发病率逐年上升、且极难治愈，促炎和抗炎反应失衡是该病的重要诱因。气道粘膜终生暴露于烟曲霉孢子的刺激中，却不会因此产生炎症损伤，肺泡巨噬细胞（AMs）促炎和抗炎表型平衡在其中发挥关键作用，但其调节机制不明。我们既往研究发现维生素D可以避免AMs表型向促炎方向过度极化，从而避免烟曲霉孢子暴露下AMs的过度炎症应答。已知支气管上皮细胞组成性表达活化维生素D的关键酶1α-羟化酶，课题组前期研究证实烟曲霉孢子的刺激会显著增加支气管上皮细胞内1α-羟化酶的表达，并对其活化维生素D产生协同作用。鉴于AMs的表型受气道粘膜微环境的影响，面对烟曲霉孢子的终生暴露，支气管上皮活化的维生素D极可能对AMs表型产生旁分泌调节，以免其产生过度炎症反应。课题组拟通过在体外和体内分别干扰维生素D在支气管上皮细胞内的活化证实该猜想，并为进一步探究以气道粘膜内的维生素D信号为靶点防治肺曲霉病提供基础。