宣威燃煤相关肺部疾病分子靶标和化学预防研究

Yunnan Xuanwei, is an area with burning smoky coals in unvented households, which has caused high smoking coal related lung disease incidence. However, the researches about xuanwei coal pathogenic molecular targets and chemical prevention are scarce. In our previous study, we has screened 20 significant different molecules using mRNA chip from coal combustion-associated pneumonia, pulmonary atypical hyperplasia, lung cancer specimens in Xuanwei (Result One).Further study shows that CYP1B1, MGST1 and NPC1L1 are high expression in xuanwei lung cancer tissues (Result Two), and they can promote the bronchial epithelial cell proliferation (Result three). TMS, ZnSO4 and Ezetimibe , which are relatively specific intervention drugs of CYP1B1, MGST1 and NPC1L1 ,could reverse the malignant transformation of bronchial epithelial cells induced by PAH obviously (Result Six～Nine). It is showed that CYP1B1, MGST1 and NPC1L1 are likely to become chemoprophylaxis candidate targets of a coal related lung diseases. This project intends to use the mice lung disease model caused by coal, aimed at getting reliable evidence that TMS, ZnSO4 and Ezetimibe target CYP1B1, MGST1 and NPC1L1 to prevent lung disease caused by coal, to provide experimental basis for its primary prevention.

云南宣威传统的室内燃煤习惯，导致燃煤相关肺部疾病发病居高不下，然而有关宣威燃煤致病分子靶标和化学预防的研究十分匮乏。我们前期采用mRNA芯片从宣威燃煤相关肺炎、肺不典型增生、肺癌标本中筛选出20个差异表达基因（结果一）。进一步研究发现，CYP1B1、MGST1和NPC1L1在宣威肺癌组织高表达（结果二）；且均可促进支气管上皮细胞增殖（结果三）；CYP1B1、MGST1和NPC1L1相关特异性干预药物TMS、ZnSO4和Ezetimibe明显逆转PAH诱导的支气管上皮细胞恶性转化（结果七～九）。提示：CYP1B1、MGST1和NPC1L1极有可能成为燃煤相关肺部疾病化学预防的候选靶标。本项目拟利用燃煤所致小鼠肺部疾病模型，旨在获得TMS、ZnSO4和Ezetimibe靶向CYP1B1、MGST1和NPC1L1预防燃煤所致肺部疾病的可靠证据，为其一级预防提供实验依据。

云南宣威独特的二叠纪烟煤成矿环境和传统的室内燃煤习惯，导致燃煤相关肺部疾病发病居高不下；筛选宣威燃煤相关肺部疾病特异的分子靶标，寻找相关化学干预药物对于宣威肺部疾病的防治至关重要。我们前期研究发现，CYP1B1、MGST1 和 NPC1L1可能是燃煤相关肺部疾病化学预防的候选靶标。进一步实验发现，过表达CYP1B1、MGST1和NPC1L1促进BEAS-2B细胞增殖，下调CYP1B1、MGST1和NPC1L1抑制XLA-07细胞增殖，联合应用具有协同增强作用。PAH处理的BEAS-2B细胞增殖能力增强，而TMS、ZnSO4和Ezetimibe逆转BEAS-2B细胞的恶性转化，三药联合处理组效果最好。动物实验中，我们利用宣威燃煤诱导方法构建了肺炎-肺不典型增生-肺癌的动物模型，TMS、ZnSO4和Ezetimibe靶向干预CYP1B1、MGST1和NPC1L1抑制小鼠肺癌转变进程，联合治疗组中TMS+ZnSO4效果最好。由上可见，CYP1B1、MGST1 和 NPC1L1是宣威燃煤相关肺部疾病化学预防的候选靶标，靶向干预可以逆转肺癌疾病进程，为宣威高发肺部疾病的靶向防治提供了实验证据。