miR506通过NF-κB/TGF-β通路对ARDS小鼠相关肺纤维化的影响及机制研究

目的 探究miR506通过核因子-κB(NF-κB)/转化生长因子-β(TGF-β)通路影响急性呼吸窘迫综合征(ARDS)小鼠相关肺纤维化的作用及机制,希望为ARDS相关肺纤维化患者的防治和预后改善提供新思路。方法39只小鼠随机分为对照组(n=10)、脂多糖(LPS)组(n=9)、LPS+NF-κB抑制剂组(n=10)和LPS+miR506抑制剂组(n=10)。除对照组外,其余3组小鼠均采用LPS诱导构建ARDS相关肺纤维化模型,LPS+NF-κB抑制剂组和LPS+miR506抑制剂组小鼠采用NF-κB抑制剂(BAY 11-7082)和miR506抑制剂组(miR506-antagomir)处理,对照组和LPS不做干预。28 d后,苏木精-伊红(HE)染色观察各组小鼠肺组织病理变化;比较各组小鼠体质量、肺湿干重比值(W/D)、肺系数、肿瘤坏死因子-α(TNF-α)、白细胞介素-4(IL-4)、IL-6、IL-1β、上皮细胞钙黏蛋白(E-cadherin)、α-平滑肌肌动蛋白(α-SMA)、波形纤维蛋白(Vimentin)、NF-κB、TGF-β1、SMAD同源物3(SMAD3)和SMAD7水平。结果 HE染色结果显示,对照组小鼠肺泡组织结构完整,未出现水肿及炎症细胞浸润;LPS组小鼠肺组织明显改变,肺泡间隔增厚,肺泡凹陷增多,有不同程度增生、融合出现,可见明显充血及炎症细胞浸润;LPS+NF-κB抑制剂组小鼠肺泡结构较LPS组相对完整,肺泡间隔增厚和肺泡凹陷情况明显改善,水肿及炎症细胞浸润明显缓解;LPS+miR506抑制剂组肺泡组织结构破坏严重,相较于LPS组肺泡间隔和凹陷加剧,增生及肺泡融合情况更明显,充血及炎症细胞浸润程度更重。与对照组比较,LPS组、LPS+NF-κB抑制剂组和LPS+miR506抑制剂组小鼠体质量均减轻,W/D和肺系数升高,差异均有统计学意义(P均<0.05);与LPS组比较,LPS+NF-κB抑制剂组体质量增加,W/D和肺系数下降,差异均有统计学意义(P均<0.05);与LPS+NF-κB抑制剂组比较,LPS+miR506抑制剂组小鼠体质量减轻,W/D和肺系数升高,差异均有统计学意义(P均<0.05)。与对照组比较,LPS组、LPS+NF-κB抑制剂组和LPS+miR506抑制剂组小鼠TNF-α、IL-6、IL-8和IL-1β含量均升高,小鼠肺组织中E-cadherin、SMAD7蛋白表达下调,α-SMA、Vimentin、NF-κB、TGF-β1和SMAD3蛋白表达上调,差异均有统计学意义(P均<0.05);与LPS组比较,LPS+NF-κB抑制剂组小鼠TNF-α、IL-6、IL-8和IL-1β含量均降低,肺组织中E-cadherin、SMAD7蛋白表达上调,α-SMA和Vimentin、NF-κB、TGF-β1和SMAD3蛋白表达均下调,差异均有统计学意义(P均<0.05);与LPS+NF-κB抑制剂组比较,LPS+miR506抑制剂组小鼠TNF-α、IL-6、IL-8和IL-1β含量均升高,肺组织中E-cadherin、SMAD7蛋白表达下调,α-SMA、Vimentin、NF-κB、TGF-β1和SMAD3蛋白表达上调,差异均有统计学意义(P均<0.05)。结论miR506通过抑制炎症反应、α-SMA、Vimentin、NF-κB、TGF-β1和SMAD3表达,上调SMAD7表达来抑制ARDS相关肺纤维化进展,其机制可能与调控NF-κB/TGF-β信号通路有关。

MicroRNA-506 is up-regulated in the development of pancreatic ductal adenocarcinoma and is associated with attenuated disease progression

Background: MicroRNA?506(miR?506) has been reported to function in several tumors as a tumor suppressor gene or oncogene. However, the expression and role of miR?506 in pancreatic ductal adenocarcinoma(PDAC) remains unclear. In this study, we aimed to evaluate the phenotype of miR?506 in PDAC.Methods: Using mi RNA in situ hybridization, we examined the expression of miR?506 in 113 PDACs and 87 paired normal pancreatic tissues. We evaluated mi R?506 expression in PDAC cells, normal pancreatic ducts, and acinus/islands, and we analyzed the associations between miR?506 expression and the clinicopathologic characteristics of PDAC patients.Results: miR?506 expression was higher in PDAC than in matched normal pancreatic ductal cells(P < 0.001). On the other hand, the combined group of well and moderately diferentiated PDACs showed higher levels of mi R?506 than the poorly diferentiated ones(P = 0.023). Moreover, mi R?506 expression was negatively associated with pathologic T category(P = 0.004) and lymph node metastasis(P = 0.033), suggesting that mi R?506 might inhibit the progression of PDAC.Conclusions: Our results suggest that mi R?506 either plays a role as an oncogene in the tumorigenesis and a tumor suppressor in the progression or serves as a house?keeping, tumor?suppressing mi RNA, whose expression can be activated by oncogenic signals in early development to hinder the progression of PDAC.