The next challenge in pediatric cholestasis: Deciphering the pathogenesis of biliary atresia
The next challenge in pediatric cholestasis: Deciphering the pathogenesis of biliary atresia
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DOI：
10.1097/01.mpg.0000228197.28056.2f
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发表时间：
2006-07-01
影响因子：
2.9
通讯作者：
Bezerra, Jorge A.
中科院分区：
文献类型：
--
作者：
Bezerra, Jorge A.
胆汁淤积是婴儿肝脏疾病的常见症状。新生儿胆汁淤积症的主要表现是胆道闭锁，这是儿童慢性肝病最常见的原因，但对这种疾病的发病机制知之甚少。为了寻找胆道闭锁的分子基础，我们开始了两个方面的研究。在第一项研究中，我们询问了胆道闭锁儿童的肝脏转录组，并在诊断时发现了富含干扰素-γ（IFN-γ）的促炎足迹。为了直接探讨IFN γ是否在胆道损伤和梗阻中起重要作用，我们使用了实验性胆道闭锁的小鼠模型，发现小鼠IFN γ基因的失活降低了淋巴细胞对新生儿胆管的嗜性，并防止了管腔的炎性梗阻。对肝外胆道的进一步分析还概述了在胆管梗阻的发病和进展过程中更广泛的促炎基因网络，以及IFN γ、细胞凋亡和补体驱动网络的时间特异性激活。在第二种方法中，我们通过分析诊断时年龄匹配的受试者的肝脏转录组来寻找区分胆道闭锁临床形式的分子谱。我们发现了一个初步的档案，区分胚胎和围产期形式的胆道闭锁。该图谱包含参与疾病表观遗传机制的基因的差异激活。总的来说，这些研究为胆道闭锁的发病机制提供了新的见解，并确定了潜在的治疗靶点，以促进天然肝脏的长期结局。
Cholestasis is a common presenting symptom of liver disease in infants. Chief among diseases presenting as neonatal cholestasis is biliary atresia, the most common cause of chronic liver disease in children, but little is known about the pathogenesis of this disease. In search for the molecular basis of biliary atresia, we began two areas of investigation. In the first, we interrogated the hepatic transcriptome of children with biliary atresia and found an interferon-gamma (IFN gamma)-rich proinflammatory footprint at the time of diagnosis. To directly explore if IFN gamma plays an important role in biliary injury and obstruction, we used a mouse model of experimental biliary atresia and found that inactivation of the murine Ifn gamma gene decreases the tropism of lymphocytes to neonatal bile ducts and prevents the inflammatory obstruction of the duct lumen. Further analysis of the extrahepatic biliary tract also outlined a broader network of proinflammatory genes at the onset and during progression to duct obstruction, with the time-specific activation of IFN gamma-, apoptosis-, and complement-driven networks. In the second approach, we searched for molecular profiles that differentiate clinical forms of biliary atresia by analyzing the hepatic transcriptome of age-matched subjects at the time of diagnosis. We found a preliminary profile that differentiates the embryonic from the perinatal forms of biliary atresia. The profile contained the differential activation of genes involved in epigenetic mechanisms of disease. Collectively, these studies provide new insight into pathogenesis of biliary atresia and identify potential therapeutic targets to foster long-term outcome with the native liver.