Hedgehog通路在先天性胆道闭锁发病机制中研究进展
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摘要
先天性胆道闭锁(congenital biliary atresia,CBA)是一种新生儿早期胆管疾病,导致肝内肝外胆管不同程度的闭锁并造成肝组织纤维化伴肝胆管不可逆性损伤。它是新生儿阻塞性黄疸和小儿肝移植最主要的原因。其发病机制目前尚未研究清楚,是遗传与环境因素共同作用导致的复杂疾病。Hedgehog信号通路在哺乳动物胚胎发育、器官形成及发育中有重要作用。近期研究发现,Hedgehog信号通路在CBA的发生过程中也发挥重要作用。Hedgehog通路的激活会影响胚胎肝脏发育、增强肝胆管纤维化的发生并且阻碍胆管形态的形成,从而导致CBA的发生。文章重点介绍Hedgehog通路在CBA形成过程中所起的重要作用。
Congenital biliary atresia(CBA) is an early neonatal biliary disease, which results in different degrees of intrahepatic and extrahepatic biliary atresia and liver fibrosis accompanied by irreversible injury of hepatobiliary duct. It is the main cause of neonatal obstructive jaundice and liver transplantation in children. Its pathogenesis has not yet been delineated clearly, and it is a complex disease caused by the combination of genetic and environmental factors. Hedgehog signaling pathway plays an important role in mammalian embryonic development, organ formation and development. Recent studies have found that Hedgehog signaling pathway also plays an important role in the of CBA. Activation of Hedgehog pathway can affect embryonic liver development, enhance the hepatobiliary fibrosis and hinder the formation of bile duct morphology, leading to the development of CBA. This article focuses on the important role of Hedgehog pathway in the formation of CBA.
Congenital biliary atresia(CBA) is an early neonatal biliary disease, which results in different degrees of intrahepatic and extrahepatic biliary atresia and liver fibrosis accompanied by irreversible injury of hepatobiliary duct. It is the main cause of neonatal obstructive jaundice and liver transplantation in children. Its pathogenesis has not yet been delineated clearly, and it is a complex disease caused by the combination of genetic and environmental factors. Hedgehog signaling pathway plays an important role in mammalian embryonic development, organ formation and development. Recent studies have found that Hedgehog signaling pathway also plays an important role in the of CBA. Activation of Hedgehog pathway can affect embryonic liver development, enhance the hepatobiliary fibrosis and hinder the formation of bile duct morphology, leading to the development of CBA. This article focuses on the important role of Hedgehog pathway in the formation of CBA.
引文
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[36]Filmus J,Capurro M,Rast J.Glypicans[J].Genome Biol,2008,9(5):224.
[37]Garcia-Barcelo MM,Yeung MY,Miao XP,et al.Genomewide association study identifies a susceptibility locus for biliary atresia on 10q24.2[J].Hum Mol Genet,2010,19(14):2917-2925.
[38]Tsai EA,Grochowski CM,Loomes KM,et al.Replication of a GWAS signal in a Caucasian population implicates ADD3in susceptibility to biliary atresia[J].Hum Genet,2014,133(2):235-243.
[39]Tang V,Cofer ZC,Cui S,et al.Loss of a candidate biliary atresia susceptibility gene,add3a,causes biliary developmental defects in Zebrafish[J].J Pediatr Gastroenterol Nutr,2016,63(5):524-530.
[40]Cofer ZC,Cui S,EauClaire SF,et al.Methylation microarray studies highlight PDGFA expression as a factor in biliary atresia[J].PLoS One,2016,11(3):e0151521.
[41]Matthews RP,Eauclaire SF,Mugnier M,et al.DNAhypomethylation causes bile duct defects in zebrafish and is a distinguishing feature of infantile biliary atresia[J].Hepatology,2011,53(3):905-914.
[2]Chiu CY,Chen PH,Chan CF,et al.Biliary atresia in preterm infants in Taiwan:a nationwide survey[J].J Pediatr,2013,163(1):100-103.
[3]Wada H,Muraji T,Yokoi A,et al.Insignificant seasonal and geographical variation in incidence of biliary atresia in Japan:a regional survey of over 20 years[J].J Pediatr Surg,2007,42(12):2090-2092.
[4]Yoon PW,Bresee JS,Olney RS,et al.Epidemiology of biliary atresia:a population-based study[J].Pediatrics,1997,99(3):376-382.
[5]Asai A,Miethke A,Bezerra JA.Pathogenesis of biliary atresia:defining biology to understand clinical phenotypes[J].Nat Rev Gastroenterol Hepatol,2015,12(6):342-352.
[6]Strickland AD,Shannon K.Studies in the etiology of extrahepatic biliary atresia:time-space clustering[J].J Pediatr,1982,100(5):749-753.
[7]Sanchez-Valle A,Kassira N,Varela VC,et al.Biliary atresia:epidemiology,genetics,clinical update,and public health perspective[J].Adv Pediatr,2017,64(1):285-305.
[8]Feldman AG,Mack CL.Biliary atresia:clinical lessons learned[J].J Pediatr Gastroenterol Nutr,201,61(2):167-175.
[9]Nusslein-Volhard C,Wieschaus E.Mutations affecting segment number and polarity in Drosophila[J].Nature,1980,287(5785):795-801.
[10]Choi SS,Omenetti A,Witek RP,et al.Hedgehog pathway activation and epithelial-to-mesenchymal transitions during myofibroblastic transformation of rat hepatic cells in culture and cirrhosis[J].Am J Physiol Gastrointest Liver Physiol,2009,297(6):G1093-G1106.
[11]Nagase T,Nagase M,Machida M,et al.Hedgehog signaling:a biophysical or biomechanical modulator in embryonic development?[J].Ann N Y Acad Sci,2007,1101:412-438.
[12]Jacob L,Lum L.Deconstructing the hedgehog pathway in development and disease[J].Science,2007,318(5847):66-68.
[13]傅海涛,杨敏,仲人前.Hedgehog信号通路在肝脏疾病中的研究进展[J].国际检验医学杂志,2013,34(23):3188-3191.
[14]Teperino R,Aberger F,Esterbauer H,et al.Canonical and non-canonical Hedgehog signalling and the control of metabolism[J].Semin Cell Dev Biol,2014,33:81-92.
[15]Yang L,Wang Y,Mao H,et al.Sonic hedgehog is an autocrine viability factor for myofibroblastic hepatic stellate cells[J].J Hepatol,2008,48(1):98-106.
[16]Jung Y,Brown KD,Witek RP,et al.Accumulation of hedgehog-responsive progenitors parallels alcoholic liver disease severity in mice and humans[J].Gastroenterology,2008,134(5):1532-1543.
[17]Nybakken K,Perrimon N.Hedgehog signal transduction:recent findings[J].Curr Opin Genet Dev,2002,12(5):503-511.
[18]Villavicencio EH,Walterhouse DO,Iannaccone PM.The sonic hedgehog-patched-gli pathway in human development and disease[J].Am J Hum Genet,2000,67(5):1047-1054.
[19]Park SM.The crucial role of cholangiocytes in cholangiopathies[J].Gut and liver,2012,6(3):295-304.
[20]Omenetti A,Bass LM,Anders RA,et al.Hedgehog activity,epithelial-mesenchymal transitions,and biliary dysmorphogenesis in biliary atresia[J].Hepatology,2011,53(4):1246-1258.
[21]Witek RP,Yang L,Liu R,et al:Liver cell-derived microparticles activate hedgehog signaling and alter gene expression in hepatic endothelial cells[J].Gastroenterology,2009,136(1):320-330.
[22]Hirose Y,Itoh T,Miyajima A.Hedgehog signal activation coordinates proliferation and differentiation of fetal liver progenitor cells[J].Exp Cell Res,2009,315(15):2648-2657.
[23]Ober EA,Lemaigre FP.Development of the liver:Insights into organ and tissue morphogenesis[J].J Hepatol,2018,68(5):1049-1062.
[24]Choi SS,Witek RP,Yang L,et al.Activation of Rac1promotes hedgehog-mediated acquisition of the myofibroblastic phenotype in rat and human hepatic stellate cells[J].Hepatology,2010,52(1):278-290.
[25]Swiderska-Syn M,Syn WK,Xie G,et al.Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy[J].Gut,2014,63(8):1333-1344.
[26]Ebrahimi H,Naderian M,Sohrabpour AA.New concepts on pathogenesis and diagnosis of liver fibrosis;a review article[J].Middle East J Dig Dis,2016,8(3):166-178.
[27]Michelotti GA,Xie G,Swiderska M,et al.Smoothened is a master regulator of adult liver repair[J].J Clin Invest,2013,123(6):2380-2394.
[28]Xie G,Karaca G,Swiderska-Syn M,et al.Cross-talk between Notch and Hedgehog regulates hepatic stellate cell fate in mice[J].Hepatology,2013,58(5):1801-1813.
[29]Omenetti A,Porrello A,Jung Y,et al.Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans[J].J Clin Invest,2008,118(10):3331-3342.
[30]Syn WK,Jung Y,Omenetti A,et al.Hedgehog-mediated epithelial-to-mesenchymal transition and fibrogenic repair in nonalcoholic fatty liver disease[J].Gastroenterology,2009,137(4):1478-1488.
[31]Guy CD,Suzuki A,Zdanowicz M,et al.Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease[J].Hepatology,2012,55(6):1711-1721.
[32]Philips GM,Chan IS,Swiderska M,et al.Hedgehog signaling antagonist promotes regression of both liver fibrosis and hepatocellular carcinoma in a murine model of primary liver cancer[J].PloS One,2011,6(9):e23943.
[33]Jung HY,Jing J,Lee KB,et al.Sonic hedgehog(SHH)and glioblastoma-2(Gli-2)expressions are associated with poor jaundice-free survival in biliary atresia[J].J Pediatr Surg,2015,50(3):371-376.
[34]Leyva-Vega M,Gerfen J,Thiel BD,et al.Genomic alterations in biliary atresia suggest region of potential disease susceptibility in 2q37.3[J].Am J Med Genet A,2010,152A(4):886-895.
[35]Cui S,Leyva-Vega M,Tsai EA,et al.Evidence from human and zebrafish that GPC1 is a biliary atresia susceptibility gene[J].Gastroenterology,2013,144(5):1107-1115.
[36]Filmus J,Capurro M,Rast J.Glypicans[J].Genome Biol,2008,9(5):224.
[37]Garcia-Barcelo MM,Yeung MY,Miao XP,et al.Genomewide association study identifies a susceptibility locus for biliary atresia on 10q24.2[J].Hum Mol Genet,2010,19(14):2917-2925.
[38]Tsai EA,Grochowski CM,Loomes KM,et al.Replication of a GWAS signal in a Caucasian population implicates ADD3in susceptibility to biliary atresia[J].Hum Genet,2014,133(2):235-243.
[39]Tang V,Cofer ZC,Cui S,et al.Loss of a candidate biliary atresia susceptibility gene,add3a,causes biliary developmental defects in Zebrafish[J].J Pediatr Gastroenterol Nutr,2016,63(5):524-530.
[40]Cofer ZC,Cui S,EauClaire SF,et al.Methylation microarray studies highlight PDGFA expression as a factor in biliary atresia[J].PLoS One,2016,11(3):e0151521.
[41]Matthews RP,Eauclaire SF,Mugnier M,et al.DNAhypomethylation causes bile duct defects in zebrafish and is a distinguishing feature of infantile biliary atresia[J].Hepatology,2011,53(3):905-914.