Pathophysiological Roles of Ductular Reaction in Liver Inflammation and Hepatic Fibrogenesis
2022; Elsevier BV; Volume: 15; Issue: 3 Linguagem: Inglês
10.1016/j.jcmgh.2022.11.006
ISSN2352-345X
AutoresKeisaku Sato, Linh Pham, Shannon Glaser, Heather Francis, Gianfranco Alpini,
Tópico(s)Pediatric Hepatobiliary Diseases and Treatments
ResumoSee counterpoint on page 806. See counterpoint on page 806. Ductular reaction is referred to as expansion of proliferative and reactive cells that express biliary markers, such as cytokeratin (CK)-7 and CK-19.1Sato K. Marzioni M. Meng F. et al.Ductular reaction in liver diseases: pathological mechanisms and translational significances.Hepatology. 2019; 69: 420-430Crossref PubMed Scopus (209) Google Scholar Ductular reaction is identified by histologic staining in liver specimen of patients with various liver diseases including cholangiopathies, viral hepatitis, and alcoholic and nonalcoholic liver diseases.1Sato K. Marzioni M. Meng F. et al.Ductular reaction in liver diseases: pathological mechanisms and translational significances.Hepatology. 2019; 69: 420-430Crossref PubMed Scopus (209) Google Scholar Ductular reaction is clinically recognized as bile duct hyperplasia; however, the term "ductular reaction" is more commonly used in recent studies to define enhanced intrahepatic bile duct mass that can be attributed to the proliferation of cholangiocytes and/or transdifferentiation of various hepatic cells.1Sato K. Marzioni M. Meng F. et al.Ductular reaction in liver diseases: pathological mechanisms and translational significances.Hepatology. 2019; 69: 420-430Crossref PubMed Scopus (209) Google Scholar It is known that ductular reaction is associated with liver fibrosis and thought to be caused by expansion of hepatic progenitor cells (HPCs).2Williams M.J. Clouston A.D. Forbes S.J. Links between hepatic fibrosis, ductular reaction, and progenitor cell expansion.Gastroenterology. 2014; 146: 349-356Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar Accumulating evidence indicates that ductular reaction (ie, expansion of CK-7+ or CK-19+ cells) can be caused not only by HPCs, but also other hepatic cells. Bile duct epithelial cells, cholangiocytes, express CK-7 and CK-19 and proliferate during bile duct injury, which is identified as ductular reaction.1Sato K. Marzioni M. Meng F. et al.Ductular reaction in liver diseases: pathological mechanisms and translational significances.Hepatology. 2019; 69: 420-430Crossref PubMed Scopus (209) Google Scholar Furthermore, in certain pathologic conditions, hepatocytes can transdifferentiate into cholangiocyte-like cells expressing CK-7 or CK-19 to compensate the loss of cholangiocyte numbers and functions.3Nejak-Bowen K. If it looks like a duct and acts like a duct: on the role of reprogrammed hepatocytes in cholangiopathies.Gene Expr. 2020; 20: 19-23Crossref PubMed Scopus (5) Google Scholar Ductular reaction can be induced by expansion of HPCs, cholangiocytes, or hepatocytes, and functional roles of ductular reaction may differ depending on liver diseases or origins of expanding cells. This section discusses the pathophysiological roles of ductular reaction in liver diseases. Hepatic cells communicate with each other to coordinate pathophysiological responses against liver injury via secreting cytokines, chemokines, or extracellular vesicles.4Sato K. Kennedy L. Liangpunsakul S. et al.Intercellular communication between hepatic cells in liver diseases.Int J Mol Sci. 2019; 20: 2180Crossref PubMed Scopus (33) Google Scholar In the portal area and the HPC niche, HPCs, hepatic stellate cells, and macrophages secrete and receive cytokines and growth factors leading to liver inflammation and regeneration.2Williams M.J. Clouston A.D. Forbes S.J. Links between hepatic fibrosis, ductular reaction, and progenitor cell expansion.Gastroenterology. 2014; 146: 349-356Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar Ductular reaction is associated with portal inflammation and neutrophil infiltration in alcoholic hepatitis, and the cells in ductular reaction (CK-7+ cells) express elevated neutrophil recruiting chemokines and HPC markers.5Aguilar-Bravo B. Rodrigo-Torres D. Arino S. et al.Ductular reaction cells display an inflammatory profile and recruit neutrophils in alcoholic hepatitis.Hepatology. 2019; 69: 2180-2195Crossref PubMed Scopus (45) Google Scholar In nonalcoholic fatty liver disease, portal inflammation is strongly correlated with liver fibrosis levels and ductular reaction with increased portal infiltration of macrophages and lymphocytes.6Gadd V.L. Skoien R. Powell E.E. et al.The portal inflammatory infiltrate and ductular reaction in human nonalcoholic fatty liver disease.Hepatology. 2014; 59: 1393-1405Crossref PubMed Scopus (296) Google Scholar Ductular reaction and increased portal macrophage infiltration can also be identified in cholestatic liver injury.7Chen L. Zhou T. Wu N. et al.Pinealectomy or light exposure exacerbates biliary damage and liver fibrosis in cholestatic rats through decreased melatonin synthesis.Biochim Biophys Acta Mol Basis Dis. 2019; 1865: 1525-1539Crossref PubMed Scopus (17) Google Scholar Cholangiocytes become senescent during cholestatic liver injury, including primary sclerosing cholangitis (PSC).8Tabibian J.H. O'Hara S.P. Splinter P.L. et al.Cholangiocyte senescence by way of N-ras activation is a characteristic of primary sclerosing cholangitis.Hepatology. 2014; 59: 2263-2275Crossref PubMed Scopus (179) Google Scholar Senescent cholangiocytes function as a senescence-associated secretory phenotype secreting various cytokines, such as interleukin-6 and transforming growth factor-β1.8Tabibian J.H. O'Hara S.P. Splinter P.L. et al.Cholangiocyte senescence by way of N-ras activation is a characteristic of primary sclerosing cholangitis.Hepatology. 2014; 59: 2263-2275Crossref PubMed Scopus (179) Google Scholar Interleukin-6 promotes cholangiocyte proliferation and activates macrophages leading to ductular reaction and liver inflammation.9Sato K. Meng F. Giang T. et al.Mechanisms of cholangiocyte responses to injury.Biochim Biophys Acta. 2018; 1864: 1262-1269Crossref PubMed Scopus (51) Google Scholar These findings indicate the close relationship between ductular reactive cells (ie, HPCs and cholangiocytes) and portal infiltration and inflammation. Liver fibrosis is observed in various liver diseases, and the association of expansion of the HPC niche (ie, ductular reaction) with liver fibrosis has been identified.2Williams M.J. Clouston A.D. Forbes S.J. Links between hepatic fibrosis, ductular reaction, and progenitor cell expansion.Gastroenterology. 2014; 146: 349-356Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar Liver fibrosis is a hallmark in cholangiopathies, such as PSC, primary biliary cholangitis, and biliary atresia, and ductular reaction is identified along with liver fibrosis.1Sato K. Marzioni M. Meng F. et al.Ductular reaction in liver diseases: pathological mechanisms and translational significances.Hepatology. 2019; 69: 420-430Crossref PubMed Scopus (209) Google Scholar Expansion of CK-7+ or CK-19+ cells is found in liver sections of patients with hepatitis B or C virus infection, and ductular reaction levels are correlated with liver fibrosis levels.10Prakoso E. Tirnitz-Parker J.E. Clouston A.D. et al.Analysis of the intrahepatic ductular reaction and progenitor cell responses in hepatitis C virus recurrence after liver transplantation.Liver Transpl. 2014; 20: 1508-1519Crossref PubMed Scopus (21) Google Scholar Ductular reaction levels also correlate with poor prognosis of patients with alcoholic hepatitis and can be used to predict survival rates of patients in severe conditions.11Atkinson S.R. Aly M. Remih K. et al.Serum keratin 19 (CYFRA21-1) is a prognostic biomarker in severe alcoholic hepatitis.Liver Int. 2022; 42: 1049-1057Crossref PubMed Scopus (1) Google Scholar A higher grade of ductular reaction determined by histologic CK-7 staining is correlated with higher fibrosis stages in patients with nonalcoholic fatty liver disease.6Gadd V.L. Skoien R. Powell E.E. et al.The portal inflammatory infiltrate and ductular reaction in human nonalcoholic fatty liver disease.Hepatology. 2014; 59: 1393-1405Crossref PubMed Scopus (296) Google Scholar It is also suggested that ductular reaction is associated with hepatocellular carcinoma. Peritumoral ductular reaction significantly correlates with hepatic inflammation, liver fibrosis, TNM stages, and poor prognosis,12Xu M. Xie F. Qian G. et al.Peritumoral ductular reaction: a poor postoperative prognostic factor for hepatocellular carcinoma.BMC Cancer. 2014; 14: 65Crossref PubMed Scopus (20) Google Scholar indicating the association of ductular reaction with the pathophysiology of various liver diseases. Liver fibrosis is caused by accumulated extracellular matrix (ECM) secreted from activated hepatic stellate cells or myofibroblasts, major sources of ECM secretion. During PSC, senescent cholangiocytes secrete transforming growth factor-β1, which promotes hepatic stellate cell proliferation and activation leading to ECM accumulation and liver fibrosis.13Wu N. Meng F. Zhou T. et al.The secretin/secretin receptor axis modulates ductular reaction and liver fibrosis through changes in transforming growth factor-beta1-mediated biliary senescence.Am J Pathol. 2018; 188: 2264-2280Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar Because ductular reaction and liver fibrosis are closely associated and mediated by ductular reactive cells, including cholangiocytes, these cells can be a therapeutic target for liver fibrosis. Inhibition of biliary senescence by p16 Vivo-Morpholino administration downregulated cholangiocyte senescence-associated secretory phenotype secretion with attenuated ductular reaction and liver fibrosis in PSC mouse models.14Kyritsi K. Francis H. Zhou T. et al.Downregulation of p16 decreases biliary damage and liver fibrosis in the Mdr2-/- mouse model of primary sclerosing cholangitis.Gene Expr. 2020; 20: 89-103Crossref PubMed Scopus (19) Google Scholar Cholangiocytes undergo epithelial-to-mesenchymal transition and transform into myofibroblast-like profibrogenic phenotypes secreting robust ECM components contributing to hepatic fibrogenesis in cholestatic liver injury.15Zhou T. Kyritsi K. Wu N. et al.Knockdown of vimentin reduces mesenchymal phenotype of cholangiocytes in the Mdr2-/- mouse model of primary sclerosing cholangitis (PSC).EBioMedicine. 2019; 48: 130-142Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar Inhibition of cholangiocyte epithelial-to-mesenchymal transition by vimentin Vivo-Morpholino attenuated ductular reaction and liver fibrosis in PSC mouse models.15Zhou T. Kyritsi K. Wu N. et al.Knockdown of vimentin reduces mesenchymal phenotype of cholangiocytes in the Mdr2-/- mouse model of primary sclerosing cholangitis (PSC).EBioMedicine. 2019; 48: 130-142Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar Vimentin knockdown also ameliorated liver inflammation and serum transforming growth factor-β1 levels in PSC mice.15Zhou T. Kyritsi K. Wu N. et al.Knockdown of vimentin reduces mesenchymal phenotype of cholangiocytes in the Mdr2-/- mouse model of primary sclerosing cholangitis (PSC).EBioMedicine. 2019; 48: 130-142Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar These findings support the close association of ductular reaction and liver fibrosis, and inhibition of ductular reaction can be therapeutic in liver diseases. Current studies show the pathophysiological roles of ductular reaction and its close association with hepatic inflammation and liver fibrosis in various liver diseases (Figure 1). In PSC, inhibiting cholangiocyte senescence or epithelial-to-mesenchymal transition could be a novel therapeutic approach to improve liver conditions by attenuating ductular reaction and liver fibrosis, showing the potentials of cholangiocytes as a promising target of liver diseases. However, not only cholangiocytes but also HPCs and hepatocytes are involved in ductular reaction. The HPC niche is associated with liver fibrosis,2Williams M.J. Clouston A.D. Forbes S.J. Links between hepatic fibrosis, ductular reaction, and progenitor cell expansion.Gastroenterology. 2014; 146: 349-356Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar and elevated HPC marker expression (ie, expansion of the HPC niche) is associated with neutrophil infiltration and liver inflammation.5Aguilar-Bravo B. Rodrigo-Torres D. Arino S. et al.Ductular reaction cells display an inflammatory profile and recruit neutrophils in alcoholic hepatitis.Hepatology. 2019; 69: 2180-2195Crossref PubMed Scopus (45) Google Scholar Hepatocytes transdifferentiate into biliary-like phenotypes during cholestatic liver injury.3Nejak-Bowen K. If it looks like a duct and acts like a duct: on the role of reprogrammed hepatocytes in cholangiopathies.Gene Expr. 2020; 20: 19-23Crossref PubMed Scopus (5) Google Scholar Although it is not fully elucidated how HPCs and hepatocytes contribute to the pathophysiology of ductular reaction and liver fibrosis, targeting HPCs and hepatocytes might be another therapeutic approach in liver diseases. In conclusion, ductular reaction is closely related to liver inflammation and fibrosis and the pathophysiology of liver diseases. Understanding the full dynamic role of ductular reaction during liver injury and identification of potential targets associated with ductular reaction are of paramount significance. Ductular Reaction and Liver Regeneration: Fulfilling the Prophecy of Prometheus!Cellular and Molecular Gastroenterology and HepatologyVol. 15Issue 3PreviewMany acute and chronic liver injuries exhibit histologically as proliferating cholangiocytes, commonly referred to as ductular reaction. The origin of the cells comprising the ductular reaction is dependent on the injury (hepatocyte vs cholangiocyte) and capability of these 2-liver epithelial or "hepithelial" cells to divide and replace injured cells. The role of ductular reaction in hepatobiliary injury versus repair remains debated. Although ductular reaction has been shown to be a source of proinflammatory and profibrogenic factors, it has also been shown to contribute toward maintaining hepatobiliary function during injury. Full-Text PDF Open Access
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