- Email: [email protected]
Histamine, via the H4 Histamine Receptor, Decreases Cholangiocarcinoma Growth Both In Vitro and In Vivo by Altering EMT Processes
Su1656
Ischemia Reperfusion of the Hepatic Artery Induces the Functional Damage of Large Bile Ducts by Changes in the Expression of the Cholangiocyte Angiogenic Factors, VEGF and Angiopoietin Shannon Glaser, Romina Mancinelli, Paolo Onori, Antonio Franchitto, Julie Venter, Mellanie White, Fanyin Meng, Anastasia Renzi, Guido Carpino, Wendy Butler, Roberta Sferra, Dustin Staloch, Eugenio Gaudio, Gianfranco Alpini
Initial Development and Characterization of Primary Cultures of Small and Large Intrahepatic Cholangiocytes From Normal Rat Liver Julie Venter, Heather Francis, Fanyin Meng, Mellanie White, Dustin Staloch, Anastasia Renzi, Paolo Onori, Wendy Butler, Eugenio Gaudio, Gianfranco Alpini In the biliary tree, cholangiopathies selectively target bile ducts of specific sizes with changes in their secretory, proliferative and apoptotic activities. Thus, the development of models for studying the heterogeneous functions of cholangiocytes is key. We have isolated small (~8 μm size) and large (~13 μm size) rat cholangiocytes from small and large bile ducts, respectively, and shown that: (i) large cholangiocytes express secretin receptor (SR)==>PKA== >CFTR==>Cl-/HCO3- exchanger AE2, secrete bile in response to secretin, and proliferate in response to cholestasis by activation of cAMP-dependent PKA activation; (ii) the function of small mouse cholangiocytes (not expressing SR) is regulated by activation of IP3/Ca2+dependent signaling; and (iii) during damage of large bile ducts, small cholangiocytes maintain the homeostasis of the biliary tree by amplification of both Ca2+-signaling and acquisition of large cholangiocyte traits. Long-term cultures of small and large rat cholangiocytes are not available. We aim to develop a culture system of small and large rat cholangiocytes that has preservation of biliary functions similar to what happens In Vivo and freshly isolated cholangiocytes. Methods: Our polarized culture of pooled rat cholangiocytes (NRIC, Am J Physiol 284:G1066,2003) was separated into small and large NRIC by counterflow elutriation (2,500 rpm, centripetal forces of 22 ml/min for small NRIC, and 65 ml/min for large NRIC) followed by frequency distribution analysis. Small and large NRIC were analyzed by: (i) staining for CK-19; and (ii) measuring A. the expression of SR, CFTR, Cl-/HCO3exchanger AE2 and cAMP levels in response to secretin; and b. IP3 levels in response to HTMT, an H1 histamine receptor (H1HR) agonist activating IP3/Ca2+-signaling. In small and large NRIC, we studied the proliferation (by PCNA), phosphorylation of Ca2+-dependent PKCα and PKA in response to HTMT and secretin (trophic factor for large cholangiocytes). Small and large NRIC (currently in culture for 2 wk) will be analyzed every 3 passages to determine if they maintain traits of small and large cholangiocytes in long-term cultures. Results: Small (8.4 μm size) and large (12.6 μm size) NRIC were all CK-19 positive. Basal proliferative activity was higher in large compared to small NRIC. Only: (i) large NRIC expressed SR, CFTR, and Cl-/HCO3- exchanger AE2 and respond to secretin with increased cAMP levels, mitosis and PKA phosphorylation; and (ii) small NRIC express H1HR and respond only to HTMT with increased IP3 levels, growth and PKCα phosphorylation. Conclusions: We have isolated small and large NRIC expressing traits of freshly isolated small and large cholangiocytes. The ongoing development of long-term cultures of small and large rat cholangiocytes is key for studying the mechanisms regulating the heterogeneous functions of the biliary tree.
Liver transplantation patients often suffer from biliary dysfunction due to ischemia reperfusion (IR). The mechanisms regulating biliary damage following IR are unknown. Biliary function is regulated via autocrine and paracrine mechanisms by angiogenic factors such as, VEGF and angiopoietin. Studies have shown that VEGF stimulates normal rat biliary proliferation via autocrine mechanisms and VEGF prevents biliary apoptosis triggered by loss of biliary VEGF expression due to chronic hepatic artery ligation. The aim of the study was to demonstrate that IR-induced damage of cholangiocytes is associated with altered expression of biliary angiogenic factors in In Vivo and In Vitro models of IR. Methods: Normal and 1wk BDL rats underwent 24 hr hepatic reperfusion immediately following sham or 30 m of transient occlusion of the hepatic artery (HAIR) or portal vein (PVIR) prior to collecting serum, liver blocks and isolated cholangiocytes. Liver histomorphology, biliary apoptosis, proliferation and intrahepatic bile duct mass (IBDM) as well as the expression of VEGF-A/C, VEGFR-2/R-3, Ang-1/-2, Tie-1 and Tie-2 were evaluated in liver sections. Expression of Bax (pro-apoptotic protein), PCNA, VEGF-A/C, VEGFR-2/3, Ang-1/2 and Tie-1/2 was evaluated by real-time PCR and immunoblots in isolated cholangiocytes. Secretin-stimulated cAMP levels and bile flow (two functional markers of biliary growth) were evaluated in bile fistula rats. Normal rat intrahepatic cholangiocyte cell line (NRIC) were exposed to normoxic or hypoxic conditions for 4 hr and then to normoxia for 1 to 4 hr. Changes in proliferation, apoptosis, expression of VEGF-A/-C, VEGFR-2/-3, Ang1/2 and Tie1/2, and VEGF secretion by NRICC were evaluated. Results: In normal and BDL rats, HAIR (but not PVIR) induced a functional damage of bile ducts as demonstrated by increased apoptosis in sections and Bax expression in purified cholangiocytes. HAIR also decreased proliferation and IBDM in sections, and reduced PCNA expression and secretin-stimulated cAMP levels and bile flow. Both HAIR and PVIR induced lobular damage and focal areas of necrosis compared to sham. HAIR-induced damage of bile ducts was coupled with increased: (i) expression of VEGFA/C, VEGFR-3/R3, Ang-1/2 and Tie-1/2 in bile ducts and purified cholangiocytes; and (ii) VEGF serum levels. In Vitro during hypoxia/normoxia conditions there was increased apoptosis and reduced proliferation of NRIC concomitant with enhanced expression of biliary expression of VEGF-A/-C, VEGFR-2/-3, Ang1/2 and Tie1/2. Biliary damage induced by HAIR In Vivo and hypoxia In Vitro is associated with increased expression of cholangiocyte angiogenic factors, possibly due to a compensatory response to functional damage. The manipulation of cholangiocyte expression/secretion of angiogenic factors may be important for the management of IR induced biliary injury.
Su1657 Su1655
Histamine, via the H4 Histamine Receptor, Decreases Cholangiocarcinoma Growth Both In Vitro and In Vivo by Altering EMT Processes Fanyin Meng, Dustin Staloch, Taylor Francis, Yuyan Han, Heather Francis
Nicotine-Induced Biliary Proliferation Requires Reactive Oxygen Species Generation and is Prevented by Tauroursodeoxycholic Acid Sally Priester, Mk Munshi, Micheleine Guerrier, Shannon Glaser
Background: Cholangiocarcinoma (CCA) is a biliary cancer arising from damaged bile ducts. During carcinogenesis, epithelial-mesenchymal transition (EMT) occurs where normal epithelial cells begin to resemble mesenchymal cells leading to increased invasion potential as the extracellular matrix (ECM) degrades. Histamine exerts its effects via four G-protein receptors (H1-H4 HRs). Clobenpropit is a potent H4HR agonist shown to decrease mammary adenocarcinoma growth. We have shown that (i) cholangiocytes and CCA cell lines express H1-H4 HRs; (ii) stimulation of the H4HR using the potent agonist, clobenpropit decreases CCA migratory potential and growth via decreasing paxillin and fibronectin gene expression. The aims of this study was to evaluate the effects of clobenpropit on (ii) EMT phenotypes and subsequent invasion potential In Vitro and (ii) In Vivo effects of clobenpropit on tumor growth. Methods: In Vitro, we used CCA cells stimulated with 0.2% BSA (basal) or clobenpropit for 6 hours (10 μM). The morphological invasive potential of CCA cells was examined by a Matrigel outgrowth assay. Expression and degradation of the epithelial marker CK-19, the focal contact protein paxillin, and the mesenchymal markers fibronectin, s100A4 and vimentin was evaluated using immunofluorescence. Gene expression for these factors was verified by qPCR. Cell invasion across an ECM layer was quantitated using the Cultrex® BME Cell Invasion Assay, and matrix metalloproteinase (MMP) 1, 2, 3, 9 and 11 mRNA expression was quantitated by qPCR analysis. In Vivo, we performed experiments in nude mice injected with Mz-ChA-1 cells. Mice were treated with either 0.9% NaCl (vehicle) or clobenpropit for 39 days. Tumor volume was recorded every other day. Results: Matrigel morphology analysis demonstrated that modulation of H4HR by clobenpropit significantly affected the development of multicellular protrusions and formation of interacinar bridges, indicators of invasive behavior. After clobenpropit treatment paxillin, fibronectin, s100A4 and vimentin expression was decreased and degraded as demonstrated by immunofluorescence and qPCR. ECM invasion was reduced after clobenpropit treatment along with the up-regulation of the epithelial marker CK-19, demonstrating that this agonist is able to inhibit tumor invasion while promoting mesenchymal to epithelial transition. Furthermore, modulation of H4HR also altered the expression of MMPs, mediators involved in ECM breakdown. In Vivo, clobenpropit significantly decreased tumor volumes compared to vehicle. Conclusion: Modulation of the H4HR by clobenpropit disrupts EMT processes, ECM breakdown, invasion potential and decreases tumor growth. Interruption of tumorigenesis and invasion by histamine regulation may add to therapeutic advances for cholangiocarcinoma treatment.
Nicotine is one of the major components in tobacco and nicotine abuse has been identified as a risk factor for the development of hepatobiliary cancer in patients with primary sclerosing cholangitis. The biological effects of nicotine are mediated by interaction with nicotinic acetylcholine receptors (nAChRs), which is associated with reactive oxygen species (ROS) generation. We have previously demonstrated that nicotine stimulates cholangiocyte proliferation via α7-nAChR that was associated with increased profibrotic gene expression by cholangiocytes and deposition of collagen in portal areas. We have previously shown that tauroursodeoxycholic acid (TUDCA) prevents biliary proliferation during cholestasis and has protective effects during biliary damage. The AIMs of our study were (i) to demonstrate that the proliferative effects of nicotine is due to increased cholangiocyte ROS generation and downstream signaling mechanisms; and (2) to determine that TUDCA prevents the proliferative effects of nicotine. Methods: Studies were performed in our polarized normal intrahepatic cholangiocyte cell line (NRIC). In order to determine the effects of nicotine on ROS generation, NRIC were first pretreated with DCFH-DA (1 μM, indicator of peroxynitrite formation) for 60 minutes at 37°C and then stimulated with nicotine (1μM) for 1 hour in the presence/absence of α-bungarotoxin (ABT, 1 μM, a specific α-7 nAChR antagonist); NAcetyl-Cysteine (NAC, 1mM, an antioxidant) and TUDCA (20 μM). H2O2 (100 μM) was used as a positive control. Samples were analyzed with Cell Biolabs' OxiSelect™ ROS Assay Kit. NRIC were stimulated with nicotine in the presence and absence of NAC and TUDCA and proliferation was measured by MTS proliferation assay. ERK1/2 phosphorylation (a key signaling mechanism for biliary growth was determined by immunoblots in NRIC stimulated with nicotine in the presence and absence of ABT, NAC and TUDCA. To determine that TUDCA inhibits nicotine-induced profibrotic gene expression, TGFβ1 gene expression and secretion was evaluated in NRIC stimulated with nicotine in the presence/absence of NAC and TUDCA by real-time PCR and EIA. Results: Nicotine stimulates ROS generation in NRIC (2-fold), which is blocked by ABT, NAC, and TUDCA. Nicotine-induced proliferation was blocked by pretreatment with NAC and TUDCA indicating the involvement of ROS in the regulation of biliary growth. Nicotine-induce ERK1/2 phosphorylation was also blocked by NAC and TUDCA. NAC and TUDCA inhibited TGFβ1 gene expression and secretion in NRIC stimulated with nicotine. Conclusion: Nicotine-induced cholangiocyte proliferation and TGFβ1 gene expression and secretion is prevented by the antioxidant, NAC, and TUDCA. TUDCA prevention of nicotine-induced ROS generation may be important for blocking the progression of primary sclerosing cholangitis to cholangiocarcinoma.
S-937
AASLD Abstracts
AASLD Abstracts
Su1654
Ischemia Reperfusion of the Hepatic Artery Induces the Functional Damage of Large Bile Ducts by Changes in the Expression of the Cholangiocyte Angiogenic Factors, VEGF and Angiopoietin Shannon Glaser, Romina Mancinelli, Paolo Onori, Antonio Franchitto, Julie Venter, Mellanie White, Fanyin Meng, Anastasia Renzi, Guido Carpino, Wendy Butler, Roberta Sferra, Dustin Staloch, Eugenio Gaudio, Gianfranco Alpini
Initial Development and Characterization of Primary Cultures of Small and Large Intrahepatic Cholangiocytes From Normal Rat Liver Julie Venter, Heather Francis, Fanyin Meng, Mellanie White, Dustin Staloch, Anastasia Renzi, Paolo Onori, Wendy Butler, Eugenio Gaudio, Gianfranco Alpini In the biliary tree, cholangiopathies selectively target bile ducts of specific sizes with changes in their secretory, proliferative and apoptotic activities. Thus, the development of models for studying the heterogeneous functions of cholangiocytes is key. We have isolated small (~8 μm size) and large (~13 μm size) rat cholangiocytes from small and large bile ducts, respectively, and shown that: (i) large cholangiocytes express secretin receptor (SR)==>PKA== >CFTR==>Cl-/HCO3- exchanger AE2, secrete bile in response to secretin, and proliferate in response to cholestasis by activation of cAMP-dependent PKA activation; (ii) the function of small mouse cholangiocytes (not expressing SR) is regulated by activation of IP3/Ca2+dependent signaling; and (iii) during damage of large bile ducts, small cholangiocytes maintain the homeostasis of the biliary tree by amplification of both Ca2+-signaling and acquisition of large cholangiocyte traits. Long-term cultures of small and large rat cholangiocytes are not available. We aim to develop a culture system of small and large rat cholangiocytes that has preservation of biliary functions similar to what happens In Vivo and freshly isolated cholangiocytes. Methods: Our polarized culture of pooled rat cholangiocytes (NRIC, Am J Physiol 284:G1066,2003) was separated into small and large NRIC by counterflow elutriation (2,500 rpm, centripetal forces of 22 ml/min for small NRIC, and 65 ml/min for large NRIC) followed by frequency distribution analysis. Small and large NRIC were analyzed by: (i) staining for CK-19; and (ii) measuring A. the expression of SR, CFTR, Cl-/HCO3exchanger AE2 and cAMP levels in response to secretin; and b. IP3 levels in response to HTMT, an H1 histamine receptor (H1HR) agonist activating IP3/Ca2+-signaling. In small and large NRIC, we studied the proliferation (by PCNA), phosphorylation of Ca2+-dependent PKCα and PKA in response to HTMT and secretin (trophic factor for large cholangiocytes). Small and large NRIC (currently in culture for 2 wk) will be analyzed every 3 passages to determine if they maintain traits of small and large cholangiocytes in long-term cultures. Results: Small (8.4 μm size) and large (12.6 μm size) NRIC were all CK-19 positive. Basal proliferative activity was higher in large compared to small NRIC. Only: (i) large NRIC expressed SR, CFTR, and Cl-/HCO3- exchanger AE2 and respond to secretin with increased cAMP levels, mitosis and PKA phosphorylation; and (ii) small NRIC express H1HR and respond only to HTMT with increased IP3 levels, growth and PKCα phosphorylation. Conclusions: We have isolated small and large NRIC expressing traits of freshly isolated small and large cholangiocytes. The ongoing development of long-term cultures of small and large rat cholangiocytes is key for studying the mechanisms regulating the heterogeneous functions of the biliary tree.
Liver transplantation patients often suffer from biliary dysfunction due to ischemia reperfusion (IR). The mechanisms regulating biliary damage following IR are unknown. Biliary function is regulated via autocrine and paracrine mechanisms by angiogenic factors such as, VEGF and angiopoietin. Studies have shown that VEGF stimulates normal rat biliary proliferation via autocrine mechanisms and VEGF prevents biliary apoptosis triggered by loss of biliary VEGF expression due to chronic hepatic artery ligation. The aim of the study was to demonstrate that IR-induced damage of cholangiocytes is associated with altered expression of biliary angiogenic factors in In Vivo and In Vitro models of IR. Methods: Normal and 1wk BDL rats underwent 24 hr hepatic reperfusion immediately following sham or 30 m of transient occlusion of the hepatic artery (HAIR) or portal vein (PVIR) prior to collecting serum, liver blocks and isolated cholangiocytes. Liver histomorphology, biliary apoptosis, proliferation and intrahepatic bile duct mass (IBDM) as well as the expression of VEGF-A/C, VEGFR-2/R-3, Ang-1/-2, Tie-1 and Tie-2 were evaluated in liver sections. Expression of Bax (pro-apoptotic protein), PCNA, VEGF-A/C, VEGFR-2/3, Ang-1/2 and Tie-1/2 was evaluated by real-time PCR and immunoblots in isolated cholangiocytes. Secretin-stimulated cAMP levels and bile flow (two functional markers of biliary growth) were evaluated in bile fistula rats. Normal rat intrahepatic cholangiocyte cell line (NRIC) were exposed to normoxic or hypoxic conditions for 4 hr and then to normoxia for 1 to 4 hr. Changes in proliferation, apoptosis, expression of VEGF-A/-C, VEGFR-2/-3, Ang1/2 and Tie1/2, and VEGF secretion by NRICC were evaluated. Results: In normal and BDL rats, HAIR (but not PVIR) induced a functional damage of bile ducts as demonstrated by increased apoptosis in sections and Bax expression in purified cholangiocytes. HAIR also decreased proliferation and IBDM in sections, and reduced PCNA expression and secretin-stimulated cAMP levels and bile flow. Both HAIR and PVIR induced lobular damage and focal areas of necrosis compared to sham. HAIR-induced damage of bile ducts was coupled with increased: (i) expression of VEGFA/C, VEGFR-3/R3, Ang-1/2 and Tie-1/2 in bile ducts and purified cholangiocytes; and (ii) VEGF serum levels. In Vitro during hypoxia/normoxia conditions there was increased apoptosis and reduced proliferation of NRIC concomitant with enhanced expression of biliary expression of VEGF-A/-C, VEGFR-2/-3, Ang1/2 and Tie1/2. Biliary damage induced by HAIR In Vivo and hypoxia In Vitro is associated with increased expression of cholangiocyte angiogenic factors, possibly due to a compensatory response to functional damage. The manipulation of cholangiocyte expression/secretion of angiogenic factors may be important for the management of IR induced biliary injury.
Su1657 Su1655
Histamine, via the H4 Histamine Receptor, Decreases Cholangiocarcinoma Growth Both In Vitro and In Vivo by Altering EMT Processes Fanyin Meng, Dustin Staloch, Taylor Francis, Yuyan Han, Heather Francis
Nicotine-Induced Biliary Proliferation Requires Reactive Oxygen Species Generation and is Prevented by Tauroursodeoxycholic Acid Sally Priester, Mk Munshi, Micheleine Guerrier, Shannon Glaser
Background: Cholangiocarcinoma (CCA) is a biliary cancer arising from damaged bile ducts. During carcinogenesis, epithelial-mesenchymal transition (EMT) occurs where normal epithelial cells begin to resemble mesenchymal cells leading to increased invasion potential as the extracellular matrix (ECM) degrades. Histamine exerts its effects via four G-protein receptors (H1-H4 HRs). Clobenpropit is a potent H4HR agonist shown to decrease mammary adenocarcinoma growth. We have shown that (i) cholangiocytes and CCA cell lines express H1-H4 HRs; (ii) stimulation of the H4HR using the potent agonist, clobenpropit decreases CCA migratory potential and growth via decreasing paxillin and fibronectin gene expression. The aims of this study was to evaluate the effects of clobenpropit on (ii) EMT phenotypes and subsequent invasion potential In Vitro and (ii) In Vivo effects of clobenpropit on tumor growth. Methods: In Vitro, we used CCA cells stimulated with 0.2% BSA (basal) or clobenpropit for 6 hours (10 μM). The morphological invasive potential of CCA cells was examined by a Matrigel outgrowth assay. Expression and degradation of the epithelial marker CK-19, the focal contact protein paxillin, and the mesenchymal markers fibronectin, s100A4 and vimentin was evaluated using immunofluorescence. Gene expression for these factors was verified by qPCR. Cell invasion across an ECM layer was quantitated using the Cultrex® BME Cell Invasion Assay, and matrix metalloproteinase (MMP) 1, 2, 3, 9 and 11 mRNA expression was quantitated by qPCR analysis. In Vivo, we performed experiments in nude mice injected with Mz-ChA-1 cells. Mice were treated with either 0.9% NaCl (vehicle) or clobenpropit for 39 days. Tumor volume was recorded every other day. Results: Matrigel morphology analysis demonstrated that modulation of H4HR by clobenpropit significantly affected the development of multicellular protrusions and formation of interacinar bridges, indicators of invasive behavior. After clobenpropit treatment paxillin, fibronectin, s100A4 and vimentin expression was decreased and degraded as demonstrated by immunofluorescence and qPCR. ECM invasion was reduced after clobenpropit treatment along with the up-regulation of the epithelial marker CK-19, demonstrating that this agonist is able to inhibit tumor invasion while promoting mesenchymal to epithelial transition. Furthermore, modulation of H4HR also altered the expression of MMPs, mediators involved in ECM breakdown. In Vivo, clobenpropit significantly decreased tumor volumes compared to vehicle. Conclusion: Modulation of the H4HR by clobenpropit disrupts EMT processes, ECM breakdown, invasion potential and decreases tumor growth. Interruption of tumorigenesis and invasion by histamine regulation may add to therapeutic advances for cholangiocarcinoma treatment.
Nicotine is one of the major components in tobacco and nicotine abuse has been identified as a risk factor for the development of hepatobiliary cancer in patients with primary sclerosing cholangitis. The biological effects of nicotine are mediated by interaction with nicotinic acetylcholine receptors (nAChRs), which is associated with reactive oxygen species (ROS) generation. We have previously demonstrated that nicotine stimulates cholangiocyte proliferation via α7-nAChR that was associated with increased profibrotic gene expression by cholangiocytes and deposition of collagen in portal areas. We have previously shown that tauroursodeoxycholic acid (TUDCA) prevents biliary proliferation during cholestasis and has protective effects during biliary damage. The AIMs of our study were (i) to demonstrate that the proliferative effects of nicotine is due to increased cholangiocyte ROS generation and downstream signaling mechanisms; and (2) to determine that TUDCA prevents the proliferative effects of nicotine. Methods: Studies were performed in our polarized normal intrahepatic cholangiocyte cell line (NRIC). In order to determine the effects of nicotine on ROS generation, NRIC were first pretreated with DCFH-DA (1 μM, indicator of peroxynitrite formation) for 60 minutes at 37°C and then stimulated with nicotine (1μM) for 1 hour in the presence/absence of α-bungarotoxin (ABT, 1 μM, a specific α-7 nAChR antagonist); NAcetyl-Cysteine (NAC, 1mM, an antioxidant) and TUDCA (20 μM). H2O2 (100 μM) was used as a positive control. Samples were analyzed with Cell Biolabs' OxiSelect™ ROS Assay Kit. NRIC were stimulated with nicotine in the presence and absence of NAC and TUDCA and proliferation was measured by MTS proliferation assay. ERK1/2 phosphorylation (a key signaling mechanism for biliary growth was determined by immunoblots in NRIC stimulated with nicotine in the presence and absence of ABT, NAC and TUDCA. To determine that TUDCA inhibits nicotine-induced profibrotic gene expression, TGFβ1 gene expression and secretion was evaluated in NRIC stimulated with nicotine in the presence/absence of NAC and TUDCA by real-time PCR and EIA. Results: Nicotine stimulates ROS generation in NRIC (2-fold), which is blocked by ABT, NAC, and TUDCA. Nicotine-induced proliferation was blocked by pretreatment with NAC and TUDCA indicating the involvement of ROS in the regulation of biliary growth. Nicotine-induce ERK1/2 phosphorylation was also blocked by NAC and TUDCA. NAC and TUDCA inhibited TGFβ1 gene expression and secretion in NRIC stimulated with nicotine. Conclusion: Nicotine-induced cholangiocyte proliferation and TGFβ1 gene expression and secretion is prevented by the antioxidant, NAC, and TUDCA. TUDCA prevention of nicotine-induced ROS generation may be important for blocking the progression of primary sclerosing cholangitis to cholangiocarcinoma.
S-937
AASLD Abstracts
AASLD Abstracts
Su1654