scholarly journals CFTR dysfunction predisposes to fibrotic liver disease in a murine model

2012 ◽  
Vol 303 (4) ◽  
pp. G474-G481 ◽  
Author(s):  
Camilia R. Martin ◽  
Munir M. Zaman ◽  
Gyanprakash A. Ketwaroo ◽  
Abdul Q. Bhutta ◽  
Emmanuel Coronel ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Liver Disease ◽  
Growth Factor ◽  
Bile Duct ◽  
Bile Duct Injury ◽  
Sclerosing Cholangitis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Fibrotic Liver ◽  
Fibrotic Liver Disease

Cystic fibrosis liver disease (CFLD) is a rapidly progressive biliary fibrosis, resembling primary sclerosing cholangitis that develops in 5–10% of patients with cystic fibrosis. Further research and evaluation of therapies are hampered by the lack of a mouse model for CFLD. Although primary sclerosing cholangitis is linked to both ulcerative colitis and loss of cystic fibrosis transmembrane conductance regulator (CFTR) ion channel function, induction of colitis with dextran sodium sulfate (DSS) in cftr−/− mice causes bile duct injury but no fibrosis. Since profibrogenic modifier genes are linked to CFLD, we examined whether subthreshhold doses of the profibrogenic xenobiotic 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), along with DSS-induced colitis, lead to bile duct injury and liver fibrosis in mice that harbor loss of CFTR function. Exon 10 heterozygous ( cftr+/−) and homozygous ( cftr−/−) mice treated with DDC demonstrated extensive mononuclear cell inflammation, bile duct proliferation, and periductular fibrosis. In contrast, wild-type ( cftr+/+) littermates did not develop bile duct injury or fibrosis. Histological changes corresponded to increased levels of alkaline phosphatase, hydroxyproline, and expression of profibrogenic transcripts for transforming growth factor-β1, transforming growth factor-β2, procollagen α1(I), and tissue inhibitor of matrix metaloproteinase-1. Immunohistochemistry demonstrated fibrosis and activation of periductal fibrogenic cells based on positive staining for lysyl oxidase-like-2, α-smooth muscle actin, and collagen I. These data demonstrate that subthreshold doses of DDC, in conjunction with DSS-induced colitis, results in bile duct injury and periductal fibrosis in mice with partial or complete loss of CFTR function and may represent a useful model to study the pathogenic mechanisms by which CFTR dysfunction predisposes to fibrotic liver disease and potential therapies.

scholarly journals The Role of Hepatic Stellate Cells and Transforming Growth Factor-β1 in Cystic Fibrosis Liver Disease

2002 ◽  
Vol 160 (5) ◽  
pp. 1705-1715 ◽  
Author(s):  
Peter J. Lewindon ◽  
Tamara N. Pereira ◽  
Anita C. Hoskins ◽  
Kim R. Bridle ◽  
Richard M. Williamson ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Liver Disease ◽  
Growth Factor ◽  
Hepatic Stellate Cells ◽  
Transforming Growth Factor ◽  
Stellate Cells ◽  
Transforming Growth Factor Β1

scholarly journals Hepatitis C Virus (HCV) Proteins Induce NADPH Oxidase 4 Expression in a Transforming Growth Factor β-Dependent Manner: a New Contributor to HCV-Induced Oxidative Stress

2009 ◽  
Vol 83 (24) ◽  
pp. 12934-12946 ◽  
Author(s):  
Howard E. Boudreau ◽  
Suzanne U. Emerson ◽  
Agnieszka Korzeniowska ◽  
Meghan A. Jendrysik ◽  
Thomas L. Leto
Keyword(s):  
Oxidative Stress ◽  
Hepatitis C Virus ◽  
Liver Disease ◽  
Hepatitis C ◽  
Growth Factor ◽  
Nadph Oxidase ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Dominant Negative ◽  
Ros Production

ABSTRACT Viral hepatitis-induced oxidative stress accompanied by increased levels of transforming growth factor β (TGF-β) and hepatic fibrosis are hallmarks of hepatitis C virus (HCV) infection. The mechanisms of redox regulation in the pathogenesis of HCV-induced liver disease are not clearly understood. The results of our current studies suggest that reactive oxygen species (ROS) derived from Nox4, a member of the NADPH oxidase (Nox) family, could play a role in HCV-induced liver disease. We found that the expression of HCV (genotype 1a) cDNA constructs (full-length and subgenomic), core protein alone, viral RNA, or replicating HCV (JFH-AM2) induced Nox4 mRNA expression and ROS generation in human hepatocyte cell lines (Huh-7, Huh-7.5, HepG2, and CHL). Conversely, hepatocytes expressing Nox4 short hairpin RNA (shRNA) or an inactive dominant negative form of Nox4 showed decreased ROS production when cells were transfected with HCV. The promoters of both human and murine Nox4 were used to demonstrate transcriptional regulation of Nox4 mRNA by HCV, and a luciferase reporter tied to an ∼2-kb promoter region of Nox4 identified HCV-responsive regulatory regions modulating the expression of Nox4. Furthermore, the human Nox4 promoter was responsive to TGF-β1, and the HCV core-dependent induction of Nox4 was blocked by antibody against TGF-β or the expression of dominant negative TGF-β receptor type II. These findings identified HCV as a regulator of Nox4 gene expression and subsequent ROS production through an autocrine TGF-β-dependent mechanism. Collectively, these data provide evidence that HCV-induced Nox4 contributes to ROS production and may be related to HCV-induced liver disease.

scholarly journals A135 HEPATOLITHIASIS AND CHOLANGIOPATHY IN PEDIATRIC CYSTIC FIBROSIS: A CASE REPORT

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. 156-157
Author(s):  
S Kortbeek ◽  
S Bhandal ◽  
H Machida ◽  
S R Martin ◽  
G J Galante
Keyword(s):  
Cystic Fibrosis ◽  
Abdominal Pain ◽  
Liver Disease ◽  
Bile Duct ◽  
Sclerosing Cholangitis ◽  
Pediatric Population ◽  
Filling Defect ◽  
Biliary Cirrhosis ◽  
Secondary Sclerosing Cholangitis ◽  
Recurrent Pyogenic Cholangitis

Abstract Background Liver disease has emerged as an important cause of cystic fibrosis (CF)-associated morbidity due to recent advancements in management and a resultant increase in life expectancy. Although focal biliary cirrhosis remains the pathognomonic finding in CF, other hepatic manifestations exist but are not as well described, particularly in the pediatric population. Aims Present two rare manifestations of pediatric CF-associated liver disease. Methods In this report, we present a pediatric CF patient with chronic abdominal pain who was found to have hepatolithiasis, cholangitis and secondary sclerosing cholangitis. Results A 12-year-old boy with CF was seen for abdominal pain with functional impairment. He had prior evidence of calculi in the common bile duct (CBD) and right intrahepatic (IH) duct, and had undergone endoscopic retrograde cholangiopancreatography (ERCP) twice with sphincterotomy once. Magnetic resonance cholangiopancreatography (MRCP) at presentation showed dilated CBD and bilateral IH ducts with calculi, evidence of acute cholecystitis and early cholangitis. He subsequently underwent a third ERCP with stone retrieval, stent placement and a laparoscopic cholecystectomy. Ursodiol dose was optimized and antibiotics were initiated. Follow-up MRCP showed improvement in CBD and IH duct dilation; the stent was removed. One month later, a fifth ERCP was performed for worsening symptoms associated with a distal filling defect in the left IH duct. Sludge was removed from the CBD and another stent was placed. A sixth ERCP with stent removal showed no stones. Interval MRCP showed resolution of IH calculi, a CBD filling defect suggestive of sludge, and thickening and enhancement of IH bile ducts with focal areas of alternating narrowing and dilation. He was maintained on antibiotics, and his symptoms persisted over the following months despite resolution of sludge, peri-portal edema and duct-wall enhancement. There was a background of increased IH ductal dilation with “beaded appearance”. Interval imaging has demonstrated persistence of these findings with recurrence of hepatolithiasis in both IH ducts, despite improved symptoms. Conclusions This case describes two rare manifestations of pediatric CF-associated liver disease: hepatolithiasis and secondary sclerosing cholangitis. While CFTR dysfunction alone predisposes to gallstone formation, the patient’s clinical course supports a theory for the development of hepatolithiasis resembling that of recurrent pyogenic cholangitis, whereby bacteriobilia from chronic or recurrent infection may promote lithogenesis in the presence of inflammatory bile duct damage. In this patient, secondary sclerosing cholangitis may have resulted from cycles of cholangitis and hepatolithiasis; alternatively, it may represent under-recognized cholangiopathy in the pediatric CF population. Funding Agencies None

Epigenetic histone methylation regulates transforming growth factor β-1 expression following bile duct ligation in rats

2013 ◽  
Vol 49 (8) ◽  
pp. 1285-1297 ◽  
Author(s):  
Shyr-Ming Sheen-Chen ◽  
Chung-Ren Lin ◽  
Kuan-Hung Chen ◽  
Chien-Hui Yang ◽  
Chien-Te Lee ◽  
...  
Keyword(s):  
Growth Factor ◽  
Bile Duct ◽  
Histone Methylation ◽  
Transforming Growth Factor ◽  
Bile Duct Ligation ◽  
Transforming Growth Factor Β ◽  
Duct Ligation

scholarly journals Induction of colitis in cftr−/− mice results in bile duct injury

2004 ◽  
Vol 287 (2) ◽  
pp. G491-G496 ◽  
Author(s):  
Paola G. Blanco ◽  
Munir M. Zaman ◽  
Omer Junaidi ◽  
Sunil Sheth ◽  
Rhonda K. Yantiss ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Inflammatory Bowel Disease ◽  
Alkaline Phosphatase ◽  
Bile Duct ◽  
Docosahexaenoic Acid ◽  
Bile Duct Injury ◽  
Sclerosing Cholangitis ◽  
Serum Alkaline Phosphatase ◽  
Wild Type ◽  
Inflammatory Bowel

It is unknown why some patients with inflammatory bowel disease develop primary sclerosing cholangitis. We have recently shown that patients with primary sclerosing cholangitis have an increased prevalence of mutations in the gene responsible for cystic fibrosis (CFTR) compared with individuals with inflammatory bowel disease alone. Our aim was to examine whether induction of colitis by oral dextran leads to bile duct injury in mice heterozygous or homozygous for mutations in CFTR. The effect of oral administration of docosahexaenoic acid to correct a fatty acid imbalance associated with cystic fibrosis was also examined to determine whether this would prevent bile duct inflammation. Wild-type mice and mice heterozygous and homozygous for CFTR mutations were given dextran orally for 14 days to induce colitis. Bile duct injury was quantitated by blinded histological scoring and measurement of serum alkaline phosphatase activity. The effect of pretreatment with docosahexaenoic acid for 7 days was examined. Treatment of mice with 100 mg dextran/day for 9 days followed by 85 mg/day for 5 days resulted in a significant increase in bile duct injury as determined by histological scoring in homozygous cystic fibrosis mice compared with wild-type mice ( P = 0.005). The bile duct injury seen in cystic fibrosis mice was reflected in a threefold increase in serum alkaline phosphatase ( P = 0.0006). Pretreatment with oral docosahexaenoic acid decreased both histological evidence of bile duct injury and serum alkaline phosphatase levels. In the setting of colitis, loss of CFTR function leads to bile duct injury.

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