Integrin αvβ6 and Mediators of Extracellular Matrix Deposition Are Up-Regulated in Experimental Biliary Atresia

Nadler, Evan P.; Patterson, Danielle; Violette, Shelia M.; Weinreb, Paul H.; Lewis, Michael R.; Magid, Margaret S.; Greco, M. Alba

doi:10.1016/j.jss.2008.05.023

Cited by 21 publications

(28 citation statements)

References 30 publications

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“…We initially performed routine hematoxylin and eosin staining, which revealed neutrophil infiltration and bile duct proliferation after RRV infection, but lack of fibrosis ( Figure 3A), similar to previously described findings in this model (4,5). Treatment with MM284 prior to RRV infection revealed a reduction of infiltration of neutrophils and inflammatory foci in the liver confirmed by myeloperoxidase staining when compared with the RRV-only group ( Figure 3A).…”

Section: Mm284 Ameliorates the Inflammatory Response In Ba Micesupporting

confidence: 72%

“…We previously demonstrated a dramatic increase of mRNA expression of certain mediators of inflammation and fibrosis, such as TIMP-1, TIMP-4, PAI-1, MMP-7 and MMP-9 in the mouse model of BA (4). In the present study, we found that treatment with MM284 significantly reduced expression of two of these mediators, TIMP-4 and MMP-7, in the liver homogenates of mice with RRV-induced BA.…”

Section: Mm284 Ameliorates the Inflammatory Response In Ba Micesupporting

confidence: 68%

“…The cDNA pools were generated by the RT reaction using standard reagents (Invitrogen) and Oligo-dT primer and subjected to RT-PCR on an ABI PCR machine using SYBR GreenPCR Master mix (BioRad). The mRNA expression of selected cytokines and fibrotic mediators were then quantified relative to the reference housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH), using techniques previously described (4). All measurements were done in triplicate.…”

Section: Rna Isolation and Real-time Reverse Transcriptase-polymerasementioning

confidence: 99%

“…In our early studies using this model, we demonstrated increased mRNA expression of the matrix metalloproteinases (MMPs) in liver tissue samples of infected mice (4). We had initially suspected that these genes may be upregulated via the transforming growth factor (TGF)β pathway, as we had also seen perturbations in mRNA expression of tissue inhibitor of metalloproteinases (TIMP) Tatiana Iordanskaia, 1 Miroslav Malesevic,2 Gunter Fischer, 3 Tatiana Pushkarsky, 4 Michael Bukrinsky, 4 and Evan P Nadler 1 as well as plasminogen activator inhibitor-1 (PAI-1), which are all regulated by TGFβ. However, several experiments utilizing anti-TGF strategies, comprised mainly of antibody blockade of TGF and its pathway members, failed to demonstrate any effect in this animal model (data not shown).…”

Section: Introductionmentioning

confidence: 99%

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Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia

Iordanskaia

Malešević

Fischer

et al. 2015

Mol Med

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Biliary atresia (BA) is a devastating liver disease of unknown etiology affecting children generally within the first 3 months of life. The disease is manifested by inflammation and subsequent obstruction of the extrahepatic bile ducts, fibrosis and liver failure. The mechanisms responsible for disease pathogenesis are not fully understood, but a number of factors controlled by the SMAD signaling pathway have been implicated. In this study, we investigated the role of a known proinflammatory factor, extracellular cyclophilin A (CypA), in the pathogenesis of biliary atresia using the rhesus rotavirus (RRV) murine model. We used a unique cyclosporine A derivative, MM284, which does not enter cells and therefore inactivates exclusively extracellular cyclophilins, as a potential treatment. We demonstrated that levels of CypA in plasma of RRV-infected mice were increased significantly, and that treatment of mice with MM284 prior to or one day after disease initiation by RRV infection significantly improved the status of mice with experimental BA: weight gain was restored, bilirubinuria was abrogated, liver infiltration by inflammatory cells was reduced and activation of the SMAD pathway and SMAD-controlled fibrosis mediators and tissue inhibitor of metalloproteinases (TIMP)-4 and matrix metalloproteinase (MMP)-7 was alleviated. Furthermore, treatment of human hepatic stellate cells with recombinant cyclophilin recapitulated SMAD2/3 activation, which was also suppressed by MM284 treatment. Our data provide the first evidence that extracellular cyclophilins activate the SMAD pathway and promote inflammation in experimental BA, and suggest that MM284 may be a promising therapeutic agent for treating BA and possibly other intrahepatic chronic disorders.

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Section: Mm284 Ameliorates the Inflammatory Response In Ba Micesupporting

confidence: 72%

Section: Mm284 Ameliorates the Inflammatory Response In Ba Micesupporting

confidence: 68%

Section: Rna Isolation and Real-time Reverse Transcriptase-polymerasementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia

Iordanskaia

Malešević

Fischer

et al. 2015

Mol Med

Self Cite

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“…Other experimental studies in mice demonstrated that expression of ␣ 2 ␤ 1 integrin on cholangiocytes confers susceptibility to rotavirus (RV)-induced experimental biliary atresia (31,44). Integrin blocking assays using monoclonal antibodies and short-interfering RNA led to a significant reduction in attachment and yield of virus in RV-infected cholangiocytes.…”

Section: Cholestatic Liver Diseasesmentioning

confidence: 99%

Role of integrins in fibrosing liver diseases

Patsenker

Stickel

2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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Integrins and other cell adhesion molecules regulate numerous physiological and pathological mechanisms by mediating the interaction between cells and their extracellular environment. Although the significance of integrins in the evolution and progression of certain cancers is well recognized, their involvement in nonmalignant processes, such as organ fibrosis or inflammation, is only beginning to emerge. However, accumulating evidence points to an instrumental role of integrin-mediated signaling in a variety of chronic and acute noncancerous diseases, particularly of the liver.

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Expansion of prominin-1-expressing cells in association with fibrosis of biliary atresia

et al. 2014

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Biliary atresia (BA), the most common cause of end-stage liver disease and the leading indication for pediatric liver transplantation, is associated with intrahepatic ductular reactions within regions of rapidly expanding periportal biliary fibrosis. While the extent of such biliary fibrosis is a negative predictor of long-term transplant-free survival, the cellular phenotypes involved in the fibrosis are not well established. Using a Rhesus rotavirus (RRV)-induced mouse model of BA, we demonstrate significant expansion of a cell population expressing the putative stem/progenitor cell marker PROMININ-1 (PROM1) adjacent to ductular reactions within regions of periportal fibrosis. PROM1positive (pos) cells express Collagen-1α1. Subsets of PROM1pos cells co-express progenitor cell marker CD49f, epithelial marker E-CADHERIN, biliary marker CYTOKERATIN-19, and mesenchymal markers VIMENTIN and α-SMOOTH MUSCLE ACTIN. Expansion of the PROM1pos cell population is associated with activation of Fibroblast Growth Factor (FGF) and Transforming Growth Factor-β (TGFβ) signaling. In vitro co-treatment of PROM1-expressing Mat1a−/− hepatic progenitor cells with recombinant human FGF10 and TGFβ1 promotes morphologic transformation toward a myofibroblastic cell phenotype with increased expression of myofibroblastic genes Collagen-1α1, Fibronectin, and α–Smooth muscle actin. Infants with BA demonstrate similar expansion of periportal PROM1pos cells with activated SMAD3 signaling in association with increased hepatic expression of FGF10, FGFR1, and FGFR2 as well as mesenchymal genes SLUG and SNAIL. Infants with perinatal subtype of BA have higher tissue levels of PROM1 expression than those with embryonic subtype. Conclusion Expansion of collagen-producing PROM1pos cells within the regions of periportal fibrosis is associated with activated FGF and TGFβ pathways in both experimental and human BA. PROM1pos cells may, therefore, play an important role in the biliary fibrosis of BA.

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Integrin αvβ6 and Mediators of Extracellular Matrix Deposition Are Up-Regulated in Experimental Biliary Atresia

Cited by 21 publications

References 30 publications

Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia

Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia

Role of integrins in fibrosing liver diseases

Expansion of prominin-1-expressing cells in association with fibrosis of biliary atresia

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