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Iordanskaia T, Malesevic M, Fischer G, et al. Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia. Mol Med. 2015;21(1):657-664doi: 10.2119/molmed.2015.00076.
Iordanskaia, T., Malesevic, M., Fischer, G., Pushkarsky, T., Bukrinsky, M., & Nadler, E. P. (2015). Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia. Molecular medicine (Cambridge, Mass.), 21(1), 657-664. https://doi.org/10.2119/molmed.2015.00076
Iordanskaia, Tatiana, et al. "Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia." Molecular medicine (Cambridge, Mass.) vol. 21,1 (2015): 657-664. doi: https://doi.org/10.2119/molmed.2015.00076
Iordanskaia T, Malesevic M, Fischer G, Pushkarsky T, Bukrinsky M, Nadler EP. Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia. Mol Med. 2015 Oct;21(1):657-664. doi: 10.2119/molmed.2015.00076. Epub 2015 Jul 24. PMID: 26225831; PMCID: PMC4749494.
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Mol Med. 2015 Oct;21(1):657-664. doi: 10.2119/molmed.2015.00076. Epub 2015 Jul 24.

Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia.

Molecular medicine (Cambridge, Mass.)

Tatiana Iordanskaia, Miroslav Malesevic, Gunter Fischer, Tatiana Pushkarsky, Michael Bukrinsky, Evan P Nadler

Affiliations

  1. Division of Pediatric Surgery, Children's National Medical Center, Washington, District of Columbia, United States of America.
  2. Institute of Biochemistry, Martin Luther-University Halle-Wittenberg, Halle, Germany.
  3. Max-Planck-Institute for Biophysical Chemistry Gottingen, Halle, Germany.
  4. George Washington University School of Medicine and Health Sciences, Department of Microbiology, Immunology and Tropical Medicine Washington, District of Columbia, United States of America.

PMID: 26225831 PMCID: PMC4749494 DOI: 10.2119/molmed.2015.00076

Abstract

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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