Kendal Updike

Introduction. Primary Sclerosing Cholangitis (PSC) is a cholestatic liver disease affecting bile modification due to damage to cholangiocytes and intra- and extra-hepatic bile ducts1-3. Cholangiocytes are the only cell type in the liver that secrete secretin and express the G-protein coupled secretin receptor3. Through an autocrine mechanism, secretin interacts with secretin receptors (SRs) which triggers stimulation of TGF-β1 release by cholangiocytes4,5. TGF-β1 acts via autocrine mechanisms to increase senescence and fibrosis of cholangiocytes as well as affecting hepatic stellate cells (HSCs) by decreasing their senescence and consequently increasing fibrosis4-6. The Sct/SR/TGF-β1 axis is shown to be upregulated in PSC human samples and results in increased fibrosis and ductular reaction7,8. These findings could suggest that SR knockouts will decrease fibrosis and cellular senescence in mice with PSC. Methods. Currently, MDR2-/- mice are the best model for PSC through genetic depletion of necessary phospholipids resulting in degeneration of cholangiocyte cell membranes9. Sirius red staining was used to detect the presence of collagen as a measure of fibrosis4. Immunofluorescence techniques employed the use of antibodies for collagen type I, α-SMA (alpha smooth muscle actin), and desmin to measure fibrosis4. Results. Knockout of SRs reduces ductular reaction in MDR2-/- mice, as well as demonstrating that SR-/-/Mdr2-/- mice have decreased collagen deposition when compared to Mdr2-/- mice4. Furthermore, SR-/-/Mdr2-/- mice showed decreased presence of type I collagen, actin, and desmin compared to MDR2-/- mice model of PSC4. Subsequent studies have demonstrated similar results using a secretin receptor antagonist, Sec 5–27, to block the Sct/SR/TGF-β1 axis7. Administration of the Sec 5–27 antagonist to Mdr2-/- mice shows decreased ductular reaction and hepatic fibrosis compared to control mice, as well as decreasing TGF-β1 levels in cholangiocytes7. Conclusions. Blocking the Sct/SR/TGF- β1 axis with a SR antagonist may be a target for future therapies to decrease fibrosis, ductular reaction, and hepatic stellate cell senescence. However, future research must identify ways to target the liver and elongate half-life, such as with a nanoparticle approach.

1. Prokopič M, Beuers Management of primary sclerosing cholangitis and its complications: an algorithmic approach. Hepatol Int. 2021;15(1):6-20. doi:10.1007/s12072-020-10118-x
2. Hirschfield GM, Karlsen TH, Lindor KD, Adams DH. Primary sclerosing cholangitis. Lancet. 2013;382(9904):1587-1599. doi:10.1016/S0140-6736(13)60096-3
3. Sato K, Meng F, Giang T, Glaser S, Alpini G. Mechanisms of cholangiocyte responses toinjury. Biochim Biophys Acta Mol Basis Dis. 2018;1864(4 Pt B):1262-1269. doi:10.1016/j.bbadis.2017.06.017
4. Zhou T, Wu N, Meng F, et Knockout of secretin receptor reduces biliary damage and liver fibrosis in Mdr2-/- mice by diminishing senescence of cholangiocytes. Lab Invest. 2018;98(11):1449-1464. doi:10.1038/s41374-018-0093-9
5. Kennedy L, Francis H, Invernizzi P, et Secretin/secretin receptor signaling mediates biliary damage and liver fibrosis in early-stage primary biliary cholangitis. FASEB J. 2019;33(9):10269-10279. doi:10.1096/fj.201802606R
6. Ferreira-Gonzalez S, Lu WY, Raven A, et al. Paracrine cellular senescence exacerbates biliary injury and impairs regeneration. Nat Commun. 2018;9(1):1020. Published 2018 Mar 9. doi:10.1038/s41467- 018-03299-5
7. Wu N, Meng F, Invernizzi P, et The secretin/secretin receptor axis modulates liver fibrosis through changes in transforming growth factor-β1 biliary secretion in mice. Hepatology. 2016;64(3):865-879. doi:10.1002/hep.28622
8. Thoeni C, Waldherr R, Scheuerer J, et al. Expression Analysis of ATP-Binding Cassette Transporters ABCB11 and ABCB4 in Primary Sclerosing Cholangitis and Variety of Pediatric and Adult Cholestatic and Noncholestatic Liver Diseases. Can J Gastroenterol Hepatol. 2019;2019:1085717. Published 2019 Dec 10. doi:10.1155/2019/1085717
9. Mariotti V, Strazzabosco M, Fabris L, Calvisi Animal models of biliary injury and altered bile acid metabolism. Biochim Biophys Acta Mol Basis Dis. 2018;1864(4 Pt B):1254-1261. doi:10.1016/j.bbadis.2017.06.027