Yıl 2020, Cilt 11 , Sayı 39, Sayfalar 26 - 30 2020-05-19

The Effects of Halofuginone and Ursodeoxycholic Acid in Prevention of Sclerosing Cholangitis Caused by Scolocidal Agents
Skolosidal Ajanlardan Kaynaklanan Sklerozan Kolanjitin Önlenmesinde Halofuginon ve Ursodeoksikolik Asidin Etkileri

Doğan YILDIRIM [1] , Okan Murat AKTÜRK [2] , Ahmet KOCAKUŞAK [3] , Mikail ÇAKIR [4] , Oğuzhan SUNAMAK [5] , Adnan HUT [6] , Abdullah Kağan ZENGİN [7] , Murat ÖZCAN [8] , Hilal AKI [9] , Huriye BALCI [10]


Aim: Biliary sclerosis is a life treatening condition caused by auto-immunity, operative trauma, toxic agents, cancer and chronic inflammatory conditions. The liver tissue may progress into overt cirrhosis by the progression of fibrotic scar tissue. Halofuginone, which is the active component of the plant alkaloid febrifugine, has been shown to inhibit fibrosis. 


Material and Method: Fifty rats were randomized on 5 groups to form a biliary sclerosis model by a scolocidal agent povidone iodine(PI) injection into the common bile duct with a control group of saline infusion included. The four PI groups were later treated by halofuginone, ursodeoxycholic acid (UDCA), with both and none. The rats were sacrificed 90 days later for intrahepatic and hilar fibrosis. Laboratory parameters of liver damage and levels of hydroxypryroline to show collagen degradation were obtained and histological examination of the liver and the common bile duct for fibrotic changes were carried out. 


Results: With or without application of ursodeoxycholic acid, the halofuginone groups showed significantly less sclerosis according to histological analysis. In regard to serum analysis of SGOT,  SGPT and ALP; there were significant differences between “PI only” group and halofuginone groups. GGT was significantly high in “PI only” group. There was not any significant difference between the groups in regard to bilirubin levels. Hydroxyproline serum levels were highest in “PI only” group,  followed by “UDCA only” group and then halofuginone groups.


Conclusion: Halofuginone was effective in preventing fibrosis as an additional medical therapy to UDCA in an induced sclerosing cholangitis model in rats.

Amaç: Biliyer skleroz, otoimmünite, operatif travma, toksik ajanlar, kanser ve kronik inflamatuvar koşulların neden olduğu yaşamı tehdit eden durumdur. Karaciğer dokusu, fibrotik skar dokusunun ilerlemesi ile belirgin siroza doğru ilerleyebilir. Alkaloid febrifugine bitkisinin aktif bileşeni olan  halofuginonun, fibrozisi inhibe ettiği gösterilmiştir.


Gereç ve Yöntemler: Elli sıçan, bir tanesi salin infüzyonu içeren bir kontrol grubu da içinde olmak üzere beş gruba randomize edilerek, koledoka skolosidal bir ajan olan povidon iyot (PI) enjeksiyonu ile bir biliyer skleroz modeli oluşturuldu. PI grupları (kontrol hariç tüm gruplar) daha sonra ya halofuginon, ya ursodeoksikolik asit (UDCA), ya ikisi beraber, ya da hiçbir madde verilmeyerek 90 gün takip edildi. Takip sonunda sıçanlar, intrahepatik ve hiler fibrozis tespiti için sakrifiye edildi. Karaciğer hasarının laboratuvar parametreleri ve kollajen degradasyonunu göstermek üzere hidroksiprolin düzeyleri serumda çalışıldı. Fibrotik değişikliklerin analizi için karaciğer ve koledokun histolojik incelemesi yapıldı.


Bulgular: Ursodeoksikolik asit kullanılmış olsun veya olmasın, halofuginon kullanılan grupların histolojik analizinde diğer gruplara göre istatistiksel açıdan alamlı derecede az skleroz mevcut idi. SGOT, SGPT ve ALP'nin serum analizleri incelendiğinde; "sadece PI kullanılan grup" ve halofuginon grupları arasında anlamlı farklılıklar vardı. GGT sadece PI kullanılan grup için anlamlı derecede yüksekti. Bilirubin düzeyleri açısından gruplar arasında anlamlı fark yoktu. Hidroksiprolin serum düzeyleri "sadece PI kullanılan grup" için en yüksek olup, bunu sadece UDCA kulanılan grup ve ardından halofuginon grupları izledi.


Sonuç: Halofuginon, sıçanlarda indüklenen bir sklerozan kolanjit modelinde UDCA'ya ek bir tıbbi tedavi olarak karaciğer ve safra yollarında fibrozun önlenmesinde etkili olmuştur.   

  • Portmann B, Zen Y. Inflammatory disease of the bile ducts-cholangiopathies: liver biopsy challenge and clinicopathological correlation. Histopathology 2012; 60: 236–48.
  • Hirschfield GM, Karlsen TH, Lindor KD, Adams DH. Primary sclerosing cholangitis. Lancet 2013; 382:1587–99.
  • MacCarty RL, LaRusso NF, Wiesner RH, Ludwig J. Primary sclerosing cholangitis: findings on cholangiography and pancreatography. Radiology 1983; 149: 39–44.
  • Tsochatzis EA, Bosch J, Burroughs AK. Liver cirrhosis. Lancet 2014; 383: 1749–61.
  • Penz-Österreicher M, Österreicher CH, Trauner M. Fibrosis in autoimmune and cholestatic liver disease. Best Pract Res Clin Gastroenterol 2011; 25: 245–58.
  • Ruemmele P, Hofstaedter F, Gelbmann CM. Secondary sclerosing cholangitis. Nat Rev Gastroenterol Hepatol 2009; 6:287-95.
  • Coatney GR, Cooper WC, Culwell WB, White WC, Imboden CA Jr. Studies in human malaria. XXV. Trial of febrifugine, an alkaloid obtained from Dichroa febrifuga lour., against the Chesson strain of Plasmodium vivax. J Natl Malar Soc 1950; 9: 183–6.
  • Sundrud MS, Koralov SB, Feuerer M, Calado DP, Kozhaya AE, Rhule-Smith A, et al. Halofuginone inhibits TH17 cell differentiation by activating the amino acid starvation response. Science 2009; 324: 1334–8.
  • Keller TL, Zocco D, Sundrud MS, Hendrick M, Edenius M, Yum J, et al. Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase. Nat Chem Biol 2012; 8: 311-7.
  • Ward A, Brogden RN, Heel RC, Speight TM, Avery GS. Ursodeoxycholic acid: a review of its pharmacological properties and therapeutic efficacy. Drugs 1984;27:95-131.
  • Saksena S, Tandon RK. Ursodeoxycholic acid in the treatment of liver diseases. Postgraduate Med J 1997; 73: 75-80.
  • Paumgartner G, Beuers U. Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. Hepatology 2002; 36: 525-531.
  • Hohenester S, Oude-Elferink RPJ, Beuers U. Primary biliary cirrhosis. Seminars in Immunopathology. 2009;31(3):283-307.
  • Zhen YZ, Li NR, He HW, Zhao SS, Zhang GL, Hao XF, et al. Protective effect of bicyclol against bile duct ligation-induced hepatic fibrosis in rats. World J Gastroenterol 2015; 21: 7155-64.
  • Reyes-Gordillo K, Segovia J, Shibayama M, Tsutsumi V, Vergara P, Moreno MG, et al. Curcumin prevents and reverses cirrhosis induced by bile duct obstruction or CCl4 in rats: role of TGF-beta modulation and oxidative stress. Fundam Clin Pharmacol 2008; 22:417–27.
  • Pines M, Halevy O. Halofuginone and muscular dystrophy. Histol Histopathol 2011;26: 135-46.
  • Cui Z, Crane J, Xie H, Jin X, Zhen G, Li C, et al. Halofuginone attenuates osteoarthritis by inhibition of TGF-β activity and H-type vessel formation in subchondral bone. Ann Rheum Dis 2016; 75: 1714-21.
  • Pines M, Knopov V, Genina O, Lavelin I, Nagler A. Halofuginone, a specific inhibitor of collagen type I synthesis, prevents dimethylnitrosamine-induced liver cirrhosis. J Hepatol 1997; 27: 391-8.
  • Bruck R, Genina O, Aeed H, Alexiev R, Nagler A, Avni Y, Pines M. Halofuginone to prevent and treat thioacetamide-induced liver fibrosis in rats. Hepatology 2001; 33: 379-86.
  • Liang J, Zhang B, Shen RW, Liu J-B, Gao M-h, Li Y, et al. Preventive Effect of Halofuginone on Concanavalin A-Induced Liver Fibrosis. PLoS ONE 2013; 8: e82232. doi:10.1371/journal.pone.0082232.
  • Yavas G, Calik M, Calik G, Yavas C, Ata O, Esme H. The effect of Halofuginone in the amelioration of radiation induced-lung fibrosis. Med Hypotheses 2013; 80: 357-9.
  • Choi ET, Callow AD, Sehgal NL, Brown DM, Ryan US. Halofuginone, a specific collagen type I inhibitor, reduces anastomotic intimal hyperplasia. Arch Surg 1995; 130:257-61.
  • Nagler A, Miao HQ, Aingorn H, Pines M, Genina O, Vlodavsky I. Inhibition of collagen synthesis, smooth muscle cell proliferation, and injury-induced intimal hyperplasia by halofuginone. Arterioscler Thromb Vasc Biol 1997; 17: 194-202.
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Bölüm Özgün Makaleler
Yazarlar

Yazar: Doğan YILDIRIM
Kurum: Department of General Surgery, Health Ministery Haseki Teaching and Research State Hospital, University of Health Sciences, Istanbul
Ülke: Turkey


Yazar: Okan Murat AKTÜRK
Kurum: Department of General Surgery, Health Ministery Haseki Teaching and Research State Hospital, University of Health Sciences, Istanbul
Ülke: Turkey


Orcid: 0000-0001-9685-6660
Yazar: Ahmet KOCAKUŞAK (Sorumlu Yazar)
Kurum: Department of General Surgery, Health Ministery Haseki Teaching and Research State Hospital, University of Health Sciences, Istanbul
Ülke: Turkey


Yazar: Mikail ÇAKIR
Kurum: Department of General Surgery, Health Ministery Haseki Teaching and Research State Hospital, University of Health Sciences, Istanbul
Ülke: Turkey


Yazar: Oğuzhan SUNAMAK
Kurum: Department of General Surgery, Health Ministery Haydarpasa Numune Teaching and Research State Hospital, University of Health Sciences, Istanbul
Ülke: Turkey


Yazar: Adnan HUT
Kurum: Department of General Surgery, Health Ministery Haseki Teaching and Research State Hospital, University of Health Sciences, Istanbul
Ülke: Turkey


Yazar: Abdullah Kağan ZENGİN
Kurum: Department of General Surgery, Cerrahpasa Medical Faculty, Istanbul University, Istanbul
Ülke: Turkey


Yazar: Murat ÖZCAN
Kurum: Department of General Surgery, Cerrahpasa Medical Faculty, Istanbul University, Istanbul
Ülke: Turkey


Yazar: Hilal AKI
Kurum: Department of Pathology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul
Ülke: Turkey


Yazar: Huriye BALCI
Kurum: Department of Biochemistry, Cerrahpasa Medical Faculty, Istanbul University, Istanbul
Ülke: Turkey


Tarihler

Başvuru Tarihi : 20 Mayıs 2018
Kabul Tarihi : 15 Mayıs 2019
Yayımlanma Tarihi : 19 Mayıs 2020

Vancouver YILDIRIM D , AKTÜRK O , KOCAKUŞAK A , ÇAKIR M , SUNAMAK O , HUT A , ZENGİN A , ÖZCAN M , AKI H , BALCI H . The Effects of Halofuginone and Ursodeoxycholic Acid in Prevention of Sclerosing Cholangitis Caused by Scolocidal Agents. Mustafa Kemal Üniversitesi Tıp Dergisi. 2020; 30-26.