Skolosidal Ajanlardan Kaynaklanan Sklerozan Kolanjitin Önlenmesinde Halofuginon ve Ursodeoksikolik Asidin Etkileri

Yıl 2020, Cilt: 11 Sayı: 39, 26 - 30, 19.05.2020

Doğan Yıldırım Okan Murat Aktürk Ahmet Kocakuşak Mikail Çakır Oğuzhan Sunamak Adnan Hut Abdullah Kağan Zengin Murat Özcan Hilal Akı Huriye Balcı

https://doi.org/10.17944/mkutfd.425288

Öz

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.   

Anahtar Kelimeler

Halofuginon, siroz, ursodeoksikolik asit, sklerozan kolanjit, fibrozis, skolosidal

The Effects of Halofuginone and Ursodeoxycholic Acid in Prevention of Sclerosing Cholangitis Caused by Scolocidal Agents

Öz

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.

Anahtar Kelimeler

Halofuginone, cirrhosis, ursodeoxycholic acid, sclerosing cholangitis, fibrosis, scolocidal

Kaynakça

• 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.