Silymarin Reduces Profibrogenic Cytokines and Reverses Hepatic Fibrosis in Chronic Murine Schistosomiasis

Abstract

In chronic schistosomiasis, hepatic fibrosis is linked to the portal hypertension that causes morbidity in Schistosoma mansoni infection. Silymarin (SIL) is a hepatoprotective and antioxidant medicament largely prescribed against liver diseases that has previously been shown to prevent fibrosis during acute murine schistosomiasis. Here we employed silymarin to try to reverse established hepatic fibrosis in chronic schistosomiasis. Silymarin or vehicle was administered to BALB/c mice every 48 h, starting on the 40th (80 days of treatment), 70th (50 days), or 110th (10 days) day postinfection (dpi). All mice were sacrificed and analyzed at 120 dpi. Treatment with silymarin reduced liver weight and granuloma sizes, reduced the increase in alanine aminotransferase and aspartate aminotransferase levels, and reduced the established hepatic fibrosis (assessed by hydroxyproline contents and picrosirius staining). Treatment with silymarin also reduced the levels of interleukin-13 (IL-13) in serum and increased the gamma interferon (IFN-␥)/IL-13 ratio. There was a linear correlation between IL-13 levels in serum and hydroxyproline hepatic content in both infected untreated and SIL-treated mice, with decreased IL-13 levels corresponding to decreased hydroxyproline hepatic contents. Treatment with either SIL or N-acetylcysteine reduced both proliferation of fibroblast cell lines and basal/IL-13-induced production of collagen I, indicating that besides inhibiting IL-13 production during infection, SIL antioxidant properties most likely contribute to inhibition of collagen production downstream of IL-13. These results show that silymarin interferes with fibrogenic cytokines, reduces established fibrosis, and inhibits downstream effects of IL-13 on fibrogenesis, indicating the drug as a safe and cheap treatment to liver fibrotic disease in schistosomiasis. Schistosomiasis is a chronic disease of high prevalence and wide distribution around the world (1) caused by worms that parasitize the vascular system. The morbidity in schistosomiasis is associated with the arrival of worm eggs to the liver and the stimulation of a granulomatous reaction (2). Chronic liver pathology is closely associated to the nature of the host inflammatory response. The immunological progression of this disease is frequently divided in distinct phases: prepostural acute Th1 phase, postural acute Th2 phase, and chronic Th2 downmodulated phase (3). The control of this Th response throughout the chronic phase may be associated with the reduction of morbidity in schistosomiasis. During acute murine infection, administration of antioxidant drugs such as curcumin (4), resveratrol (5), n-acetylcysteine (6), artemether (7), and silymarin (8) is used to reduce morbidity and prevent hepatic fibrosis. The reversal of established hepatic fibrosis at the chronic stage is directly linked to the portal hypertension, the major cause of morbidity in Schistosoma mansoni infection, and was not attained in any of these previous works. Currently, there is no medical treatmen...

Ceratonia siliqua pod extract ameliorates Schistosoma mansoni-induced liver fibrosis and oxidative stress

“…This explains the positive correlation between liver tissue egg counts and septal as well as total fibrosis scores. As a result, collagen is deposited around the eggs by myofibroblasts [38]. …”

Cytokine patterns in experimental schistosomiasis mansoni infected mice treated with silymarin

“…Using Silymarin as an antifibrotics drug can inhibit hepatic stellate cells activation that subsequently reduced the production of extracellular matrix components and slow down the progression of liver fibrosis (Afdhal and Nunes 2004;Wu et al 2009). In this study, the obtained reduction in granuloma diameter could be explained by the action of silymarin on the production of pro-inflammatory cytokines/chemokines in hepatic tissue accumulation (Trapoliere et al 2009;Mata-Santos et al 2014). Its anti fibrotic effect may attribute to the high levels of IFN-c and low levels of TNF-a.…”

“…These results confirmed previously published data that showed that cases of severe portal fibrosis were shown to be associated with low levels of IFN-c and high levels of TNF-a (Henri et al 2002;Booth et al 2004;de Jesus et al 2004). Indeed, silymarin was found to be able to reduce IL-4 whereas IL-4 was shown to play the role of pro-fibrogenic cytokine (Mata-Santos et al 2014).…”

“…This effect could be attributed to its role as an antioxidant, antifibrotic, and antiinflammatory/immunomodulatory agent (Mata-Santos et al 2010). Mata-Santos et al (2014) showed that treatment with silymarin leads to a decrease in hepatic granulomas size and to a reduction in liver fibrosis. Their results indicate that silymarin treatment can minimize the deleterious effects of experimental S. mansoni infection.…”

Cell therapy as a new approach on hepatic fibrosis of murine model ofSchistosoma mansoniinfection

“…Schistosomiasis is a chronic disease that is widespread all over the world. Schistosomiasis is endemic in 76 countries distributed all over the world especially in Africa and Asia ( Mata-Santos et al, 2014 ). SEM plays a significant role in clarifying the detailed of the tegument of S. mansoni ( El-Shabasy et al, (2015) ; Kamel et al, (2017)).…”