Amygdalin (Vitamin B17) pretreatment attenuates experimentally induced acute autoimmune hepatitis through reduction of CD4+ cell infiltration
Introduction
Autoimmune hepatitis (AIH) is an immune-mediated inflammation of the liver characterized by disorganized hepatic parenchyma and inflammatory cell infiltration (Christen and Hintermann, 2016). The exact etiology of AIH is still unknown (Aizawa and Hokari, 2017), however, different pathogens as environmental factors, viruses and chemicals have been postulated (Czaja, 2011). AIH reported a progressive increased prevalence and incidence in all ages and ethnic groups (Gatselis et al., 2015). Yet, the management of AIH is still largely restricted to steroids and cytostatic drugs (Czaja, 2011). The poor understanding of the detailed immunopathogenic changes accompanying AIH hampers the development of novel therapeutic strategies (Burak et al., 2013).
A known experimental model of drug-induced AIH in mice is the use of Concanavalin A (Con A) (Mao et al., 2015). Con A-induced acute hepatitis matches the histopathological picture of AIH patients (Ye et al., 2018). Induced autoimmune hepatitis involves the release of inflammatory mediators and inflammatory cell infiltration. These pathologic changes can proceed with time to chronic liver disease (De Biasio et al., 2006). As in other body tissues, the orderly step that follows inflammation is tissue healing by fibrosis which is a beneficial reversible defense mechanism aiming to encapsulate the tissue injury (Ebrahimi et al., 2016). However, the ultimate progression to advanced hepatic fibrosis and/or cirrhosis, which is an irreversible tissue response, disrupt the liver architecture and function (Friedman, 2008).
CD4+ cells are key mediators of inflammatory responses which play a crucial role in initial phases of liver injury, regeneration and graft rejection (Yamamoto et al., 2002). CD4+ cells were supposed to induce cytokine responses that control liver response to injury (Salgame et al., 1991). CD4+ cells were reported to direct the Con A-induced AIH through oxidative stress (Tiegs et al., 1992). Furthermore, the absence of CD4+ cells was found to improve the recovery of the liver from oxidant-mediated damage (Zwacka et al., 1997). In this context, agents that can suppress CD4+ cells infiltration could withhold the subsequent inflammatory cell infiltration, oxidative stress and improve liver tissue histopathological changes.
Amygdalin (Amg., Vitamin B17) is a cyanogenic glycoside compound which belongs to the group widely distributed in plants like apricot and peach (Santos Pimenta et al., 2014; Song and Xu, 2014). Amg. has multiple therapeutic effects as antiatherogenic, antifibrotic, anti-inflammatory and antiulcer agent (Chang et al., 2005; Du et al., 2010; Mirmiranpour et al., 2012). A particular action of Amg. on the liver is the ability to lower levels of AST, ALT, increase hydroxyproline content and inhibit proliferation of connective tissue in CCl4 and D-galactosamine treated rats (Wei et al., 2009).
Exploring the relation between CD4+ cells infiltration and the migration and engraftment of the inflammatory cells with subsequent liver histopathological changes in AIH can help to define new therapeutic agents. The tissue and the cellular distortion accompanying Con A-induced AIH and the postulated protective effect of Amg. were investigated in this study aiming for the implication of nontraditional management procedure.
Section snippets
Materials and methods
30 adult male Swiss albino mice (20–22 g) obtained from Mansoura Experimental Research Center, Mansoura, Egypt, were used in this study. The animals were maintained in the animal house, under specific pathogen-free conditions in metal cages with softwood chips for bedding under standard laboratory conditions of temperature and relative humidity. The animals were allowed free access to a standard commercial diet and tap water ad libitum with a 12 h light–dark cycle for two weeks before the
Biochemical analysis
AIH group showed a significant increase in the serum level of ALT and AST, compared to the control animals. The liver oxidative stress markers showed a significant elevation of MDA and a significant decline in SOD and GSH. Amg. pretreatment in AIH-Amg. group significantly decreased the serum ALT and AST and decreased the liver MDA and SOD and increased GSH to near normal levels compared to the AIH group (Table 1, Fig.1).
Histopathological, immunohistochemical studies
In comparison to the controls, H&E stained sections of the AIH group showed
Discussion
The immune system plays a major role in the regulation of the liver regenerative and reparative responses. An interaction between the immune cells and liver controls liver regeneration and repair (de et al., 2018). AIH is an immune-mediated inflammatory process triggered by a variety of factors including drugs, alcohol and increased dietary load of free fatty acids (Tsuneyama et al., 2013). AIH can be also propagated by viral infections like hepatitis C, cytomegalovirus, and influenza A viruses
Conclusion
The present data demonstrate that Amg. pretreatment protected the liver by reducing the number of infiltrating CD4+ cells. The decreased CD4+ cells infiltration pursued a decreased inflammatory cell infiltration and inhibited AIH-induced tissue and the cellular changes. Amg. protective effect is attributed to its anti-inflammatory and antioxidant activities. These findings suggest that Amg. could be a therapeutic agent in the management of AIH. More detailed studies may be needed for further
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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