The spleen is a secondary lymphoid organ which can influence the progression of multiple diseases, notably liver cirrhosis. In chronic liver diseases, splenomegaly and hypersplenism can manifest following the development of portal hypertension. These splenic abnormalities correlate with and have been postulated to facilitate the progression of liver fibrosis to cirrhosis, although precise mechanisms remain poorly understood. In this review, we summarize the literature to highlight the mechanistic contributions of splenomegaly and hypersplenism to the development of liver cirrhosis, focusing on three key aspects: hepatic fibrogenesis, hepatic immune microenvironment dysregulation and liver regeneration. We conclude with a discussion of the possible therapeutic strategies for modulating splenic abnormalities, including the novel potential usage of nanomedicine in non-surgically targetting splenic disorders for the treatment of liver cirrhosis.
The spleen is a secondary lymphoid organ containing specialized subsets of lymphocytes and myeloid cells, which are spatially organized within at least two functionally distinct regions. As the largest lymphoid organ in the body, the spleen contains highly elaborate tissue structures and is anatomically linked to the liver via the portal vein system [1, 2]. Clinically, liver cirrhosis is frequently accompanied by multiple complications including splenomegaly and hypersplenism [3, 4]. Previous studies have suggested that these splenic abnormalities may promote the progression of liver fibrosis to cirrhosis and exacerbate disease prognosis through multiple possible pathways [5,6,7,8]. Precise mechanisms, however, remain unclear and the overall impact of splenic contributions to the pathogenesis of liver cirrhosis remains to be clarified. Recently, additional mechanistic insights have been reported by several independent studies, prompting a timely review of the contributions of the spleen to liver cirrhosis progression.
Spleen Download For Pc [FULL]l
In this review, we focus on the features and mechanisms of splenic dysregulation which may occur during liver cirrhosis. We first discuss the splenic alterations which potentially contribute to the cellular crosstalk between the spleen and liver. We propose that splenic contributions to liver cirrhosis mainly occur through the promotion of hepatic fibrogenesis, perturbation of the hepatic immune microenvironment and inhibition of liver regeneration. We further suggest that splenic immune cell alterations, especially in macrophages, monocytes and T cells, may be the most important perpetrator of this pathological process. Finally, we discuss the translational implications of these research findings, especially in application to nanomedicine and the discovery of novel and non-surgical strategies for the treatment of liver cirrhosis.
Spleen sizes can vary between cirrhotic patients by primary disease etiologies, with hepatitis C virus (HCV) infected and non-alcoholic hepatitis patients showing significantly larger organ dimensions compared to alcoholic hepatitis patients [18]. Histologically, chronic portal hypertension-induced splenomegaly features expanded white pulp and marginal zone areas and appears different to congestive splenomegaly, which is characterized by more prominent red pulp and less distinct white pulp regions [19, 20]. Clinically, splenomegaly has been associated with a poor prognosis in liver cirrhosis and utilized during radioactive or acoustic examinations as an index for the non-invasive assessment of esophageal varices and bleeding risks [1, 21, 22]. Splenic stiffness can also increase as splenomegaly advances [23]. Portal congestion is widely considered the initial cause of splenomegaly during liver cirrhosis [5, 24]. The subsequent changes in the enlarged spleen are complex and difficult to elucidate, considering the concurrent involvement of multiple cell populations in different compartments. Recently, Mejias et al. induced splenomegaly in rats using a partial portal vein ligation (PPVL) model of chronic portal hypertension. Interestingly, significantly increased activation of the mTOR signaling pathway was observed within the enlarged spleen. More importantly, mTOR inhibition using rapamycin profoundly ameliorated splenomegaly, causing a 44% decrease in spleen size [20]. Although the PPVL model more closely simulates human idiopathic portal hypertension (IPH), these findings remain suggestive for the study of cirrhosis-associated portal hypertension. In another study, Chen et al. utilized a rat model of portal hypertension induced by a combination of bile duct ligation (BDL) and PPVL. They reported that rapamycin-induced mTOR inhibition significantly decreased splenomegaly through the inhibition of lymphocyte proliferation, angiogenesis, fibrogenesis and tissue inflammation levels, which ultimately led to a decrease in portal pressure [25]. Consistent with Mejias et al., the findings from Chen et al. are insightful as the combination of BDL and PPVL models the augmentation of portal hypertension by biliary cirrhosis, which more closely mimics clinical cirrhosis conditions. Overall, the identification of portal hypertension-induced mTOR signaling alterations may be highly significant due to its central roles in immune cell modulation, angiogenesis and hepatic fibrogenesis [26,27,28]. Further investigations utilizing animal models of liver cirrhosis-associated portal hypertension will be required to confirm whether and how the mTOR signaling pathway may contribute to liver cirrhosis-associated splenomegaly.
An association between the liver and spleen has been proposed at least for three major reasons. Anatomically, both organs are important components of portal circulation. Histologically, the liver and spleen possess similar reticuloendothelial structures, which continuously participate in substance exchange and cellular migration [44]. Immunologically, both the liver and spleen play essential roles in immune homeostasis as well as pathogen clearance. Thus, the concept of a liver-spleen axis has been proposed as an intersection linking immunity, pathogen clearance and metabolism in various conditions including chronic liver diseases [45]. Previous studies have unanimously implicated innate and adaptive immune cells in development of liver fibrosis or cirrhosis [46,47,48,49]. However, direct evidence for the involvement of splenic immune cells or spleen-derived factors has only recently emerged, suggesting that splenic contributions to hepatic fibrogenesis, hepatic immune microenvironment dysregulation and the disruption of liver regeneration may be responsible.
During liver fibrosis, hepatic stellate cells (HSCs) and Kupffer cells (KCs) act as the initial effectors of collagen deposition and inflammation modulation with the aid of the pro-fibrogenic cytokine transforming growth factor beta 1 (TGF-β1) [50, 51]. Previous studies have reported splenic TGF-β1 production in the context of liver cirrhosis and hypersplenism and emphasized its critical role in the development of hepatic fibrogenesis. Splenic macrophages have been suggested as one source of TGF-β1. In a study by Akahoshi et al., a rat model of liver cirrhosis was induced by intraperitoneal injection of thioacetamide (TAA) for 24 weeks, and followed by either a splenectomy or sham operation. Splenic red pulp macrophages were suggested as a major source of TGF-β1 in this study, and splenectomy was reported to decrease serum TGF-β1 levels significantly whilst improve liver fibrosis and regeneration parameters [6]. A recent study by Asanoma et al. detected increased TGF-β1 expression from the resected spleens of liver cirrhotic patients by immunofluorescence staining, and reported it to be significantly correlated with the progression of liver cirrhosis. TGF-β1 immunofluorescence further overlapped with the staining of CD68, a pan marker of tissue macrophages [52]. Overall, the studies from Akahoshi et al. and Asanoma et al. both implicate that splenic involvement during hepatic fibrogenesis may be mediated through splenic macrophage production and secretion of TGF-β1. Thus, further studies elucidating the explicit mechanisms driving splenic macrophage TGF-β1 production during liver cirrhosis in the presence or absence of hypersplenism will be of great interest.
As the largest lymphoid organ in the body, the spleen contains multiple immune cell subsets which are differentially distributed within white and red pulp and marginal zone regions. B cells are mainly distributed within splenic follicles whilst T cells predominate in the white pulp regions. By contrast, DCs and macrophages are located predominately in the marginal zone (MZ) and red pulp regions. Immune cell migration between these different regions is necessary for splenic maintenance of immune cell homeostasis, tolerance and pathogen clearance [13, 53,54,55]. Interestingly, the red pulp has been revealed to maintain a reservoir of monocytes capable of rapidly migrating into injured tissues and mediating local inflammatory responses [56]. Similarly, T lymphocytes and some innate lymphoid cell (ILC) subsets have also been reported to be capable of splenic extravasation [57, 58].
As the liver and spleen are closely associated via the portal vein system, it is more likely for the spleen to exert its influences on the hepatic immune microenvironment by cell migration or the secretion of splenic soluble factors via portal vein blood flow (Fig. 2). In a recent study by Yada et al., splenectomy significantly increased the hepatic accumulation of Ly-6Clow monocytes or macrophages in a thioacetamide-induced murine model of liver cirrhosis with hypersplenism, implicating a role for the splenic control of hepatic monocyte or macrophage phenotypes [59]. Although no splenic monocyte tracing studies have been conducted in the setting of liver fibrosis or cirrhosis, the findings from Yada et al. are potentially suggestive when considering the directional movement of red pulp monocyte reservoirs towards cardiac lesions [56]. 2ff7e9595c
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