Rapamycin Attenuates Splenomegaly in both Intrahepatic and Prehepatic Portal Hypertensive Rats by Blocking mTOR Signaling Pathway

Abstract

BackgroundSpleen enlargement is often detected in patients with liver cirrhosis, but the precise pathogenetic mechanisms behind the phenomenon have not been clearly elucidated. We investigated the pathogenetic mechanisms of splenomegaly in both portal hypertensive patients and rats, and tried to identify the possible therapy for this disease.MethodsSpleen samples were collected from portal hypertensive patients after splenectomy. Rat models of portal hypertension were induced by common bile duct ligation and partial portal vein ligation. Spleen samples from patients and rats were used to study the characteristics of splenomegaly by histological, immunohistochemical, and western blot analyses. Rapamycin or vehicle was administered to rats to determine the contribution of mTOR signaling pathway in the development of splenomegaly.ResultsWe found that not only spleen congestion, but also increasing angiogenesis, fibrogenesis, inflammation and proliferation of splenic lymphoid tissue contributed to the development of splenomegaly in portal hypertensive patients and rats. Intriguingly, splenomegaly developed time-dependently in portal hypertensive rat that accompanied with progressive activation of mTOR signaling pathway. mTOR blockade by rapamycin profoundly ameliorated splenomegaly by limiting lymphocytes proliferation, angiogenesis, fibrogenesis and inflammation as well as decreasing portal pressure.ConclusionsThis study provides compelling evidence indicating that mTOR signaling activation pathway plays a key role in the pathogenesis of splenomegaly in both portal hypertensive patients and rats. Therapeutic intervention targeting mTOR could be a promising strategy for patients with portal hypertension and splenomegaly.

In relation to NO-System, Stable Pentadecapeptide BPC 157 Counteracts Lidocaine-Induced Adverse Effects in Rats and Depolarisation In Vitro

“…is may be the rapid activation of the bypassing loop that occurs in the rat with the infrarenal occlusion of the inferior caval vein (and thereby resolved Virchow) much like in the rats with ischemic/reperfusion colitis, duodenal venous congestion lesions, a perforated caecum, bile duct ligation-induced liver cirrhosis, and portal hypertension [48-50, 74, 81]. Accordingly, BPC 157 interacts with several molecular pathways [1,74,[82][83][84][85][86][87][88]. In particular, BPC 157 increased the expression and internalisation of VEGFR2 and the activation of the VEGFR2-Akt-eNOS signalling pathway without the need for other known ligands or shear stress [85].…”

Thalidomide for the Treatment of Thrombocytopenia and Hypersplenism in Patients With Cirrhosis or Thalassemia

“…There is increasing evidence that angiogenesis and neovascularization play an important role in the development of splenomegaly and hypersplenism. For example, the mammalian target of rapamycin (mTOR) and Janus kinase-2 (JAK2/STAT3) signaling pathways, which are known regulators of angiogenesis, have been implicated in the development of portal hypertension and splenomegaly, and inhibition of these signaling pathways has been shown to reduce splenomegaly ( Mejias et al., 2010 ; Wang et al., 2015 ; Chen et al., 2016 ; Wang et al., 2016 ). Furthermore, it has been reported that elevated levels of vascular endothelial growth factor (VEGF), a critical regulator of angiogenesis and neovascularization, are associated with splenomegaly in patients with chronic myeloid leukemia ( Liu et al., 2005 ) and polycythemia vera ( Murphy et al., 2002 ).…”

Integrated analysis of microRNA and mRNA expression profiles in splenomegaly induced by non-cirrhotic portal hypertension in rats

“…Other studies also showed that splenomegaly was associated with splenic fibrosis in rats with PPVL 31 and that mTOR signaling promoted splenomegaly in these rats 31,32 . While splenic fibrosis was in agreement with our study, our results do not implicate genes related to mTOR signaling in splenomegaly.…”