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

• Published in: PloS one 2016-01, Vol.11 (1), p.e0141159-e0141159
• Main Authors: Chen, Yunyang, Wang, Weijie, Wang, Huakai, Li, Yongjian, Shi, Minmin, Li, Hongwei, Yan, Jiqi
• Format: Article
• Language: English
• Subjects: Activation; Angiogenesis; Animal models; Animals; Anti-Infective Agents - therapeutic use; Apoptosis; Bile ducts; Care and treatment; Cirrhosis; Complications and side effects; Cytokines; Development and progression; Enlargement; Female; Fibrosis; Hepatology; Hospitals; Humans; Hypertension; Hypertension, Portal - complications; Hypertension, Portal - drug therapy; Hypertension, Portal - metabolism; Hypertension, Portal - pathology; Kinases; Laboratory animals; Liver; Liver cirrhosis; Lymphocytes; Lymphoid tissue; Male; Medicine; Middle Aged; Mitochondrial DNA; Neovascularization, Pathologic - pathology; Neovascularization, Pathologic - prevention & control; Pathogenesis; Patient outcomes; Patients; Portal Pressure - drug effects; Portal vein; Proteins; Rapamycin; Rats; Rats, Sprague-Dawley; Risk factors; Rodents; Signal transduction; Signal Transduction - drug effects; Signaling; Sirolimus - therapeutic use; Spleen; Spleen - blood supply; Spleen - drug effects; Spleen - metabolism; Spleen - pathology; Splenectomy; Splenomegaly; Splenomegaly - complications; Splenomegaly - drug therapy; Splenomegaly - metabolism; Splenomegaly - pathology; Surgery; TOR protein; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism; Tumor necrosis factor-TNF; Vascular endothelial growth factor
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0141159

Spleen 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. Spleen 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. We 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. This 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.