Relevance of the mTOR signaling pathway in the pathophysiology of splenomegaly in rats with chronic portal hypertension.
OBJECTIVE
Splenomegaly is a frequent hallmark of portal hypertension that, in some cases, can be very prominent and cause symptoms like abdominal pain, splenic infarction, and cytopenia. This study characterizes the pathogenetic mechanisms leading to spleen enlargement in portal hypertensive rats and focuses on mTOR pathway as a potential modulator of splenomegaly in portal hypertension.


METHODS
Characterization of splenomegaly was performed by histological, hematological, immunohistochemical and Western blot analyses in rats with portal hypertension induced by portal vein ligation, and compared with sham-operated animals. The contribution of the mTOR signaling pathway to splenomegaly was determined in rats with fully developed portal hypertension and control rats by treatment with rapamycin or vehicle.


RESULTS
Our results illustrate that splenomegaly in portal hypertensive rats arises as a consequence of the interplay of several factors, including not only spleen congestion, as traditionally thought, but also enlargement and hyperactivation of the splenic lymphoid tissue, as well as increased angiogenesis and fibrogenesis. Since mTOR signaling plays a central role in immunological processes, angiogenesis and fibrogenesis, we next determined the involvement of mTOR in splenomegaly. Interestingly, mTOR signaling was overactivated in the spleen of portal hypertensive rats, and mTOR blockade by rapamycin profoundly ameliorated splenomegaly, causing a 44% decrease in spleen size. This effect was most likely accounted for the inhibitory action of rapamycin on lymphocyte proliferation, neovascularization and fibrosis.


CONCLUSIONS
These findings shed light on the pathogenesis of splenomegaly in portal hypertension, and identify mTOR signaling as a potential target for therapeutic intervention in this disease.
Mejias
Marc
M
Liver Unit, Institute of Biomedical Research IDIBAPS, CIBERehd, Hospital Clinic, University of Barcelona, Villarroel 170, Barcelona, Spain.
Garcia-Pras
Ester
E
Gallego
Javier
J
Mendez
Raul
R
Bosch
Jaime
J
Fernandez
Mercedes
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D005355:Fibrosis; D006400:Hematocrit; D006975:Hypertension, Portal / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects; D008221:Lymphoid Tissue / Q000378:metabolism / Q000473:pathology; D008297:Male; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D009929:Organ Size; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology*; D013154:Spleen / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D013163:Splenomegaly / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology*; D058570:TOR Serine-Threonine Kinases
D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus