Z Gastroenterol 2017; 55(08): e57-e299
DOI: 10.1055/s-0037-1605053
Kurzvorträge
Leber und Galle
Leberchirurgie und experimentelle Grundlagen: Donnerstag, 14 September 2017, 11:30 – 12:42, Rotterdam/Forschungsforum 2
Georg Thieme Verlag KG Stuttgart · New York

Non-inflammatory liver congestion causes bridging fibrosis via biomechanic signaling of stellate cells: Evidence for pressure-induced cirrhosis

T Peccerella
1   Innere Medizin, Salem Krankenhaus und Center for Alcohol Research, Universität Heidelberg, Heidelberg, Deutschland
,
V Rausch
1   Innere Medizin, Salem Krankenhaus und Center for Alcohol Research, Universität Heidelberg, Heidelberg, Deutschland
,
T Longerich
2   Institut für Pathologie, Aachen, Deutschland
,
F Lasitschka
3   CMCP-Center of Model System and Comparative Pathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Deutschland
,
T Poth
3   CMCP-Center of Model System and Comparative Pathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Deutschland
,
S Mueller
1   Innere Medizin, Salem Krankenhaus und Center for Alcohol Research, Universität Heidelberg, Heidelberg, Deutschland
› Author Affiliations
Further Information

Publication History

Publication Date:
02 August 2017 (online)

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    Objectives:

    The underlying molecular mechanisms of liver cirrhosis are still poorly understood and no efficient treatment strategies are available. Recently, the sinusoidal pressure hypothesis (SPH) has been introduced that explains fibrosis progression by an elevated sinusoidal pressure and biomechanic signaling of perisinusoidal stretch forces. We here present further evidence for the SPH using a non-inflammatory animal model of liver congestion and biomechanic stretch experiments of cultured cells.

    Methods:

    The caval vein was subphrenically clamped in male Wistar rats for 1 day, or 1, 4, 8 and 16 weeks. Altogether 70 animals were studied (clamps = 30, sham operated = 26, controls = 14). LS was measured invasively using the novel µFibroscan platform (Echosens, Paris). In addition, liver histology (semiquantitative Chevallier fibrosis score and Kleiner score), hepatic mRNA expression of fibrosis-relates genes, blood count and serum laboratory tests were performed. Data were analyzed using paired T-Test and Spearman rank correlation. Finally, hepatic stellate (HSC, LX2), endothelial (HUVEC), macrophages (THP-1) and hepatoma (Huh7) cells were stretched by 20% using 6-well bioflex tension plates (Flexcell IC, Burlington, NC, USA) and a customized stretch chamber.

    Results:

    Congestion significantly and immediately increased LS from mean 4.0 to 12.4 kPa (P < 0.001) and remained stable over 4 months. No apparent inflammation or necrosis was seen whether in the histology or in serum tests. Starting from week 8, a significantly increased histological fibrosis score (P < 0.005) was seen. In some animals, even bridging fibrosis and F4 cirrhosis was observed after 4 months. Increased LS was highly associated with alphaSMA (P < 0.00005), TGF-beta (P < 0.0005), collagen1 and MMP14 (P < 0.001). Stretching of cultured cells only increased collagen1 in HSC while TGFbeta was induced both in HSC and HUVEC.

    Conclusion:

    Our findings indicate that increased pressure alone is able to induce a pronounced profibrogenic response and bridging fibrosis in the absence of inflammation. Mechanic stimulation of HSC and crosstalk with endothelial cells seem to be the major cellular cascade in response to an elevated sinusoidal pressure.