OBJECTIVE: Physiological liver regeneration requires adequate microvascular perfusion after partial hepatectomy. Although Kupffer cells (KCs) are known to play a key role in modulating hepatocyte proliferation, their impact on regulating hepatic microcirculation during liver regeneration has so far been disregarded. With respect to their expression and modulation of vasoactive mediators, KCs may provide important signals that regulate hepatic perfusion during liver regeneration. METHODS: Intravital fluorescence microscopy, immunohistochemistry, Western blot analysis, and RT-PCR were used to analyze livers of KC-depleted mice (liposome-encapsulated clodronate application) and KC-competent mice at days 3, 5, and 8 after 68% hepatectomy. RESULTS: Selective and long-lasting KC elimination limited the resection-associated hyperperfusion, as evidenced by an only 1.7- to 2-fold increase of sinusoidal volumetric blood flow and shear stress in contrast to a 3.5- to 5-fold increase in KC-competent mice. In accordance to that livers of KC-depleted mice showed an altered pattern of vasoregulatory gene expression. KC-depleted mice failed to show resection-induced increase of HO-1 and eNOS protein expression, but revealed a reduction of hepatic eNOS and HO-1 protein levels to 22 and 12% of the corresponding values in KC-competent mice. In addition, the eNOS inhibitory protein caveolin-1 was increased in KC-depleted animals prior to as well as after resection. Furthermore, resection-associated accumulation of ET-1 mRNA was absent in KC-depleted livers. Finally, liver mass restoration was impaired, with a regain of only 79% weight within 8 days after resection in KC-depleted mice. CONCLUSION: The present study documents a remarkable change of the vasoactive mediator profile upon KC-depletion and liver resection, limiting intrahepatic hyperperfusion. Therefore, KC-dependent molecular mechanisms seem to be mandatory in regulating vasotonus during the process of liver regeneration and therewith maintaining intrahepatic shear stress as a trigger of hepatic proliferation.
OBJECTIVE: Physiological liver regeneration requires adequate microvascular perfusion after partial hepatectomy. Although Kupffer cells (KCs) are known to play a key role in modulating hepatocyte proliferation, their impact on regulating hepatic microcirculation during liver regeneration has so far been disregarded. With respect to their expression and modulation of vasoactive mediators, KCs may provide important signals that regulate hepatic perfusion during liver regeneration. METHODS: Intravital fluorescence microscopy, immunohistochemistry, Western blot analysis, and RT-PCR were used to analyze livers of KC-depleted mice (liposome-encapsulated clodronate application) and KC-competent mice at days 3, 5, and 8 after 68% hepatectomy. RESULTS: Selective and long-lasting KC elimination limited the resection-associated hyperperfusion, as evidenced by an only 1.7- to 2-fold increase of sinusoidal volumetric blood flow and shear stress in contrast to a 3.5- to 5-fold increase in KC-competent mice. In accordance to that livers of KC-depleted mice showed an altered pattern of vasoregulatory gene expression. KC-depleted mice failed to show resection-induced increase of HO-1 and eNOS protein expression, but revealed a reduction of hepatic eNOS and HO-1 protein levels to 22 and 12% of the corresponding values in KC-competent mice. In addition, the eNOS inhibitory protein caveolin-1 was increased in KC-depleted animals prior to as well as after resection. Furthermore, resection-associated accumulation of ET-1 mRNA was absent in KC-depleted livers. Finally, liver mass restoration was impaired, with a regain of only 79% weight within 8 days after resection in KC-depleted mice. CONCLUSION: The present study documents a remarkable change of the vasoactive mediator profile upon KC-depletion and liver resection, limiting intrahepatic hyperperfusion. Therefore, KC-dependent molecular mechanisms seem to be mandatory in regulating vasotonus during the process of liver regeneration and therewith maintaining intrahepatic shear stress as a trigger of hepatic proliferation.
Authors: Patricio Godoy; Nicola J Hewitt; Ute Albrecht; Melvin E Andersen; Nariman Ansari; Sudin Bhattacharya; Johannes Georg Bode; Jennifer Bolleyn; Christoph Borner; Jan Böttger; Albert Braeuning; Robert A Budinsky; Britta Burkhardt; Neil R Cameron; Giovanni Camussi; Chong-Su Cho; Yun-Jaie Choi; J Craig Rowlands; Uta Dahmen; Georg Damm; Olaf Dirsch; María Teresa Donato; Jian Dong; Steven Dooley; Dirk Drasdo; Rowena Eakins; Karine Sá Ferreira; Valentina Fonsato; Joanna Fraczek; Rolf Gebhardt; Andrew Gibson; Matthias Glanemann; Chris E P Goldring; María José Gómez-Lechón; Geny M M Groothuis; Lena Gustavsson; Christelle Guyot; David Hallifax; Seddik Hammad; Adam Hayward; Dieter Häussinger; Claus Hellerbrand; Philip Hewitt; Stefan Hoehme; Hermann-Georg Holzhütter; J Brian Houston; Jens Hrach; Kiyomi Ito; Hartmut Jaeschke; Verena Keitel; Jens M Kelm; B Kevin Park; Claus Kordes; Gerd A Kullak-Ublick; Edward L LeCluyse; Peng Lu; Jennifer Luebke-Wheeler; Anna Lutz; Daniel J Maltman; Madlen Matz-Soja; Patrick McMullen; Irmgard Merfort; Simon Messner; Christoph Meyer; Jessica Mwinyi; Dean J Naisbitt; Andreas K Nussler; Peter Olinga; Francesco Pampaloni; Jingbo Pi; Linda Pluta; Stefan A Przyborski; Anup Ramachandran; Vera Rogiers; Cliff Rowe; Celine Schelcher; Kathrin Schmich; Michael Schwarz; Bijay Singh; Ernst H K Stelzer; Bruno Stieger; Regina Stöber; Yuichi Sugiyama; Ciro Tetta; Wolfgang E Thasler; Tamara Vanhaecke; Mathieu Vinken; Thomas S Weiss; Agata Widera; Courtney G Woods; Jinghai James Xu; Kathy M Yarborough; Jan G Hengstler Journal: Arch Toxicol Date: 2013-08-23 Impact factor: 5.153