title: Delayed liver regeneration in C3H/HeJ mice: possible involvement of haemodynamic and structural changes in the hepatic microcirculation.
abstract: What is the central question of this study? The liver regenerative process is complex and involves a sequence of signalling events, but the possible involvement of structural and haemodynamic changes in vivo during this process has never been explored. What is the main finding and its importance? Normal sinusoidal blood flow and velocity are crucial for a normal regenerative response, and delays in these haemodynamic events resulted in impaired liver regeneration in lipopolysaccharide-insensitive, C3H/HeJ mice. Toll-like receptor 4 signalling is required for restoration of normal liver architecture during the liver regenerative process. Liver regeneration is delayed in mice with a defective Toll-like receptor 4 (TLR4; C3H/HeJ mice) but is normal in TLR4 knockouts (TLR4-/-). Here, we investigated the possible involvement of structural and haemodynamic changes in vivo in the underlying mechanism. In lipopolysaccharide-sensitive (C3H/HeN and C57BL/6) and lipopolysaccharide-insensitive (C3H/HeJ and TLR4-/-) mice, a 70% partial hepatectomy (PH) was performed under inhalational anaesthesia. At days 3 and 7 after PH, the hepatic microcirculation was interrogated using intravital microscopy. Delayed liver regeneration was confirmed in C3H/HeJ, but not in C3H/HeN, C57BL/6 (WT) or TLR4-/-mice by liver weight-to-body-weight ratio, the percentage of proliferating cell nuclear antigen (PCNA)-positive cells and mitotic index data. At day 3 after PH, sinusoidal red blood cell velocity increased by 100% in C3H/HeN mice, but by only 40% in C3H/HeJ mice. Estimated sinusoidal blood flow was significantly higher at day 7 after PH in C3H/HeN than in C3H/HeJ mice. The hepatic cord width was significantly larger in C3H/HeN than in C3H/HeJ mice at day 3 and it was significantly larger in TLR4-/-than in C57BL/6 WT mice at day 7 after PH. Hepatocyte nucleus density and functional sinusoidal density was significantly reduced at days 3 and 7 after PH in all mouse strains compared with their zero-time controls. Functional sinusoidal density was significantly lower in C3H/HeJ compared with C3H/HeN mice at day 7 after PH. The present study indicates that altered sinusoidal blood flow and velocity in C3H/HeJ mice may contribute to the observed delay in the regenerative response in these mice. In addition, restoration of normal liver architecture may be delayed in TLR4-/-mice.
authors.affiliation: Physiology, School of Medicine, National University of Ireland Galway, Galway, Ireland.|Department of Physiology, University of Otago, Dunedin, New Zealand.|Medical Faculty, Universiti Sains Islam Malaysia, Kuala Lumpur, Malaysia.
authors.forename: Muhamad
authors.initials: M
authors.lastname: Marlini
authors.affiliation: Department of Physiology, University of Otago, Dunedin, New Zealand.
authors.forename: Ayako
authors.initials: A
authors.lastname: Mabuchi
authors.affiliation: Physiology, School of Medicine, National University of Ireland Galway, Galway, Ireland.|Department of Physiology, University of Otago, Dunedin, New Zealand.
authors.forename: Beth L
authors.initials: BL
authors.lastname: Mallard
authors.affiliation: Physiology, School of Medicine, National University of Ireland Galway, Galway, Ireland.|Medical Faculty, Universiti Sains Islam Malaysia, Kuala Lumpur, Malaysia.
authors.forename: Ngatiman
authors.initials: N
authors.lastname: Hairulhisyam
authors.affiliation: Department of Microbiology and Immunology, Aichi Medical University, Nagakute, Aichi, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Akashi-Takamura
authors.affiliation: Malaghan Institute of Medical Research, Wellington, New Zealand.
authors.forename: Jacquie L
authors.initials: JL
authors.lastname: Harper
authors.affiliation: Physiology, School of Medicine, National University of Ireland Galway, Galway, Ireland.|Department of Physiology, University of Otago, Dunedin, New Zealand.
authors.forename: Antony M
authors.initials: AM
authors.lastname: Wheatley
mesh_terms: D000818:Animals; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D008115:Liver Regeneration / Q000187:drug effects / Q000502:physiology*; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4