The importance of liver microcirculation in promoting autoimmune hepatitis via maintaining an inflammatory cytokine milieu – A mathematical model study

• Published in: Journal of theoretical biology 2014-05, Vol.348, p.33-46
• Main Authors: Lettmann, Karsten Alexander, Hardtke-Wolenski, Matthias
• Format: Article
• Language: English
• Subjects: Algorithms; Autoimmune hepatitis; Blood Flow Velocity - immunology; Cytokines - immunology; Hepatitis, Autoimmune - immunology; Humans; Inflammation Mediators - immunology; Inflammatory cytokine milieu; Liver Circulation - immunology; Liver oxygen consumption rates; Microcirculation - immunology; Microcirculation within liver tissue; Models, Cardiovascular; Models, Immunological; Oxygen Consumption - immunology; T-Lymphocytes, Helper-Inducer - immunology
• ISSN: 0022-5193; 1095-8541
• DOI: 10.1016/j.jtbi.2014.01.016

In autoimmune diseases, inflammatory cytokine concentrations are important for initiating and maintaining the status of autoimmunity. Autoimmune hepatitis (AIH) is an inflammatory liver disease characterized by a loss of immune tolerance against specific antigens located in hepatocytes. During the progression of the disease, antigen-presenting cells and different classes of T-helper cells secrete specific cytokines important for maintaining the disease. As these cytokines are secreted into the local liver environment, the blood flow in liver sinusoids might influence the local cytokine concentration. Considering the liver tissue as a porous medium, based on Darcy׳s law, the microcirculation within a liver lobule was modelled. Using realistic physiological pressure differences and tissue permeabilities, the blood velocity inside the sinusoids could be calculated and validated with blood velocity data obtained via Orthogonal Polarization Spectral Imaging (OPSI). Furthermore, oxygen consumption is modelled to obtain Rappaport׳s acinus model. Finally, steady state spatial distributions of secreted cytokines within the liver lobule could be estimated for specified realistic production rates of T-helper cells. It could be demonstrated that the characteristics of the liver microcirculation have an important impact on establishing inflammatory cytokine levels within the portal fields and the vascular septa promoting the occurrence of interface hepatitis. •The microcirculation of liver lobules was modelled using a porous-medium approach.•Rappaport׳s oxygen zonation could be captured.•The concentrations of inflammatory cytokines secreted by T-helper cells were modelled.•The liver׳s microcirculation is important for an inflammatory cytokine milieu.