Abstract
Engineered tissues provide an opportunity to investigate important physiological processes difficult to study in whole perfused organs and animal models. For example, a hepatocyte culture model consisting of rat hepatocytes cultured in a collagen sandwich configuration, which exhibits stable differentiated liver-specific functions, may be useful to investigate liver pathophysiology. To investigate systemic inflammation-related hepatic failure, we chronically exposed hepatocytes to the inflammatory mediators interleukin-1β (IL-1β) and interleukin-6 (IL-6) for up to 4 weeks. IL-6 (2.5 ng/mL) transiently suppressed albumin (-90%) and chronically increased fibrinogen (+6-fold) production. IL-6 inhibited urea synthesis at 2.5 ng/mL and stimulated it at 0.025 ng/mL. IL-1β (10 ng/mL) inhibited albumin (-90%), urea (-40 to 50%), and IL-6-stimulated fibrinogen (-90%) secretion. The inhibitory effect of IL-1β on urea secretion was dose-dependent. Furthermore, IL-1β transiently stimulated nitric oxide (NO) synthesis; however, NO did not mediate the effect of IL-1β on albumin and fibrinogen production, and played a minor role in IL-1β-mediated urea synthesis suppression. In conclusion, IL-1β and IL-6 exert, via a direct effect on hepatocytes, long-term inhibitory effects on hepatic functions that are potentially important for the survival of the host, which may contribute to hepatic dysfunction in prolonged inflammatory states.
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