Heme and heme degradation products as effectors of hepatic perfusion and excretion failure

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Extracellular "free" heme is increasingly recognized to promote the development of sepsisassociated organ failure. Vice versa, buffering or degradation of tissue free heme has been shown to mediate "disease tolerance", a state in which presence of bacteria does not propagate organ dysfunction. The development of strategies to induce disease tolerance is necessary because conventional strategies to control progression from uncomplicated infection to sepsis with organ failure are limited in the light of an increasing burden of antimicrobial resistances.The prognostic significance of development of hepatic excretory failure in bacterial sepsis was previously demonstrated by our group. In the first funding period of FOR 1738, we confirmed an unexpected role of heme as a strong vasoconstrictor and cytotoxic factor which could beneutralized by albumin. Similarly, profound protection against hemodynamic and cytotoxic actions of heme could be achieved by prior induction of heme oxygenase gene expression. Bilirubin oxidation end products Z-BOX A and B as higher-order metabolites of heme degradation failed to affect vascular tone but could be characterized as partial agonists of Rev-erba, a transcriptional regulator of tissue development and circadian rhythm. Both BOXes acted on the organization of the hepatocellular cytoskeleton, an important factor controlling the canalicular membrane organization associated with hepatic excretory failure.In this funding period we aim to further characterize the role of heme and heme degradation products (HHDPs) in the pathogenesis of sepsis-induced excretory liver failure. Specifically, we will characterize the cell type-specific adaptive role of heme oxygenase 1 (HO1) by tamoxifeninduced unspecific or cell type-specific knock-down of its gene expression in hepatocytes, Kupffer cells and vascular endothelium, and, thus, investigating the role of HHDPs in distinct compartments. Conditional and cell type-specific knock-down mouse strains will be subjected to both, assessment of hemodynamic response to heme perfusion as well as to systematic studies of their stress tolerance in health and disease with or without prior induction of HO1. These model systems will enable us to study the interaction of heme as a constrictor and carbon monoxide (CO) as a dilator generated upon heme degradation and factors that limit HO1-mediated protection, such as formation of BOXes A and B. These higher-order metabolites of bilirubin will be tested specifically regarding their role in disturbing the canalicular membrane organization upon inflammatory stimuli. These studies will characterize the unexpected functions of heme as well as its degradation products Z-BOX A and B on hepatic cell morphology and function observed in the first funding period.