The aim of the group is to apply and further develop intravital imaging techniques to investigate toxic and pathophysiologically relevant mechanisms at cellular and subcellular levels. Although a specific focus is the mouse liver, imaging of other organs which affects/affected by liver diseases- e.g., kidneys, intestine, and brain- is also possible. Videos can be recorded at spatial resolution of ~200 nm, and with temporal resolution in the millisecond range (see examples below).
A specific focus of the research is to investigate the pathogenesis of cholestatic liver diseases, the mechanisms of drug-induced liver injury:
Rupture of the apical hepatocyte membrane in acute cholestasis
Bile infarcts- first described in 1876 by Charcot and Gombault- are known to occur in acute obstructive cholestasis. However, the leading mechanisms and pathophysiological relevance were unclear. Using mouse models of obstructive cholestasis, we discovered that rupture of the apical hepatocyte membrane is an initial key event. The systemic consequence of this mechanism is currently investigated.
Futile cycling of bile acids aggravates APAP hepatotoxicity
Acetaminophen (APAP) overdose is a leading cause of acute liver failure. Only one antidote, N-acetyl cysteine, is approved for therapy which is effective only when administered in the first 8 hours of intoxication. Using intravital imaging techniques, a novel mechanism how APAP kills hepatocytes was discovered. APAP compromises the bile-blood barrier so that bile acids (BA) from the bile canaliculi leak into the sinusoidal blood then taken up into hepatocytes, secreted into bile canaliculi and thereby causing `futile BA cycling´. This causes BA accumulation in hepatocytes to levels above toxic thresholds. Interruption of this futile BA cycling by blocking the uptake carriers ameliorates hepatotoxicity. This novel therapy will be further exploited to treat patients with APAP overdose.