Anti-apoptotic therapeutic approaches in liver diseases: do they really make sense?

Abstract

A variety of data suggesting apoptotic cell death as a key feature of liver injury stimulated researchers to investigate the therapeutic potential of anti-apoptotic strategies in experimental models. However, the overestimated role of apoptotic cell death in liver injury has tempered the clinical translation of the protection afforded by anti-apoptotic regimes in experimental models. Thus, the hope for apoptosis modulation as potential treatment strategy for injured liver in humans could not be confirmed. Herein, we evaluated the degree of apoptosis in different hepatic stress models which are relevant for the human pathophysiology. Using morphological criteria of apoptosis, caspase-3 activation as well as TUNEL assay in combination with a positive control of apoptosis in liver injury, we quantified apoptotic cell death discriminating between parenchymal and non-parenchymal cells and confirmed these results by cleaved caspase-3 and PARP-1 protein expression. Discussing our findings and relating them to the existing literature on the potential role of apoptotic cell death, we strongly recommend reconsidering anti-apoptotic strategies to ameliorate liver injury efficiently.

Intercellular crosstalk of liver sinusoidal endothelial cells in liver fibrosis, cirrhosis and hepatocellular carcinoma

“…Interestingly, anti-CD147 antibodies inhibit angiogenesis via VEGF-A/VEGFR2 pathway, thus ameliorate liver fibrosis progression [69] . However, due to the failure to protect neighbouring cells, inhibiting hepatocyte apoptosis following injury does not benefit liver fibrosis prevention [70] . Furthermore, the interaction between hepatocytes and LSECs promotes LSECs capillarisation, reduces portal angiogenesis, and subsequently drives liver fibrosis progression.…”

Sinusoidal communication in liver fibrosis and regeneration

“…It would be reasonable to extrapolate that under pathophysiological situations, the mechanisms that would otherwise protect neighbouring cells fail. Inhibiting hepatocyte apoptosis following injury does not convey benefit [36], and an alternative strategy could be aimed at either blocking the capturing of the apoptotic bodies by non-parenchymal cells, or building a ‘screen’ between hepatocytes and HSC/KC. To test these hypotheses however, we first need to understand when cell dysfunction initially occurs, and to which cell.…”

Apelin protects against acute renal injury by inhibiting TGF-β1

“…Caspase-3 has been shown to be primarily responsible for the cleav-390 age of poly(ADP-ribose) polymerase-1 (PARP-1) during cell death [46]. 3, caspase-8 and PARP-1, and these changes were markedly attenuated 394 by apelin over-expression (Fig.…”

“…AKI always im- 45 plies a poor prognosis with no effective therapy currently available [3]. 46 Renal I/R injury usually causes primary tubular epithelial cell injury, in-47 cluding tubular obstruction and reduced tubular re-absorption of NaCl. 48 However, several studies reported that hemodynamic changes induced 49 by renal I/R injury also occur, which lead to mesangial contraction and 50 cessation of glomerular filtration.…”