3 years ago

Acid Sphingomyelinase Inhibition Prevents Development of Sepsis Sequelae in the Murine Liver

Markus H. Gräler, C. Julius Witt, Amelie Lupp, Tony Bruns, Benjamin Giszas, Nayla Jbeily, Falk A. Gonnert, Ha-Yeun Chung, Ralf A. Claus, Andreas Stallmach, Jorge Hurtado-Oliveros
The molecular mechanisms of maladaptive response in liver tissue with respect to the acute and post-acute phase of sepsis are not yet fully understood. Long-term sepsis survivors might develop hepatocellular/hepatobiliary injury and fibrosis. Here, we demonstrate that acid sphingomyelinase, an important regulator of hepatocyte apoptosis and hepatic stellate cell (HSC) activation, is linked to the promotion of liver dysfunction in the acute phase of sepsis as well as to fibrogenesis in the long-term. In both phases, we observed a beneficial effect of partial genetic sphingomyelinase deficiency in heterozygous animals (smpd1+/−) on oxidative stress levels, hepatobiliary function, macrophage infiltration and on HSC activation. Strikingly, similar to heterozygote expression of SMPD1, either preventative (p-smpd1+/+) or therapeutic (t-smpd1+/+) pharmacological treatment strategies with desipramine – a functional inhibitor of acid sphingomyelinase (FIASMA) – significantly improved liver function and survival. The inhibition of sphingomyelinase exhibited a protective effect on liver function in the acute-phase, and the reduction of HSC activation diminished development of sepsis-associated liver fibrosis in the post-acute phase of sepsis. In summary, targeting sphingomyelinase with FDA-approved drugs is a novel promising strategy to overcome sepsis-induced liver dysfunction.

Publisher URL: https://www.nature.com/articles/s41598-017-11837-2

DOI: 10.1038/s41598-017-11837-2

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