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

Abstract

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.

Acid Sphingomyelinase Inhibition Stabilizes Hepatic Ceramide Content and Improves Hepatic Biotransformation Capacity in a Murine Model of Polymicrobial Sepsis

“…However, ceramide content did not further increase following septic insult. This stabilization of hepatic ceramide content results from a lack of increase in SMPD1 activity during host response, as we have demonstrated recently [ 25 ]. From these data, we conclude that modifications in lipid composition of the cell membrane, such as an increase of ceramide content, and changes in ceramide/sphingomyelin ratio following a biological stimulus are decisive rather than the baseline content of ceramide.…”

“…In human volunteers, injection of endotoxin resulted in a significant suppression of CYP activity, which additionally correlated to the degree of circulating IL-6 in plasma in these individuals [ 14 ]. In a previous study, we were already able to demonstrate that partial genetic inihibition of the conserved stress responsive enzyme acid sphingomyelinase results in an improved hepatobiliary function, diminished hepatic pro-inflammatory response and reduced hepatic stellate cell activation during the course of systemic inflammation [ 25 ]. In the present study, as an immediate surrogate for increased SMPD1 activity, liver tissue levels of C16- and C18-ceramide were increased in wild-type animals after sepsis induction, reflecting cellular stress response, whereas levels of C20-, C22- and C24-ceramide remained stable.…”

“…The plasma activity of acid sphingomyelinase correlates with the severity of the disease and allows for the discrimination of patient outcomes [ 16 , 22 , 23 ]. In the course of endotoxemia and Staphylococcus aureus induced sepsis [ 24 ], functional inhibition of SMPD1 exerted protective effects and improved survival rates [ 16 , 25 , 26 ].…”

Crosstalk Between Acid Sphingomyelinase and Inflammasome Signaling and Their Emerging Roles in Tissue Injury and Fibrosis

“…In addition, recent studies show that inhibition of ASM exhibited a protective effect on liver function. Long term sepsis survivor develops liver fibrosis from hepatic stellate cell (HSC) activation (Gonnert et al, 2012), and heterozygote expression of ASM or pharmacological treatment with desipramine improves liver function and fibrosis by decreasing the production of cytokine IL-1β and MCP1 (Chung et al, 2017). The controversial action of ASM on liver fibrosis may be due to the various functions of ceramide, the use of different cells, or different murine models in different studies.…”

“…The properties of tricyclic antidepressants and analogs lead them trapped and accumulated into the lysosome thereby detaching the ASM for lysosomal degradation, which makes these drugs as functional ASM inhibitor (Beckmann et al, 2014). The application of amitriptyline (Ma et al, 2017;Hong et al, 2019), desipramine (Chung et al, 2017), or imipramine (Biswas et al, 2017) normalizes ceramide levels and attenuates tissue injury and fibrosis. Importantly, a clinical trial shows systematic application of amitriptyline to CF patient results in beneficial effects on the lung and an increase in lung function (Nahrlich et al, 2013).…”