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

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  • Additional Information
    • Source:
      Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE
    • Publication Information:
      Original Publication: London : Nature Publishing Group, copyright 2011-
    • Subject Terms:
      Desipramine/*pharmacology ; Liver/*drug effects ; Liver Cirrhosis/*prevention & control ; Sepsis/*complications ; Sphingomyelin Phosphodiesterase/*antagonists & inhibitors; Animals ; Apoptosis/drug effects ; Cell Line ; Desipramine/therapeutic use ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Female ; Hepatic Stellate Cells/drug effects ; Hepatic Stellate Cells/pathology ; Humans ; Liver/cytology ; Liver/pathology ; Liver Cirrhosis/etiology ; Liver Cirrhosis/pathology ; Male ; Mice ; Mice, Transgenic ; Oxidative Stress/drug effects ; Sphingomyelin Phosphodiesterase/genetics ; Sphingomyelin Phosphodiesterase/metabolism ; Treatment Outcome
    • 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.
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    • Accession Number:
      EC 3.1.4.12 (ASMase, mouse)
      EC 3.1.4.12 (SMPD1 protein, human)
      EC 3.1.4.12 (Sphingomyelin Phosphodiesterase)
      TG537D343B (Desipramine)
    • Publication Date:
      Date Created: 20170929 Date Completed: 20190705 Latest Revision: 20201104
    • Publication Date:
      20221213
    • Accession Number:
      PMC5617833
    • Accession Number:
      10.1038/s41598-017-11837-2
    • Accession Number:
      28955042