Acid sphingomyelinase inhibition protects mice from lung edema and lethal Staphylococcus aureus sepsis.

Abstract

UNLABELLED:

Pulmonary edema associated with increased vascular permeability is a severe complication of Staphylococcus aureus-induced sepsis and an important cause of human pathology and death. We investigated the role of the mammalian acid sphingomyelinase (Asm)/ceramide system in the development of lung edema caused by S. aureus. Our findings demonstrate that genetic deficiency or pharmacologic inhibition of Asm reduced lung edema in mice infected with S. aureus. The Asm/ceramide system triggered the formation of superoxide, resulting in degradation of tight junction proteins followed by lung edema. Treatment of infected mice with amitriptyline, a potent inhibitor of Asm, protected mice from lung edema caused by S. aureus, but did not reduce systemic bacterial numbers. In turn, treatment with antibiotics reduced bacterial numbers but did not protect mice from lung edema. In contrast, only the combination of antibiotics and amitriptyline inhibited both pulmonary edema and bacteremia protecting mice from lethal sepsis and lung dysfunction suggesting the combination of both drugs as novel treatment option for sepsis.

KEY MESSAGES:

Antibiotics are often insufficient to cure S. aureus-induced sepsis. S. aureus induces lung edema via the Asm/ceramide system. Genetic deficiency of Asm inhibits lung dysfunction upon infection with S. aureus. Pharmacologic inhibition of Asm reduces lung edema induced by S. aureus. Antibiotics plus amitriptyline protect mice from lung edema and lethal S. aureus sepsis.

• Authors: Huiming Peng, Cao Li, Stephanie Kadow, Brian D Henry, Jörg Steinmann, Katrin Anne Becker, Andrea Riehle, Natalie Beckmann, Barbara Wilker, Pin-Lan Li, Timothy Pritts, Michael J Edwards, Yang Zhang, Erich Gulbins, Heike Grassmé
• Journal: Journal of molecular medicine (Berlin, Germany) (J Mol Med (Berl)) Vol. 93 Issue 6 Pg. 675-89 (Jun 2015) ISSN: 1432-1440 [Electronic] Germany
• PMID: 25616357 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Ceramides
• Enzyme Inhibitors
• Superoxides
• Amitriptyline
• acid sphingomyelinase-1
• Sphingomyelin Phosphodiesterase

Topics

• Amitriptyline (therapeutic use)
• Animals
• Anti-Bacterial Agents (therapeutic use)
• Ceramides (metabolism)
• Enzyme Inhibitors (therapeutic use)
• Gene Knockout Techniques
• Lung (drug effects, metabolism, microbiology, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Pulmonary Edema (genetics, microbiology, pathology, therapy)
• Sepsis (genetics, microbiology, pathology, therapy)
• Sphingomyelin Phosphodiesterase (antagonists & inhibitors, genetics, metabolism)
• Staphylococcal Infections (complications, genetics, pathology, therapy)
• Staphylococcus aureus (drug effects)
• Superoxides (antagonists & inhibitors, metabolism)