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Published on: August 25, 2013
Acid sphingomyelinase inhibition protects mice from lung edema and lethal Staphylococcus aureus sepsis
Huiming Peng1, Cao Li, Stephanie Kadow
1Department of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany.
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.
Insights
Staphylococcus aureus sepsis causes lung edema through the acid sphingomyelinase (Asm)/ceramide system. Inhibiting Asm with amitriptyline, combined with antibiotics, protected mice from lethal sepsis and lung dysfunction.
Area of Science:
- Pulmonary Medicine
- Microbiology
- Biochemistry
Background:
- Staphylococcus aureus sepsis can lead to severe pulmonary edema, a significant cause of mortality.
- Increased vascular permeability is a hallmark of this condition.
- The role of the mammalian acid sphingomyelinase (Asm)/ceramide system in sepsis-induced lung edema is not fully understood.
Purpose of the Study:
- To investigate the involvement of the Asm/ceramide system in Staphylococcus aureus-induced pulmonary edema.
- To evaluate the therapeutic potential of inhibiting Asm in managing sepsis-related lung complications.
Main Methods:
- Utilized a mouse model of Staphylococcus aureus infection.
- Assessed the effects of genetic deficiency and pharmacologic inhibition of Asm on lung edema.
- Administered amitriptyline (an Asm inhibitor) and/or antibiotics to infected mice.
- Measured bacterial load, superoxide formation, tight junction protein integrity, and lung edema.
Main Results:
- Genetic deficiency or pharmacologic inhibition of Asm significantly reduced lung edema in S. aureus-infected mice.
- The Asm/ceramide pathway promoted superoxide formation, leading to tight junction protein degradation and edema.
- Amitriptyline treatment protected against lung edema but did not reduce bacterial burden.
- Antibiotic treatment reduced bacterial burden but did not prevent lung edema.
- Combined treatment with antibiotics and amitriptyline effectively inhibited both pulmonary edema and bacteremia, protecting mice from lethal sepsis.
Conclusions:
- The Asm/ceramide system is a key mediator of S. aureus-induced lung edema.
- Pharmacologic inhibition of Asm, particularly in combination with antibiotics, offers a promising therapeutic strategy for sepsis.
- Standard antibiotic treatment alone may be insufficient for managing severe sepsis complications like pulmonary edema.
