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

Abstract

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 messagesAntibiotics 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00109-014-1246-y) contains supplementary material, which is available to authorized users.

Staphylococcus aureus Survives in Cystic Fibrosis Macrophages, Forming a Reservoir for Chronic Pneumonia

“…The S. aureus strain used in the present study has been previously described and extensively characterized (43). The strain was isolated from a patient with sepsis and expresses alpha-toxin and enterotoxin D but not the Panton-Valentine leukocidin or toxic shock syndrome toxin (43).…”

“…The S. aureus strain used in the present study has been previously described and extensively characterized (43). The strain was isolated from a patient with sepsis and expresses alpha-toxin and enterotoxin D but not the Panton-Valentine leukocidin or toxic shock syndrome toxin (43). To exclude strain-specific results, we repeated the principal experiments with the well-characterized S. aureus strain Newman (ATCC 25904) (43).…”

“…The strain was isolated from a patient with sepsis and expresses alpha-toxin and enterotoxin D but not the Panton-Valentine leukocidin or toxic shock syndrome toxin (43). To exclude strain-specific results, we repeated the principal experiments with the well-characterized S. aureus strain Newman (ATCC 25904) (43). Bacteria were grown overnight on 5% sheep blood Trypticase soy agar plates (BD), removed from the plates, resuspended in 40 ml tryptic soy broth (BD) at an optical density of 0.2 to 0.25, and incubated at 37°C with shaking at 125 rpm for 75 min.…”

Amitriptyline Usage Exacerbates the Immune Suppression Following Burn Injury

“…For pretreatment with amitriptyline before scald, mice were injected intraperitoneally with 10 mg/kg amitriptyline (Sigma-Aldrich, St. Louis, MO) twice daily for 2 days as previously described (23). The last dose was given 1 h before injury.…”

Acid Sphingomyelinase Promotes Endothelial Stress Response in Systemic Inflammation and Sepsis

“…FI-ASMA are a group of compounds including Food and Drug Administration (FDA) approved and heavily prescribed antidepressant drugs, such as desipramine, which due to their weak basic properties accumulate in the lysosomes and lead to the degradation of acid sphingomyelinase (23). Pharmacological inhibition by desipramine was proven beneficial to the outcome in Staphylococcus aureus infection (24), however, the role and mechanisms of SMPD1 activation during endothelial stress response due to sepsis remain unclear. Amino bisphosphonates are promising candidates for direct inhibition (25).…”