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

作者：Peng Huiming; Li Cao; Kadow Stephanie; Henry Brian D; Steinmann Joerg; Becker Katrin Anne; Riehle Andrea; Beckmann Natalie; Wilker Barbara; Li Pin Lan; Pritts Timothy; Edwards Michael J; Zhang Yang; Gulbins Erich^*; Grassme Heike

来源：Journal of Molecular Medicine-JMM, 2015, 93(6): 675-689.

DOI：10.1007/s00109-014-1246-y

• Acid sphingomyelinase/ceramide system
• Lung edema
• Superoxide
• Staphylococcus aureus

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.

• 出版日期2015-6