Details

Autor(en) / Beteiligte

• Essandoh, Kobina
• Yang, Liwang
• Wang, Xiaohong
• Huang, Wei
• Qin, Dongze
• Hao, Jiukuan
• Wang, Yigang
• Zingarelli, Basilia
• Peng, Tianqing
• Fan, Guo-Chang

Titel

Blockade of exosome generation with GW4869 dampens the sepsis-induced inflammation and cardiac dysfunction

Ist Teil von

• Biochimica et biophysica acta. Molecular basis of disease, 2015-11, Vol.1852 (11), p.2362-2371

Ort / Verlag

Elsevier B.V

Erscheinungsjahr

2015

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Sepsis is an infection-induced severe inflammatory disorder that leads to multiple organ failure. Amongst organs affected, myocardial depression is believed to be a major contributor to septic death. While it has been identified that large amounts of circulating pro-inflammatory cytokines are culprit for triggering cardiac dysfunction in sepsis, the underlying mechanisms remain obscure. Additionally, recent studies have shown that exosomes released from bacteria-infected macrophages are pro-inflammatory. Hence, we examined in this study whether blocking the generation of exosomes would be protective against sepsis-induced inflammatory response and cardiac dysfunction. To this end, we pre-treated RAW264.7 macrophages with GW4869, an inhibitor of exosome biogenesis/release, followed by endotoxin (LPS) challenge. In vivo, we injected wild-type (WT) mice with GW4869 for 1h prior to endotoxin treatment or cecal ligation/puncture (CLP) surgery. We observed that pre-treatment with GW4869 significantly impaired release of both exosomes and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) in RAW264.7 macrophages. At 12h after LPS treatment or CLP surgery, WT mice pre-treated with GW4869 displayed lower amounts of exosomes and pro-inflammatory cytokines in the serum than control PBS-injected mice. Accordingly, GW4869 treatment diminished the sepsis-induced cardiac inflammation, attenuated myocardial depression and prolonged survival. Together, our findings indicate that blockade of exosome generation in sepsis dampens the sepsis-triggered inflammatory response and thereby, improves cardiac function and survival. •GW4869 treatment reduces exosome and cytokine release from LPS-treated macrophages.•GW4869 blocks circulating exosome and cytokine content in endotoxemia and CLP mice.•Pre-treatment with GW4869 alleviates sepsis-induced cardiac dysfunction and death.