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Blockade of Exosome Generation With GW4869 Dampens the Sepsis-Induced Inflammation and Cardiac Dysfunction

Blockade of Exosome Generation With GW4869 Dampens the Sepsis-Induced Inflammation and Cardiac Dysfunction

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

Biochim Biophys Acta. 2015 Nov;1852(11):2362-71.

PMID: 26300484

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP6823694	GW4869		6823-69-4	Price

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