title: Blockade of exosome generation with GW4869 dampens the sepsis-induced inflammation and cardiac dysfunction.
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.
authors: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors: Kobina
authors: K
authors: Essandoh
authors: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; Shanxi University of Traditional Chinese Medicine, Taiyuan, Shanxi Province, China.
authors: Liwang
authors: L
authors: Yang
authors: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors: Xiaohong
authors: X
authors: Wang
authors: Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors: Wei
authors: W
authors: Huang
authors: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; The First Hospital, Shanxi Medical University, Taiyuan, Shanxi Province, China.
authors: Dongze
authors: D
authors: Qin
authors: Division of Pharmaceutical Sciences, University of Cincinnati College of Pharmacy, Cincinnati, OH 45267, USA.
authors: Jiukuan
authors: J
authors: Hao
authors: Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors: Yigang
authors: Y
authors: Wang
authors: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors: Basilia
authors: B
authors: Zingarelli
authors: Critical Illness Research, Lawson Health Research Institute, ON N6A 4G5, Canada.
authors: Tianqing
authors: T
authors: Peng
authors: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. Electronic address: fangg@ucmail.uc.edu.
authors: Guo-Chang
authors: GC
authors: Fan
keywords: Cardiac dysfunction; Exosomes; Inflammatory response; Macrophages; Sepsis