2. Academic Validation
  3. 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

  • Biochim Biophys Acta. 2015 Nov;1852(11):2362-71. doi: 10.1016/j.bbadis.2015.08.010.
Kobina Essandoh 1,  Liwang Yang 2,  Xiaohong Wang 1,  Wei Huang 3,  Dongze Qin 4,  Jiukuan Hao 5,  Yigang Wang 3,  Basilia Zingarelli 6,  Tianqing Peng 7,  Guo-Chang Fan 8
Affiliations

Affiliations

  • 1 Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
  • 2 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.
  • 3 Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
  • 4 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.
  • 5 Division of Pharmaceutical Sciences, University of Cincinnati College of Pharmacy, Cincinnati, OH 45267, USA.
  • 6 Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • 7 Critical Illness Research, Lawson Health Research Institute, ON N6A 4G5, Canada.
  • 8 Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. Electronic address: fangg@ucmail.uc.edu.
PMID: 26300484 DOI: 10.1016/j.bbadis.2015.08.010
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.

Keywords

Cardiac dysfunction; Exosomes; Inflammatory response; Macrophages; Sepsis.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z