Affordable Access

deepdyve-link
Publisher Website

Protective effects of VGX-1027 in PM2.5-induced airway inflammation and bronchial hyperresponsiveness

Authors
  • Xu, M
  • Li, F
  • Wang, M
  • Zhang, H
  • Xu, L
  • Adcock, IM
  • Chung, KF
  • Zhang, Y
Publication Date
Nov 07, 2018
Identifiers
DOI: 10.1016/j.ejphar.2018.11.010
OAI: oai:spiral.imperial.ac.uk:10044/1/66292
Source
Spiral - Imperial College Digital Repository
Keywords
License
Unknown

Abstract

Fine particulate matter (PM2.5) can penetrate into alveolar spaces and induce airway inflammation. Recent evidence suggests that the activation of Toll-like receptor 4 (TLR4) signaling may participate in PM2.5-induced acute lung injury. We investigated the effect of VGX-1027, a TLR4 blocker, on PM2.5-induced airway inflammation and bronchial hyperresponsiveness (BHR) in a murine model in vivo and on inflammatory mechanisms in vitro in human airway epithelial cells. Mice were injected intraperitoneally with vehicle (PBS) or VGX-1027 (25 mg/kg) one hour before intranasal instillation of vehicle (PBS) or PM2.5 (7.8 mg/kg) for two consecutive days and inflammatory events and BHR studied 24 h later. Human airway epithelial Beas-2b cells were pretreated with vehicle or VGX-1027 (50 μM) in vitro one hour before incubation with vehicle or PM2.5 (150 ng/ml) for 24 h and effects on inflammatory mediators and mechanisms studied. VGX-1027 pretreatment attenuated PM2.5-induced BHR and elevated total and neutrophils, macrophages, lymphocytes and eosinophils numbers in bronchoalveolar lavage (BAL) fluid in vivo. PM2.5-induced BAL fluid inflammatory mediator levels including TNF-α, chemokine (C-X-C motif) ligand1, IL-1β, IL-6 and IL-18 were reduced by VGX-1027. PM2.5-induced increases in TNF-α, IL-1β, IL-6 and IL-18 mRNA levels in Beas-2b cells were also reduced by VGX-1027. Mechanistically, VGX-1027 inhibited PM2.5-induced activation of the TLR4-NF-κB-p38 MAPK and NLRP3-caspase-1 pathways as well as the dysregulation of mitochondrial fusion/fission proteins in vivo and in vitro. VGX-1027 may be a potential prophylactic treatment for PM2.5-induced acute lung injury that has airway inflammation, BHR and mitochondrial damage.

Report this publication

Statistics

Seen <100 times