Protective effects of VGX-1027 in PM2.5-induced airway inflammation and bronchial hyperresponsiveness
Author(s)
Type
Journal Article
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.
Date Issued
2019-01-05
Date Acceptance
2018-11-07
Citation
European Journal of Clinical Pharmacology, 2019, 842, pp.373-383
ISSN
0031-6970
Publisher
Springer (part of Springer Nature)
Start Page
373
End Page
383
Journal / Book Title
European Journal of Clinical Pharmacology
Volume
842
Copyright Statement
© 2018 Elsevier B.V. All rights reserved. This manuscript is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence http://creativecommons.org/licenses/by-nc-nd/4.0/
Sponsor
Wellcome Trust
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000453397300043&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Grant Number
093080/Z/10/Z
Subjects
Science & Technology
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Fine particulate matters (PM2.5)
Airway inflammation
Bronchial hyperresponsiveness
VGX-1027
Toll-like receptor 4
Mitochondrial damage
MITOCHONDRIAL DAMAGE
PARTICULATE MATTER
OXIDATIVE STRESS
AMBIENT PM2.5
ACTIVATION
INJURY
EXPRESSION
RESPONSES
EXPOSURE
INNATE
Publication Status
Published
Date Publish Online
2018-11-09