Protective effects of VGX-1027 in PM2.5-induced airway inflammation and bronchial hyperresponsiveness.
Eur J Pharmacol
; 842: 373-383, 2019 Jan 05.
Article
em En
| MEDLINE
| ID: mdl-30419239
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 (25â¯mg/kg) one hour before intranasal instillation of vehicle (PBS) or PM2.5 (7.8â¯mg/kg) for two consecutive days and inflammatory events and BHR studied 24â¯h later. Human airway epithelial Beas-2b cells were pretreated with vehicle or VGX-1027 (50⯵M) in vitro one hour before incubation with vehicle or PM2.5 (150â¯ng/ml) for 24â¯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-1ß, IL-6 and IL-18 were reduced by VGX-1027. PM2.5-induced increases in TNF-α, IL-1ß, 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.
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Oxazóis
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Hiper-Reatividade Brônquica
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En
Ano de publicação:
2019
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Article