4-PBA inhibits LPS-induced inflammation through regulating ER stress and autophagy in acute lung injury models

•4-PBA protects LPS-induced acute lung injury and inflammation in mouse model.•4-PBA decreases the levels of ER stress and autophagy induced by LPS in vivo and in vitro.•Inhibition of autophagy by 3-MA aggravates cell injury induced by LPS, ER stress-associated autophagy may play a protective effect...

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Veröffentlicht in:Toxicology letters Jg. 271; S. 26 - 37
Hauptverfasser: Zeng, Meichun, Sang, Wenhua, Chen, Sha, Chen, Ran, Zhang, Hailin, Xue, Feng, Li, Zhengmao, Liu, Yu, Gong, Yongsheng, Zhang, Hongyu, Kong, Xiaoxia
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Netherlands Elsevier B.V 05.04.2017
Schlagworte:
Acute Lung Injury - chemically induced
Acute Lung Injury - metabolism
Acute Lung Injury - pathology
Acute Lung Injury - prevention & control
ALI
Animals
Anti-Inflammatory Agents - pharmacology
Autophagy
Autophagy - drug effects
Cell Line, Tumor
Cytokines - metabolism
Cytoprotection
Disease Models, Animal
Dose-Response Relationship, Drug
Endoplasmic reticulum stress
Endoplasmic Reticulum Stress - drug effects
Humans
Inflammation Mediators - metabolism
Lipopolysaccharides
LPS
Lung - drug effects
Lung - metabolism
Lung - pathology
Male
Mice, Inbred ICR
NF-kappa B - metabolism
NF-κB
Phenylbutyrates - pharmacology
Pneumonia - chemically induced
Pneumonia - metabolism
Pneumonia - pathology
Pneumonia - prevention & control
Proto-Oncogene Proteins c-akt - metabolism
Signal Transduction - drug effects
TOR Serine-Threonine Kinases - metabolism
IκB
NF-κB
ER stress
Autophagy
ALI
LPS
Endoplasmic reticulum stress
ISSN:0378-4274, 1879-3169, 1879-3169
Online-Zugang:Volltext
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Zusammenfassung:•4-PBA protects LPS-induced acute lung injury and inflammation in mouse model.•4-PBA decreases the levels of ER stress and autophagy induced by LPS in vivo and in vitro.•Inhibition of autophagy by 3-MA aggravates cell injury induced by LPS, ER stress-associated autophagy may play a protective effect in LPS-induced lung injury. Acute lung injury (ALI) is a common clinical disorder that causes substantial health problems worldwide. An excessive inflammatory response is the central feature of ALI, but the mechanism is still unclear, especially the role of endoplasmic-reticulum (ER) stress and autophagy. To identify the cellular mechanism of lung inflammation during lipopolysaccharide (LPS)-induced mouse model of ALI, we investigated the influence of classic ER stress inhibitor 4-phenyl butyric acid (4-PBA) on ER stress and autophagy, which partially affect the activation of inflammation, both in LPS-induced ALI mouse model and human alveolar epithelial cell model. We demonstrated that 4-PBA, which further prevented the activation of the NF-κB pathway, decreased the release of the pro-inflammatory mediators IL-1β, TNF-α and IL-6, significantly inhibited LPS-activated ER stress. Moreover, it was found that autophagy was also decreased by the treatment of 4-PBA, which may play a protective role in ALI models through the classical AKT/mTOR signaling pathway. Inhibition of autophagy by 3-MA exacerbates cytotoxicity induced by LPS in A549 alveolar epithelial cells. Taken together, our study indicated that ER stress is a key promoter in the induction of inflammation by LPS, the protective effect of 4-PBA is related to the inhibition of ER stress and autophagy in LPS-induced ALI models. Furthermore, the role of autophagy that contributes to cell survival may depend on the activation of ER stress.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0378-4274
1879-3169
1879-3169
DOI:10.1016/j.toxlet.2017.02.023