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

Abstract

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.

• Authors: Meichun Zeng, Wenhua Sang, Sha Chen, Ran Chen, Hailin Zhang, Feng Xue, Zhengmao Li, Yu Liu, Yongsheng Gong, Hongyu Zhang, Xiaoxia Kong
• Journal: Toxicology letters (Toxicol Lett) Vol. 271 Pg. 26-37 (Apr 05 2017) ISSN: 1879-3169 [Electronic] Netherlands
• PMID: 28245985 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• Anti-Inflammatory Agents
• Cytokines
• Inflammation Mediators
• Lipopolysaccharides
• NF-kappa B
• Phenylbutyrates
• 4-phenylbutyric acid
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Acute Lung Injury (chemically induced, metabolism, pathology, prevention & control)
• Animals
• Anti-Inflammatory Agents (pharmacology)
• Autophagy (drug effects)
• Cell Line, Tumor
• Cytokines (metabolism)
• Cytoprotection
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Endoplasmic Reticulum Stress (drug effects)
• Humans
• Inflammation Mediators (metabolism)
• Lipopolysaccharides
• Lung (drug effects, metabolism, pathology)
• Male
• Mice, Inbred ICR
• NF-kappa B (metabolism)
• Phenylbutyrates (pharmacology)
• Pneumonia (chemically induced, metabolism, pathology, prevention & control)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (metabolism)