Journal
TOXICOLOGY LETTERS
Volume 271, Issue -, Pages 26-37Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.toxlet.2017.02.023
Keywords
ALI; LPS; Endoplasmic reticulum stress; Autophagy; NF-kB
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Funding
- Zhejiang Provincial Natural Science Funding [LY17H010005, LY17H010009, Y17H160193]
- National Natural Science Funding of China [81472165]
- Zhejiang Provincial Program of Medical and Health Science [2014KYA131]
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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-kB pathway, decreased the release of the pro- inflammatory mediators IL-1 beta, TNF-alpha 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. (C) 2017 Elsevier B.V. All rights reserved.
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