title: 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.affiliation: School of Basic Medical Sciences, Institute of Hypoxia Research, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China. Electronic address: achilles112@126.com.
authors.forename: Meichun
authors.initials: M
authors.lastname: Zeng
authors.affiliation: School of Basic Medical Sciences, Institute of Hypoxia Research, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China. Electronic address: sangwenhua123@126.com.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Sang
authors.affiliation: School of Basic Medical Sciences, Institute of Hypoxia Research, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China. Electronic address: chensha2302058@126.com.
authors.forename: Sha
authors.initials: S
authors.lastname: Chen
authors.affiliation: School of Basic Medical Sciences, Institute of Hypoxia Research, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China. Electronic address: chenran505@163.com.
authors.forename: Ran
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Children's Respiration, The Second Affiliated Hospital & Yuying Children's Hospital, Wenzhou Medical University, Wenzhou 325027, Zhejiang, China. Electronic address: zhlwz97@hotmail.com.
authors.forename: Hailin
authors.initials: H
authors.lastname: Zhang
authors.affiliation: School of Basic Medical Sciences, Institute of Hypoxia Research, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Xue
authors.affiliation: School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China. Electronic address: lzm.az@qq.com.
authors.forename: Zhengmao
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Chest Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China. Electronic address: 48936053@qq.com.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: School of Basic Medical Sciences, Institute of Hypoxia Research, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China. Electronic address: 1398146361@qq.com.
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Gong
authors.affiliation: School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China. Electronic address: hyzhang@wmu.edu.cn.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhang
authors.affiliation: School of Basic Medical Sciences, Institute of Hypoxia Research, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China. Electronic address: kongxx@wmu.edu.cn.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Kong
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D019610:Cytoprotection; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000378:metabolism; D010654:Phenylbutyrates / Q000494:pharmacology*; D011014:Pneumonia / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010654:Phenylbutyrates; C075773:4-phenylbutyric acid; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: ALI; Autophagy; Endoplasmic reticulum stress; LPS; NF-κB