title: Amelioration of hypoxia and LPS-induced intestinal epithelial barrier dysfunction by emodin through the suppression of the NF-κB and HIF-1α signaling pathways.
abstract: Intestinal barrier dysfunction occurs in critical illnesses and involves the inflammatory and hypoxic injury of intestinal epithelial cells. Researchers are still defining the underlying mechanisms and evaluating therapeutic strategies for restoring intestinal barrier function. The anti-inflammatory drug, emodin, has been shown to exert a protective effect on intestinal barrier function; however, its mechanisms of action remain unknown. In this study, we investigated the protective effects of emodin on intestinal barrier function and the underlying mechanisms in intestinal epithelial cells challenged with lipopolysaccharide (LPS) and hypoxia/reoxygenation (HR). To induce barrier dysfunction, Caco-2 monolayers were subjected to HR with or without LPS treatment. Transepithelial electrical resistance and paracellular permeability were measured to evaluate barrier function. The expression of the tight junction (TJ) proteins, zonula occludens (ZO)-1, occludin, and claudin-1, as well as that of hypoxia-inducible factor (HIF)-1α, phosphor-IκB-α, phosphor-nuclear factor (NF)-κB p65 and cyclooxygenase (COX)-2 was determined by western blot analysis. The results revealed that emodin markedly attenuated the decrease in transepithelial electrical resistance and the increase in paracellular permeability in the Caco-2 monolayers treated with LPS and subjected to HR. Emodin also markedly alleviated the damage caused by LPS and HR (manifested by a decrease in the expression of the TJ protein, ZO-1), and inhibited the expression of HIF-1α, IκB-α, NF-κB and COX-2 in a dose-dependent manner. In conclusion, our data suggest that emodin attenuates LPS- and HR-induced intestinal epithelial barrier dysfunction by inhibiting the HIF-1α and NF-κB signaling pathways and preventing the damage caused to the TJ barrier (shown by the decrease in the expression of ZO-1).
authors.affiliation: Department of ICU, Tianjin Huanhu Hospital, Tianjin, P.R. China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Lei
authors.affiliation: Department of ICU, Tianjin 4th Central Hospital, Tianjin, P.R. China.
authors.forename: Fu
authors.initials: F
authors.lastname: Qiang
authors.affiliation: Department of ICU, Tianjin Medical University, Nankai Hospital, Tianjin, P.R. China.
authors.forename: Du
authors.initials: D
authors.lastname: Chao
authors.affiliation: Department of ICU, Tianjin Huanhu Hospital, Tianjin, P.R. China.
authors.forename: Wu
authors.initials: W
authors.lastname: Di
authors.affiliation: Clinical Laboratory, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, P.R. China.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Guoqian
authors.affiliation: Graduate College, Tianjin Medical University, Tianjin, P.R. China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Bo
authors.affiliation: Graduate College, Tianjin Medical University, Tianjin, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lina
mesh_terms: D015153:Blotting, Western; D018938:Caco-2 Cells; D015687:Cell Hypoxia; D062445:Claudin-1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004642:Emodin / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D062793:Occludin / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism / Q000494:pharmacology; D010539:Permeability / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: D062445:Claudin-1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D062793:Occludin; D047428:Protein Kinase Inhibitors; D062826:Zonula Occludens-1 Protein; D000072000:NF-KappaB Inhibitor alpha; D051546:Cyclooxygenase 2; D004642:Emodin; D010100:Oxygen