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      The IL1β-HER2-CLDN18/CLDN4 axis mediates lung barrier damage in ARDS

      , 1 , 2 , 3

      Aging (Albany NY)

      Impact Journals

      acute respiratory distress syndrome, lung barrier injury, IL-1β, HER2, claudin18

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          Objective: The high mortality rate associated with acute respiratory distress syndrome (ARDS) is a major challenge for intensive care units. In the present study, we applied bioinformatics and animal models to identify core genes and potential corresponding pathways in ARDS.

          Results: Using bioinformatics analysis, IL-1β was identified as the core gene of ARDS. Cell experiments showed that up-regulation of IL-1β downregulates claudin18 to promote lung barrier function damage by regulating the IL-1β-HER2/HER3 axis, further promoting the development of ARDS. This was validated in the animal models.

          Conclusion: IL-1β promotes the development of ARDS by regulating the IL-1β-HER2/HER3 axis. These findings deepen the understanding of the pathological mechanisms of ARDS.

          Methods: Transcription data sets related to ARDS were subjected to differential expression gene analysis, functional enrichment analysis, and receiver operating characteristic curve analysis and, so as to identify core genes in ARDS. Cell experiments were used to further explore the effects of core genes on lung barrier function damage. Animal models were applied to validate the effects of core gene in mediating biological signal pathways in ARDS.

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          Most cited references 21

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          IL-1R1/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice.

          The molecular mechanisms of acute lung injury resulting in inflammation and fibrosis are not well established. Here we investigate the roles of the IL-1 receptor 1 (IL-1R1) and the common adaptor for Toll/IL-1R signal transduction, MyD88, in this process using a murine model of acute pulmonary injury. Bleomycin insult results in expression of neutrophil and lymphocyte chemotactic factors, chronic inflammation, remodeling, and fibrosis. We demonstrate that these end points were attenuated in the lungs of IL-1R1- and MyD88-deficient mice. Further, in bone marrow chimera experiments, bleomycin-induced inflammation required primarily MyD88 signaling from radioresistant resident cells. Exogenous rIL-1beta recapitulated a high degree of bleomycin-induced lung pathology, and specific blockade of IL-1R1 by IL-1 receptor antagonist dramatically reduced bleomycin-induced inflammation. Finally, we found that lung IL-1beta production and inflammation in response to bleomycin required ASC, an inflammasome adaptor molecule. In conclusion, bleomycin-induced lung pathology required the inflammasome and IL-1R1/MyD88 signaling, and IL-1 represented a critical effector of pathology and therapeutic target of chronic lung inflammation and fibrosis.
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            Pulmonary epithelial barrier function: some new players and mechanisms.

            The pulmonary epithelium serves as a barrier to prevent access of the inspired luminal contents to the subepithelium. In addition, the epithelium dictates the initial responses of the lung to both infectious and noninfectious stimuli. One mechanism by which the epithelium does this is by coordinating transport of diffusible molecules across the epithelial barrier, both through the cell and between cells. In this review, we will discuss a few emerging paradigms of permeability changes through altered ion transport and paracellular regulation by which the epithelium gates its response to potentially detrimental luminal stimuli. This review is a summary of talks presented during a symposium in Experimental Biology geared toward novel and less recognized methods of epithelial barrier regulation. First, we will discuss mechanisms of dynamic regulation of cell-cell contacts in the context of repetitive exposure to inhaled infectious and noninfectious insults. In the second section, we will briefly discuss mechanisms of transcellular ion homeostasis specifically focused on the role of claudins and paracellular ion-channel regulation in chronic barrier dysfunction. In the next section, we will address transcellular ion transport and highlight the role of Trek-1 in epithelial responses to lung injury. In the final section, we will outline the role of epithelial growth receptor in barrier regulation in baseline, acute lung injury, and airway disease. We will then end with a summary of mechanisms of epithelial control as well as discuss emerging paradigms of the epithelium role in shifting between a structural element that maintains tight cell-cell adhesion to a cell that initiates and participates in immune responses.
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              Claudin-4 augments alveolar epithelial barrier function and is induced in acute lung injury.

              Intact alveolar barrier function is associated with better outcomes in acute lung injury patients; however, the regulation of alveolar epithelial paracellular transport during lung injury has not been extensively investigated. This study was undertaken to determine whether changes in tight junction claudin expression affect alveolar epithelial barrier properties and to determine the mechanisms of altered expression. In anesthetized mice exposed to ventilator-induced lung injury, claudin-4 was specifically induced among tight junction structural proteins. Real-time PCR showed an eightfold increase in claudin-4 expression in the lung injury model. To examine the role of this protein in barrier regulation, claudin-4 function was inhibited with small interfering RNA (siRNA) and a blocking peptide derived from the binding domain of Clostridium perfringens enterotoxin (CPE(BD)). Inhibition of claudin-4 decreased transepithelial electrical resistance but did not alter macromolecule permeability in primary rat and human epithelial cells. In mice, CPE(BD) decreased air space fluid clearance >33% and resulted in pulmonary edema during moderate tidal volume ventilation that did not induce edema in control peptide-treated mice. In vitro phorbol ester induced a ninefold increase in claudin-4 expression that was dependent on PKC activation and the JNK MAPK pathway. These data establish that changes in alveolar epithelial claudin expression influence paracellular transport, alveolar fluid clearance rates, and susceptibility to pulmonary edema. We hypothesize that increased claudin-4 expression early in acute lung injury represents a mechanism to limit pulmonary edema and that the regulation of alveolar epithelial claudin expression may be a novel target for acute lung injury therapy.

                Author and article information

                Aging (Albany NY)
                Aging (Albany NY)
                Aging (Albany NY)
                Impact Journals
                29 February 2020
                15 February 2020
                : 12
                : 4
                : 3249-3265
                [1 ]Department of Intensive Care Unit, Xiangya Hospital, Central South University, Changsha, China
                [2 ]Department of Pulmonary and Critical Care Medicine, Center for Respiratory Diseases, China-Japan Friendship Hospital, National Clinical Research Center for Respiratory Diseases, Beijing, China
                [3 ]Department of Anesthesiology, First Affiliated Hospital of Hunan University of Traditional Chinese Medicine, Changsha, China
                Author notes
                Correspondence to: Xinhua Ma; email: mxh8217@163.com
                102804 102804
                Copyright © 2020 Ma et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Research Paper

                Cell biology

                acute respiratory distress syndrome, lung barrier injury, il-1β, her2, claudin18


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