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      Lipoxin A 4 ameliorates lipopolysaccharide-induced lung injury through stimulating epithelial proliferation, reducing epithelial cell apoptosis and inhibits epithelial–mesenchymal transition

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          Abstract

          Background

          Acute respiratory distress syndrome (ARDS) is characterized by alveolar epithelial disruption. Lipoxins (LXs), as so-called “braking signals” of inflammation, are the first mediators identified to have dual anti-inflammatory and inflammatory pro-resolving properties.

          Methods

          In vivo, lipoxinA 4 was administrated intraperitoneally with 1 μg/per mouse after intra-tracheal LPS administration (10 mg/kg). Apoptosis, proliferation and epithelial–mesenchymal transition of AT II cells were measured by immunofluorescence. In vitro, primary human alveolar type II cells were used to model the effects of lipoxin A 4 upon proliferation, apoptosis and epithelial–mesenchymal transition.

          Results

          In vivo, lipoxin A 4 markedly promoted alveolar epithelial type II cells (AT II cells) proliferation, inhibited AT II cells apoptosis, reduced cleaved caspase-3 expression and epithelial–mesenchymal transition, with the outcome of attenuated LPS-induced lung injury. In vitro, lipoxin A 4 increased primary human alveolar epithelial type II cells (AT II cells) proliferation and reduced LPS induced AT II cells apoptosis. LipoxinA 4 also inhibited epithelial mesenchymal transition in response to TGF-β 1, which was lipoxin receptor dependent. In addition, Smad3 inhibitor (Sis3) and PI3K inhibitor (LY294002) treatment abolished the inhibitory effects of lipoxinA 4 on the epithelial mesenchymal transition of primary human AT II cells. Lipoxin A 4 significantly downregulated the expressions of p-AKT and p-Smad stimulated by TGF-β 1 in primary human AT II cells.

          Conclusion

          LipoxinA 4 attenuates lung injury via stimulating epithelial cell proliferation, reducing epithelial cell apoptosis and inhibits epithelial–mesenchymal transition.

          Electronic supplementary material

          The online version of this article (10.1186/s12931-019-1158-z) contains supplementary material, which is available to authorized users.

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          Most cited references27

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          Role of poly(ADP-ribose) polymerase (PARP) cleavage in apoptosis. Caspase 3-resistant PARP mutant increases rates of apoptosis in transfected cells.

          An early transient burst of poly(ADP-ribosyl)ation of nuclear proteins was recently shown to be required for apoptosis to proceed in various cell lines (Simbulan-Rosenthal, C., Rosenthal, D., Iyer, S., Boulares, H., and Smulson, M. (1998) J. Biol. Chem. 273, 13703-13712) followed by cleavage of poly(ADP-ribose) polymerase (PARP), catalyzed by caspase-3. This inactivation of PARP has been proposed to prevent depletion of NAD (a PARP substrate) and ATP, which are thought to be required for later events in apoptosis. The role of PARP cleavage in apoptosis has now been investigated in human osteosarcoma cells and PARP -/- fibroblasts stably transfected with a vector encoding a caspase-3-resistant PARP mutant. Expression of this mutant PARP increased the rate of staurosporine and tumor necrosis factor-alpha-induced apoptosis, at least in part by reducing the time interval required for the onset of caspase-3 activation and internucleosomal DNA fragmentation, as well as the generation of 50-kilobase pair DNA breaks, thought to be associated with early chromatin unfolding. Overexpression of wild-type PARP in osteosarcoma cells also accelerated the apoptotic process, although not to the same extent as that apparent in cells expressing the mutant PARP. These effects of the mutant and wild-type enzymes might be due to the early and transient poly(ADP-ribose) synthesis in response to DNA breaks, and the accompanying depletion of NAD apparent in the transfected cells. The accelerated NAD depletion did not seem to interfere with the later stages of apoptosis. These results indicate that PARP activation and subsequent cleavage have active and complex roles in apoptosis.
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            Definition and epidemiology of acute respiratory distress syndrome.

            Fifty years ago, Ashbaugh and colleagues defined for the first time the acute respiratory distress syndrome (ARDS), one among the most challenging clinical condition of the critical care medicine. The scientific community worked over the years to generate a unified definition of ARDS, which saw its revisited version in the Berlin definition, in 2014. Epidemiologic information about ARDS is limited in the era of the new Berlin definition, and wide differences are reported among countries all over the world. Despite decades of study in the field of lung injury, ARDS is still so far under-recognized, with 2 out of 5 cases missed by clinicians. Furthermore, although advances of ventilator strategies in the management of ARDS associated with outcome improvements-such as protective mechanical ventilation, lower driving pressure, higher PEEP levels and prone positioning-ARDS appears to be undertreated and mortality remains elevated up to 40%. In this review, we cover the history that led to the current worldwide accepted Berlin definition of ARDS and we summarize the recent data regarding ARDS epidemiology.
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              Lipoxin and Resolvin Receptors Transducing the Resolution of Inflammation in Cardiovascular Disease

              A non-resolving inflammation results in a chronic inflammatory response, characteristic of atherosclerosis, abdominal aortic aneurysms and several other cardiovascular diseases. Restoring the levels of specialized proresolving mediators to drive the chronic cardiovascular inflammation toward resolution is emerging as a novel therapeutic principle. The lipid mediators lipoxins and resolvins exert their proresolving actions through specific G-protein coupled receptors (GPCR). So far, four GPCR have been identified as the receptors for lipoxin A4 and the D- and E-series of resolvins, namely ALX/FPR2, DRV1/GPR32, DRV2/GPR18, and ERV1/ChemR23. At the same time, other pro-inflammatory ligands also activate some of these receptors. Recent studies of genetic targeting of these receptors in atherosclerotic mouse strains have revealed a major role for proresolving receptors in atherosclerosis. The present review addresses the complex pharmacology of these four proresolving GPCRs with focus on their therapeutic implications and opportunities for inducing the resolution of inflammation in cardiovascular disease.
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                Author and article information

                Contributors
                1153669416@qq.com
                476702675@qq.com
                646199455@qq.com
                lianqingquanmz@163.com
                wangqian84@aliyun.com
                f.gaosmith@bham.ac.uk
                +44 121 371 4841 , jinshengwei69@163.com
                zsx0106014@163.com
                Journal
                Respir Res
                Respir. Res
                Respiratory Research
                BioMed Central (London )
                1465-9921
                1465-993X
                22 August 2019
                22 August 2019
                2019
                : 20
                : 192
                Affiliations
                [1 ]ISNI 0000 0004 1764 2632, GRID grid.417384.d, Department of Anesthesia and Critical Care, , The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, ; Zhejiang, 325027 China
                [2 ]ISNI 0000 0004 1936 7486, GRID grid.6572.6, Birmingham Acute Care Research Group, , Institute of Inflammation and Aging, University of Birmingham, ; Birmingham, B15 2TT UK
                Article
                1158
                10.1186/s12931-019-1158-z
                6704532
                31438948
                d15773c7-c46a-4bc4-b3cb-e0be7e23972d
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 26 May 2019
                : 6 August 2019
                Funding
                Funded by: the National Natural Science Foundation of China
                Award ID: 81401579
                Award ID: 81870065
                Award ID: 81570076
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2019

                Respiratory medicine
                acute respiratory distress syndrome,alveolar type ii cells,proliferation,apoptosis,epithelial to mesenchymal transition

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