, Volume 39, Issue 6, pp 1981–1989 | Cite as

Maresin 1 Maintains the Permeability of Lung Epithelial Cells In Vitro and In Vivo

  • Lin Chen
  • Hong Liu
  • Yaxin Wang
  • Haifa Xia
  • Jie Gong
  • Bo Li
  • Shanglong Yao
  • You Shang


Previous reports showed that Maresin 1 (MaR1) possessed organ protection effects and could attenuate acute lung injury. Here, we aim to figure out whether MaR1 can maintain the permeability of lung epithelial cells by regulating the expression of tight junction protein during lung injury. Monolayer of murine lung epithelial cells was stimulated by lipopolysaccharide (LPS) with or without MaR1 and the permeability was evaluated. The expression of Claudin-1 and ZO-1 in lung epithelial cells was analyzed by immunofluorescence staining and western blotting. MaR1 was given to the mice after LPS induced acute lung injury. The permeability of lung was assessed by Evans Blue extravasation, lung wet/dry ratio and protein concentration in bronchoalveolar lavage fluid. Lung injury score was also evaluated. The expression of Claudin-1 and ZO-1 in the lung was analyzed by immunofluorescence staining. Results showed that MaR1 maintained the permeability of lung epithelial cells and upregulated the expression of Claudin-1 and ZO-1 after LPS stimulation. In acute lung injury mice, MaR1 upregulated the expression of Claudin-1 and ZO-1, decreased lung permeability, and reduced lung injury. In summary, this study suggests that MaR1 can maintain the permeability of lung epithelial cells by upregulating the expression of Claudin-1 and ZO-1 in acute lung injury.


Maresin 1 lipopolysaccharide acute lung injury tight junction permeability 



This study was supported by grants from the National Natural Science Foundation of China (No. 30930089, 81372036, 81500064, 81671890,81601669 ) and Key Clinical Project of Ministry of Health of China (2012-47).

Authors’ Contributions

L.C. and H.L. performed the research and wrote the manuscript. Y.W. and H.X. performed the in vitro study. J.G. and B.L. carried out the animal experiment and analyzed the data. S.Y. and Y.S. designed the experiment and revised the paper.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Piantadosi, C.A., and D.A. Schwartz. 2004. The acute respiratory distress syndrome. Annals of Internal Medicine 141: 460–470.CrossRefPubMedGoogle Scholar
  2. 2.
    Rubenfeld, G.D., E. Caldwell, E. Peabody, J. Weaver, D.P. Martin, M. Neff, E.J. Stern, and L.D. Hudson. 2005. Incidence and outcomes of acute lung injury. New England Journal of Medicine 353: 1685–1693.CrossRefPubMedGoogle Scholar
  3. 3.
    Gropper, M.A., and J. Wiener-Kronish. 2008. The epithelium in acute lung injury/acute respiratory distress syndrome. Current Opinion in Critical Care 14: 11–15.CrossRefPubMedGoogle Scholar
  4. 4.
    Smith, L.S., J.J. Zimmerman, and T.R. Martin. 2013. Mechanisms of acute respiratory distress syndrome in children and adults: a review and suggestions for future research. Pediatric Critical Care Medicine 14: 631–643.CrossRefPubMedGoogle Scholar
  5. 5.
    Shen, L., C.R. Weber, and J.R. Turner. 2008. The tight junction protein complex undergoes rapid and continuous molecular remodeling at steady state. Journal of Cell Biology 181: 683–695.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Coyne, C.B., T.M. Gambling, R.C. Boucher, J.L. Carson, and L.G. Johnson. 2003. Role of claudin interactions in airway tight junctional permeability. American Journal of Physiology - Lung Cellular and Molecular Physiology 285: L1166–L1178.CrossRefPubMedGoogle Scholar
  7. 7.
    Xie, W., H. Wang, L. Wang, C. Yao, R. Yuan, and Q. Wu. 2013. Resolvin D1 reduces deterioration of tight junction proteins by upregulating HO-1 in LPS-induced mice. Laboratory Investigation 93: 991–1000.CrossRefPubMedGoogle Scholar
  8. 8.
    Miyoshi, K., S. Yanagi, K. Kawahara, M. Nishio, H. Tsubouchi, Y. Imazu, R. Koshida, N. Matsumoto, A. Taguchi, S. Yamashita, A. Suzuki, and M. Nakazato. 2013. Epithelial Pten controls acute lung injury and fibrosis by regulating alveolar epithelial cell integrity. American Journal of Respiratory and Critical Care Medicine 187: 262–275.CrossRefPubMedGoogle Scholar
  9. 9.
    Serhan, C.N., N. Chiang, and J. Dalli. 2015. The resolution code of acute inflammation: novel pro-resolving lipid mediators in resolution. Seminars in Immunology 27: 200–215.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Borgeson, E., A.M. Johnson, Y.S. Lee, A. Till, G.H. Syed, S.T. Ali-Shah, P.J. Guiry, J. Dalli, R.A. Colas, C.N. Serhan, K. Sharma, and C. Godson. 2015. Lipoxin A4 attenuates obesity-induced adipose inflammation and associated liver and kidney disease. Cell Metabolism 22: 125–137.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Kain, V., K.A. Ingle, R.A. Colas, J. Dalli, S.D. Prabhu, C.N. Serhan, M. Joshi, and G.V. Halade. 2015. Resolvin D1 activates the inflammation resolving response at splenic and ventricular site following myocardial infarction leading to improved ventricular function. Journal of Molecular and Cellular Cardiology 84: 24–35.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Li, H., Z. Wu, D. Feng, J. Gong, C. Yao, Y. Wang, S. Yuan, S. Yao, and Y. Shang. 2014. BML-111, a lipoxin receptor agonist, attenuates ventilator-induced lung injury in rats. Shock 41: 311–316.CrossRefPubMedGoogle Scholar
  13. 13.
    Gong, J., S. Guo, H.B. Li, S.Y. Yuan, Y. Shang, and S.L. Yao. 2012. BML-111, a lipoxin receptor agonist, protects haemorrhagic shock-induced acute lung injury in rats. Resuscitation 83: 907–912.CrossRefPubMedGoogle Scholar
  14. 14.
    Serhan, C.N., R. Yang, K. Martinod, K. Kasuga, P.S. Pillai, T.F. Porter, S.F. Oh, and M. Spite. 2009. Maresins: novel macrophage mediators with potent antiinflammatory and proresolving actions. The Journal of Experimental Medicine 206: 15–23.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Krishnamoorthy, N., P.R. Burkett, J. Dalli, R.E. Abdulnour, R. Colas, S. Ramon, R.P. Phipps, N.A. Petasis, V.K. Kuchroo, C.N. Serhan, and B.D. Levy. 2015. Cutting edge: maresin-1 engages regulatory T cells to limit type 2 innate lymphoid cell activation and promote resolution of lung inflammation. Journal of Immunology 194: 863–867.CrossRefGoogle Scholar
  16. 16.
    Akagi, D., M. Chen, R. Toy, A. Chatterjee, and M.S. Conte. 2015. Systemic delivery of proresolving lipid mediators resolvin D2 and maresin 1 attenuates intimal hyperplasia in mice. The FASEB Journal 29: 2504–2513.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Gong, J., Z.Y. Wu, H. Qi, L. Chen, H.B. Li, B. Li, C.Y. Yao, Y.X. Wang, J. Wu, S.Y. Yuan, S.L. Yao, and Y. Shang. 2014. Maresin 1 mitigates LPS-induced acute lung injury in mice. British Journal of Pharmacology 171: 3539–3550.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Gong, J., H. Liu, J. Wu, H. Qi, Z.Y. Wu, H.Q. Shu, H.B. Li, L. Chen, Y.X. Wang, B. Li, M. Tang, Y.D. Ji, S.Y. Yuan, S.L. Yao, and Y. Shang. 2015. Maresin 1 prevents lipopolysaccharide-induced neutrophil survival and accelerates resolution of acute lung injury. Shock 44: 371–380.CrossRefPubMedGoogle Scholar
  19. 19.
    Wang, Y., R. Li, L. Chen, W. Tan, Z. Sun, H. Xia, B. Li, Y. Yu, J. Gong, M. Tang, Y. Ji, S. Yuan, Shanglong Yao, and Y. Shang. 2015. Maresin 1 inhibits epithelial-to-mesenchymal transition in vitro and attenuates bleomycin induced lung fibrosis in vivo. Shock 44: 496–502.CrossRefPubMedGoogle Scholar
  20. 20.
    Kilkenny, C., W. Browne, I.C. Cuthill, M. Emerson, D.G. Altman, and NC3Rs Reporting Guidelines Working Group. 2010. Animal research: reporting in vivo experiments: the ARRIVE guidelines. British Journal of Pharmacology 160: 1577–1579.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Matute-Bello, G., G. Downey, B.B. Moore, S.D. Groshong, M.A. Matthay, A.S. Slutsky, W.M. Kuebler, and Acute Lung Injury in Animals Study Group. 2011. An official American Thoracic Society workshop report: features and measurements of experimental acute lung injury in animals. American Journal of Respiratory Cell and Molecular Biology 44: 725–738.CrossRefPubMedGoogle Scholar
  22. 22.
    Abdulnour, R.E., J. Dalli, J.K. Colby, N. Krishnamoorthy, J.Y. Timmons, S.H. Tan, R.A. Colas, N.A. Petasis, C.N. Serhan, and B.D. Levy. 2014. Maresin 1 biosynthesis during platelet-neutrophil interactions is organ-protective. Proceedings of the National Academy of Science 111: 16526–16531.CrossRefGoogle Scholar
  23. 23.
    Matthay, M.A., and G.A. Zimmerman. 2005. Acute lung injury and the acute respiratory distress syndrome: four decades of inquiry into pathogenesis and rational management. American Journal of Respiratory Cell and Molecular Biology 33: 319–327.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Lucas, R., A.D. Verin, S.M. Black, and J.D. Catravas. 2009. Regulators of endothelial and epithelial barrier integrity and function in acute lung injury. Biochemical Pharmacology 77: 1763–1772.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Zemans, R.L., S.P. Colgan, and G.P. Downey. 2009. Transepithelial migration of neutrophils: mechanisms and implications for acute lung injury. American Journal of Respiratory Cell and Molecular Biology 40: 519–535.CrossRefPubMedGoogle Scholar
  26. 26.
    Broermann, A., M. Winderlich, H. Block, M. Frye, J. Rossaint, A. Zarbock, G. Cagna, R. Linnepe, D. Schulte, A.F. Nottebaum, and D. Vestweber. 2011. Dissociation of VE-PTP from VE-cadherin is required for leukocyte extravasation and for VEGF-induced vascular permeability in vivo. The Journal of Experimental Medicine 208: 2393–2401.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Fang, X., A.P. Neyrinck, M.A. Matthay, and J.W. Lee. 2010. Allogeneic human mesenchymal stem cells restore epithelial protein permeability in cultured human alveolar type II cells by secretion of angiopoietin-1. The Journal of Biological Chemistry 285: 26211–26222.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Van Itallie, C.M., and J.M. Anderson. 2006. Claudins and epithelial paracellular transport. Annual Review of Physiology 68: 403–429.CrossRefPubMedGoogle Scholar
  29. 29.
    Schlingmann, B., S.A. Molina, and M. Koval. 2015. Claudins: gatekeepers of lung epithelial function. Seminars in Cell and Developmental Biology 42: 47–57.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Chen, Y.H., Q. Lu, D.A. Goodenough, and B. Jeansonne. 2002. Nonreceptor tyrosine kinase c-Yes interacts with occludin during tight junction formation in canine kidney epithelial cells. Molecular Biology of the Cell 13: 1227–1237.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Nagaoka, K., T. Udagawa, and J.D. Richter. 2012. CPEB-mediated ZO-1 mRNA localization is required for epithelial tight-junction assembly and cell polarity. Nature Communications 3: 675.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Umeda, K., T. Matsui, M. Nakayama, K. Furuse, H. Sasaki, M. Furuse, and S. Tsukita. 2004. Establishment and characterization of cultured epithelial cells lacking expression of ZO-1. The Journal of Biological Chemistry 279: 44785–44794.CrossRefPubMedGoogle Scholar
  33. 33.
    Schamberger, A.C., N. Mise, J. Jia, E. Genoyer, A.O. Yildirim, S. Meiners, and O. Eickelberg. 2014. Cigarette smoke-induced disruption of bronchial epithelial tight junctions is prevented by transforming growth factor-beta. American Journal of Respiratory Cell and Molecular Biology 50: 1040–1052.CrossRefPubMedGoogle Scholar
  34. 34.
    Grumbach, Y., N.V. Quynh, R. Chiron, and V. Urbach. 2009. LXA4 stimulates ZO-1 expression and transepithelial electrical resistance in human airway epithelial (16HBE14o-) cells. American Journal of Physiology. Lung Cellular and Molecular Physiology 296: L101–L108.CrossRefPubMedGoogle Scholar
  35. 35.
    Englert, J.A., A.A. Macias, D. Amador-Munoz, M. Pinilla Vera, C. Isabelle, J. Guan, B. Magaoay, M. Suarez Velandia, A. Coronata, A. Lee, L.E. Fredenburgh, D.J. Culley, G. Crosby, and R.M. Baron. 2015. Isoflurane ameliorates acute lung injury by preserving epithelial tight junction integrity. Anesthesiology 123: 377–388.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Krause, G., L. Winkler, S.L. Mueller, R.F. Haseloff, J. Piontek, and I.E. Blasig. 2008. Structure and function of claudins. Biochimica et Biophysica Acta 1778: 631–645.CrossRefPubMedGoogle Scholar
  37. 37.
    LaFemina, M.J., K.M. Sutherland, T. Bentley, L.W. Gonzales, L. Allen, C.J. Chapin, D. Rokkam, K.A. Sweerus, L.G. Dobbs, P.L. Ballard, and J.A. Frank. 2014. Claudin-18 deficiency results in alveolar barrier dysfunction and impaired alveologenesis in mice. American Journal of Respiratory Cell and Molecular Biology 51: 550–558.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Wray, C., Y. Mao, J. Pan, A. Chandrasena, F. Piasta, and J.A. Frank. 2009. Claudin-4 augments alveolar epithelial barrier function and is induced in acute lung injury. American Journal of Physiology. Lung Cellular and Molecular Physiology 297: L219–L227.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Cording, J., J. Berg, N. Kading, C. Bellmann, C. Tscheik, J.K. Westphal, S. Milatz, D. Günzel, H. Wolburg, J. Piontek, O. Huber, and I.E. Blasig. 2013. In tight junctions, claudins regulate the interactions between occludin, tricellulin and marvelD3, which, inversely, modulate claudin oligomerization. Journal of Cell Science 126: 554–564.CrossRefPubMedGoogle Scholar
  40. 40.
    Gan, H., G. Wang, Q. Hao, Q.J. Wang, and H. Tang. 2013. Protein kinase D promotes airway epithelial barrier dysfunction and permeability through down-regulation of claudin-1. The Journal of Biological Chemistry 288: 37343–37354.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Ragupathy, S., F. Esmaeili, S. Paschoud, E. Sublet, S. Citi, and G. Borchard. 2014. Toll-like receptor 2 regulates the barrier function of human bronchial epithelial monolayers through atypical protein kinase C zeta, and an increase in expression of claudin-1. Tissue Barriers 2: e29166.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Chatterjee, A., A. Sharma, M. Chen, R. Toy, G. Mottola, and M.S. Conte. 2014. The pro-resolving lipid mediator maresin 1 (MaR1) attenuates inflammatory signaling pathways in vascular smooth muscle and endothelial cells. PloS One 9: e113480.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of Critical Care Medicine, Institute of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
  2. 2.Department of Anesthesiology, Institute of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
  3. 3.Department of Anesthesiology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina

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