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Inflammation

, Volume 41, Issue 4, pp 1250–1258 | Cite as

Inflammatory Response of Pulmonary Artery Smooth Muscle Cells Exposed to Oxidative and Biophysical Stress

  • Joanna Costa
  • Yan Zhu
  • Timothy Cox
  • Paul Fawcett
  • Thomas Shaffer
  • Deepthi Alapati
ORIGINAL ARTICLE
First Online:

Abstract

Pulmonary hypertension in the neonate requires treatment with oxygen and positive pressure ventilation, both known to induce lung injury. The direct response of pulmonary artery smooth muscle cells, the most abundant cells in the artery wall, to the stress of positive pressure and hyperoxia has not been previously studied. Pulmonary artery smooth muscle cells were cultured in temperature- and pressure-controlled air-tight chambers under conditions of positive pressure or hyperoxia for 24 h. Control cells were cultured in room air under atmospheric pressure. After the exposure period, culture medium was collected and samples were analyzed by ELISA, Human Cytokine 25-Plex Panel using a Luminex 200 analyzer and Western blot. Secretion of various inflammatory mediators, specifically IL-6, IL-8, IL-2R, MIP-1β, MCP-1, IP-10, IL-7, IL-1RA, and IFN-α, was higher in the positive pressure and hyperoxia groups compared with control. The level of cyclin D1 was decreased in the hyperoxia and positive pressure group compared with control. Levels of fibronectin and α-smooth muscle actin were not different among the groups. Pulmonary artery smooth muscle cells directly produce multiple inflammatory mediators in response to oxidative and biophysical stress in vitro, which may be part of a cascade that leads to the vascular and perivascular changes in pulmonary hypertension.

KEY WORDS

hyperoxia inflammation positive pressure pulmonary hypertension 
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Notes

Financial Support

Support was provided in part by COBRE grant P20 GM 103464-Phase 2 from the NIGMS, a component of the NIH. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH.

Compliance with Ethical Standards

Conflicts of Interest

The authors declare that they have no conflicts of interest.

References

  1. 1.
    Angus, D.C., W.T. Linde-Zwirble, G. Clermont, M.F. Griffin, and R.H. Clark. 2001. Epidemiology of neonatal respiratory failure in the United States: projections from California and New York. American Journal of Respiratory and Critical Care Medicine 164: 1154–1160.CrossRefPubMedGoogle Scholar
  2. 2.
    Subhedar, N.V., and N.J. Shaw. 2000. Changes in pulmonary arterial pressure in preterm infants with chronic lung disease. Archives of Disease in Childhood. Fetal and Neonatal Edition 82: F243–F247.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Bhat, R., A.A. Salas, C. Foster, W.A. Carlo, and N. Ambalavanan. 2012. Prospective analysis of pulmonary hypertension in extremely low birth weight infants. Pediatrics 129: e682–e689.  https://doi.org/10.1542/peds.2011-1827. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Collaco, J.M., L.H. Romer, B.D. Stuart, J.D. Coulson, A.D. Everett, E.E. Lawson, J.I. Brenner, A.T. Brown, M.K. Nies, P. Sekar, L.M. Nogee, and S.A. McGrath-Morrow. 2012. Frontiers in pulmonary hypertension in infants and children with bronchopulmonary dysplasia. Pediatric Pulmonology 47: 1042–1053.  https://doi.org/10.1002/ppul.22609.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Mecham, R.P., L.A. Whitehouse, D.S. Wrenn, W.C. Parks, G.L. Griffin, R.M. Senior, et al. 1987. Smooth muscle-mediated connective tissue remodeling in pulmonary hypertension. Science 237: 423–426.CrossRefPubMedGoogle Scholar
  6. 6.
    Stenmark, K.R., K.A. Fagan, and M.G. Frid. 2006. Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms. Circulation Research 99: 675–691.CrossRefPubMedGoogle Scholar
  7. 7.
    Stenmark, K.R., B. Meyrick, N. Galie, W.J. Mooi, and I.F. McMurtry. 2009. Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure. American Journal of Physiology—Lung Cellular and Molecular Physiology 297: L1013–L1032.  https://doi.org/10.1152/ajplung.00217.2009. CrossRefPubMedGoogle Scholar
  8. 8.
    Speer, C.P. 2001. New insights into the pathogenesis of pulmonary inflammation in preterm infants. Biology of the Neonate 79: 205–209.CrossRefPubMedGoogle Scholar
  9. 9.
    Cool, C.D., D. Kennedy, N.F. Voelkel, and R.M. Tuder. 1997. Pathogenesis and evolution of plexiform lesions in pulmonary hypertension associated with scleroderma and human immunodeficiency virus infection. Human Pathology 28: 434–442.CrossRefPubMedGoogle Scholar
  10. 10.
    Tuder, R.M., S.H. Abman, T. Braun, F. Capron, T. Stevens, P.A. Thistlethwaite, and S.G. Haworth. 2009. Development and pathology of pulmonary hypertension. Journal of the American College of Cardiology 54: S3–S9.  https://doi.org/10.1016/j.jacc.2009.04.009.CrossRefPubMedGoogle Scholar
  11. 11.
    Pinto, R.F., L. Higuchi Mde, and V.D. Aiello. 2004. Decreased numbers of T-lymphocytes and predominance of recently recruited macrophages in the walls of peripheral pulmonary arteries from 26 patients with pulmonary hypertension secondary to congenital cardiac shunts. Cardiovascular Pathology: the Official Journal of the Society for Cardiovascular Pathology 13: 268–275.CrossRefGoogle Scholar
  12. 12.
    Humbert, M., G. Monti, F. Brenot, O. Sitbon, A. Portier, L. Grangeot-Keros, P. Duroux, P. Galanaud, G. Simonneau, and D. Emilie. 1995. Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. American Journal of Respiratory and Critical Care Medicine 151: 1628–1631.CrossRefPubMedGoogle Scholar
  13. 13.
    Soon, E., A.M. Holmes, C.M. Treacy, N.J. Doughty, L. Southgate, R.D. Machado, R.C. Trembath, S. Jennings, L. Barker, P. Nicklin, C. Walker, D.C. Budd, J. Pepke-Zaba, and N.W. Morrell. 2010. Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension. Circulation 122: 920–927.  https://doi.org/10.1161/CIRCULATIONAHA.109.933762.CrossRefPubMedGoogle Scholar
  14. 14.
    Sanchez, O., E. Marcos, F. Perros, E. Fadel, L. Tu, M. Humbert, P. Dartevelle, G. Simonneau, S. Adnot, and S. Eddahibi. 2007. Role of endothelium-derived CC chemokine ligand 2 in idiopathic pulmonary arterial hypertension. American Journal of Respiratory and Critical Care Medicine 176: 1041–1047.CrossRefPubMedGoogle Scholar
  15. 15.
    Kallapur, S.G., and A.H. Jobe. 2006. Contribution of inflammation to lung injury and development. Archives of Disease in Childhood. Fetal and Neonatal Edition 91: F132–F135.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Yee, M., R.J. White, H.A. Awad, W.A. Bates, S.A. McGrath-Morrow, and M.A. O’Reilly. 2011. Neonatal hyperoxia causes pulmonary vascular disease and shortens life span in aging mice. American Journal of Pathology 178: 2601–2610.  https://doi.org/10.1016/j.ajpath.2011.02.010.CrossRefPubMedGoogle Scholar
  17. 17.
    Wu, S., L. Capasso, A. Lessa, J. Peng, K. Kasisomayajula, M. Rodriguez, et al. 2008. High tidal volume ventilation activates Smad2 and upregulates expression of connective tissue growth factor in newborn rat lung. Pediatric Research 63: 245–250. doi:  https://doi.org/10.1203/PDR.0b013e318163a8cc.
  18. 18.
    Alapati, D., M. Rong, S. Chen, D. Hehre, S.C. Hummler, and S. Wu. 2014. Inhibition of β-catenin signaling improves alveolarization and reduces pulmonary hypertension in experimental bronchopulmonary dysplasia. American Journal of Respiratory Cell and Molecular Biology 51: 104–113.  https://doi.org/10.1165/rcmb.2013-0346OC.CrossRefPubMedGoogle Scholar
  19. 19.
    Alapati, D., M. Rong, S. Chen, D. Hehre, M.M. Rodriguez, K.E. Lipson, and S. Wu. 2011. Connective tissue growth factor antibody therapy attenuates hyperoxia-induced lung injury in neonatal rats. American Journal of Respiratory Cell and Molecular Biology 45: 1169–1177.  https://doi.org/10.1165/rcmb.2011-0023OC.CrossRefPubMedGoogle Scholar
  20. 20.
    Humbert, M., N.W. Morrell, S.L. Archer, K.R. Stenmark, M.R. MacLean, I.M. Lang, B.W. Christman, E.K. Weir, O. Eickelberg, N.F. Voelkel, and M. Rabinovitch. 2004. Cellular and molecular pathobiology of pulmonary arterial hypertension. Journal of the American College of Cardiology 43: 13S–24S.CrossRefPubMedGoogle Scholar
  21. 21.
    Pan, C., J. Wang, W. Liu, L. Liu, L. Jing, Y. Yang, and H. Qiu. 2012. Low tidal volume protects pulmonary vasomotor function from “second-hit” injury in acute lung injury rats. Respiratory Research 13: 77.  https://doi.org/10.1186/1465-9921-13-77.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Menendez, C., L. Martinez-Caro, L. Moreno, N. Nin, J. Moral-Sanz, D. Morales, A. Cogolludo, A. Esteban, J.A. Lorente, and F. Perez-Vizcaino. 2013. Pulmonary vascular dysfunction induced by high tidal volume mechanical ventilation. Critical Care Medicine 41: e149–e155.  https://doi.org/10.1097/CCM.0b013e318287ef4a. CrossRefPubMedGoogle Scholar
  23. 23.
    Zhu, Y., A. Chidekel, and T.H. Shaffer. 2010. Cultured human airway epithelial cells (calu-3): a model of human respiratory function, structure, and inflammatory responses. Critical Care Research and Practice 2010: 1–8.  https://doi.org/10.1155/2010/394578.CrossRefGoogle Scholar
  24. 24.
    Eddahibi, S., C. Guignabert, A.M. Barlier-Mur, L. Dewachter, E. Fadel, P. Dartevelle, M. Humbert, G. Simonneau, N. Hanoun, F. Saurini, M. Hamon, and S. Adnot. 2006. Cross talk between endothelial and smooth muscle cells in pulmonary hypertension: critical role for serotonin-induced smooth muscle hyperplasia. Circulation 113: 1857–1864.CrossRefPubMedGoogle Scholar
  25. 25.
    Tanaka, A., Y. Jin, S.J. Lee, M. Zhang, H.P. Kim, D.B. Stolz, S.W. Ryter, and A.M.K. Choi. 2012. Hyperoxia-induced LC3B interacts with the Fas apoptotic pathway in epithelial cell death. American Journal of Respiratory Cell and Molecular Biology 46: 507–514.  https://doi.org/10.1165/rcmb.2009-0415OC.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Zhu, Y., T.L. Miller, C.J. Singhaus, T.H. Shaffer, and A. Chidekel. 2008. Effects of oxygen concentration and exposure time on cultured human airway epithelial cells. Pediatric Critical Care Medicine 9: 224–229.  https://doi.org/10.1097/PCC.0b013e318166fbb5.CrossRefPubMedGoogle Scholar
  27. 27.
    Humbert, M., D. Montani, F. Perros, P. Dorfmüller, S. Adnot, and S. Eddahibi. 2008. Endothelial cell dysfunction and cross talk between endothelium and smooth muscle cells in pulmonary arterial hypertension. Vascular Pharmacology 49: 113–118.  https://doi.org/10.1016/j.vph.2008.06.003.CrossRefPubMedGoogle Scholar
  28. 28.
    Berkelhamer, S.K., G.A. Kim, J.E. Radder, S. Wedgwood, L. Czech, R.H. Steinhorn, and P.T. Schumacker. 2013. Developmental differences in hyperoxia-induced oxidative stress and cellular responses in the murine lung. Free Radical Biology and Medicine 61: 51–60.  https://doi.org/10.1016/j.freeradbiomed.2013.03.003.CrossRefPubMedGoogle Scholar
  29. 29.
    Rabinovitch, M., M.A. Konstam, W.J. Gamble, N. Papanicolaou, M.J. Aronovitz, S. Treves, and L. Reid. 1983. Changes in pulmonary blood flow affect vascular response to chronic hypoxia in rats. Circulation Research 52: 432–441.CrossRefPubMedGoogle Scholar
  30. 30.
    Quinn, T.P., M. Schlueter, S.J. Soifer, and J.A. Gutierrez. 2002. Cyclic mechanical stretch induces VEGF and FGF-2 expression in pulmonary vascular smooth muscle cells. American Journal of Physiology—Lung Cellular and Molecular Physiology 282: L897–L903.CrossRefPubMedGoogle Scholar
  31. 31.
    Gourh, P., F.C. Arnett, S. Assassi, F.K. Tan, M. Huang, L. Diekman, M.D. Mayes, J.D. Reveille, and S.K. Agarwal. 2009. Plasma cytokine profiles in systemic sclerosis: associations with autoantibody subsets and clinical manifestations. Arthritis Research & Therapy 11: R147.  https://doi.org/10.1186/ar2821.CrossRefGoogle Scholar
  32. 32.
    Miyata, M., F. Sakuma, A. Yoshimura, H. Ishikawa, T. Nishimaki, and R. Kasukawa. 1995. Pulmonary hypertension in rats. 2. Role of interleukin-6. International Archives of Allergy and Immunology 108: 287–291.CrossRefPubMedGoogle Scholar
  33. 33.
    Steiner, M.K., O.L. Syrkina, N. Kolliputi, E.J. Mark, C.A. Hales, and A.B. Waxman. 2009. Interleukin-6 overexpression induces pulmonary hypertension. Circulation Research 104: 236–244.  https://doi.org/10.1161/CIRCRESAHA.108.182014.CrossRefPubMedGoogle Scholar
  34. 34.
    Savale, L., L. Tu, D. Rideau, M. Izziki, B. Maitre, S. Adnot, and S. Eddahibi. 2009. Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice. Respiratory Research 10: 6.  https://doi.org/10.1186/1465-9921-10-6.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Voelkel, N.F., R.M. Tuder, J. Bridges, and W.P. Arend. 1994. Interleukin-1 receptor antagonist treatment reduces pulmonary hypertension generated in rats by monocrotaline. American Journal of Respiratory Cell and Molecular Biology 11: 664–675.CrossRefPubMedGoogle Scholar
  36. 36.
    Kirii, H., T. Niwa, Y. Yamada, H. Wada, K. Saito, Y. Iwakura, et al. 2003. Lack of interleukin-1ß decreases the severity of atherosclerosis in ApoE-deficient mice. Arteriosclerosis, Thrombosis, and Vascular Biology 23: 656–660.CrossRefPubMedGoogle Scholar
  37. 37.
    Isoda, K., M. Shiigai, N. Ishigami, T. Matsuki, R. Horai, K. Nishikawa, M. Kusuhara, Y. Nishida, Y. Iwakura, and F. Ohsuzu. 2003. Deficiency of interleukin-1 receptor antagonist promotes neointimal formation after injury. Circulation 108: 516–518.CrossRefPubMedGoogle Scholar
  38. 38.
    Ikonomidis, I., J.P. Lekakis, M. Nikolaou, I. Paraskevaidis, I. Andreadou, T. Kaplanoglou, P. Katsimbri, G. Skarantavos, P.N. Soucacos, and D.T. Kremastinos. 2008. Inhibition of interleukin-1 by anakinra improves vascular and left ventricular function in patients with rheumatoid arthritis. Circulation 117: 2662–2669.  https://doi.org/10.1161/CIRCULATIONAHA.107.731877.CrossRefPubMedGoogle Scholar
  39. 39.
    Larsen, C.M., M. Faulenbach, A. Vaag, A. Volund, J.A. Ehses, B. Seifert, et al. 2007. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. New England Journal of Medicine 356: 1517–1526.CrossRefPubMedGoogle Scholar
  40. 40.
    Lin, S.J., H.T. Yen, Y.H. Chen, H.H. Ku, F.Y. Lin, and Y.L. Chen. 2003. Expression of interleukin-1 beta and interleukin-1 receptor antagonist in oxLDL-treated human aortic smooth muscle cells and in the neointima of cholesterol-fed endothelia-denuded rabbits. Journal of Cellular Biochemistry 88: 836–847.CrossRefPubMedGoogle Scholar
  41. 41.
    Wilson, J., J. Yu, L. Taylor, and P. Polgar. 2015. Hyperplastic growth of pulmonary artery smooth muscle cells from subjects with pulmonary artery hypertension is activated through JNK and p38 MAPK. PLoS One 10 (4): e0123662.  https://doi.org/10.1371/journal.pone.0123662.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Nogueira-Ferreria, R., R. Ferreria, and T. Henriques-Coehlo. 2014. Cellular interplay in pulmonary arterial hypertension: implications for new therapies. Biochimica et Biophysica Acta 1843: 885–893.  https://doi.org/10.1016/j.bbamcr.2014.01.030.CrossRefGoogle Scholar
  43. 43.
    QI, Y.X., X.H. Jiang, X.D. Wang, et al. 2011. PDGF-BB and TGF-β on crosstalk between endothelial and smooth muscle cells in remodeling induced by low shear stress. Proceedings of the National Academy of Science of the United States 108: 1908–1913.  https://doi.org/10.1073/pnas.1019219108.CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pediatrics, Nemours/Alfred I. duPont Hospital for ChildrenWilmingtonUSA
  2. 2.Center for Pediatric Lung Research, Nemours/Alfred I. duPont Hospital for ChildrenWilmingtonUSA
  3. 3.Sidney Kimmel Medical CollegeThomas Jefferson UniversityPhiladelphiaUSA
  4. 4.Division of Neonatology, Nemours/Alfred I. duPont Hospital for ChildrenWilmingtonUSA
  5. 5.Departments of Anesthesia, Nemours/Alfred I. duPont Hospital for ChildrenWilmingtonUSA
  6. 6.Center for Clinical Diagnostics, Nemours/Alfred I. duPont Hospital for ChildrenWilmingtonUSA
  7. 7.Temple University School of MedicinePhiladelphiaUSA

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