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Dexamethasone attenuates development of monocrotaline-induced pulmonary arterial hypertension

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Abstract

Immunity and inflammation are well established factors in the pathogenesis of pulmonary arterial hypertension (PAH). We aimed to investigate whether dexamethasone (Dex), a potent immunosuppressant, could prevent the development of monocrotaline (MCT)-induced PAH in rats as compared with pyrrolidine dithiocarbamate (PDTC) and its effect on the immune mechanism. PAH in rats (n = 66) was induced by MCT (50 mg/kg) injected intraperitoneally. Two days after MCT treatment, Dex (1.0 mg/kg) and PDTC (100 mg/kg) were administered once daily for 21 days. Samples were collected at 7, 14, and 21 days. Dex effectively inhibited MCT-induced PAH and reduced the T-helper (Th) 1 dominant cytokine response (interferon-γ) but up-regulated the Th2 one (interleukin 4). It increased the number of CD4+ T cells and decreased the number of CD8+ T cells around pulmonary arteries, upregulated the mRNA expression of fractalkine and downregulated that of CX3CR1 in the lung. Serum levels of interferon γ and interleukin 4 did not significantly differ from that of controls. Dex attenuated the process of MCT-induced PAH through its immunomodulatory property. Dex could be an appropriate therapy for PAH, although more studies are needed to define the appropriate treatment regimen.

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References

  1. Tanino Y (2001) Monocrotaline-induced pulmonary hypertension in animals. Nippon Rinsho 59:1076–1080

    PubMed  CAS  Google Scholar 

  2. Sawada H, Mitani Y, Maruyama J, Jiang BH, Ikeyama Y, Dida FA, Yamamoto H, Imanaka-Yoshida K, Shimpo H, Mizoguchi A, Maruyama K, Komada Y (2007) A nuclear factor-kappaB inhibitor pyrrolidine dithiocarbamate ameliorates pulmonary hypertension in rats. Chest 132:1265–1274

    Article  PubMed  CAS  Google Scholar 

  3. Dorfmüller P, Perros F, Balabanian K, Humbert M (2003) Inflammation in pulmonary arterial hypertension. Eur Respir J 22:358–363

    Article  PubMed  Google Scholar 

  4. Nicolls MR, Taraseviciene-Stewart L, Rai PR, Badesch DB, Voelkel NF (2005) Autoimmunity and pulmonary hypertension. Eur Respir J 26:1110–1118

    Article  PubMed  CAS  Google Scholar 

  5. Lederman MM, Sereni D, Simonneau G, Voelkel NF (2008) Pulmonary arterial hypertension and its association with HIV infection: an overview. AIDS 22:S1–S6

    Article  PubMed  Google Scholar 

  6. Chan SY, Loscalzo J (2008) Pathogenic mechanisms of pulmonary arterial hypertension. J Mol Cell Cardiol 44:14–30

    Article  PubMed  CAS  Google Scholar 

  7. Tuder RM, Cool CD, Yeager M, Taraseviciene-Stewart L, Bull TM, Voelkel NF (2001) The pathobiology of pulmonary hypertension. Endothelium. Clin Chest Med 22:405–418

    Article  PubMed  CAS  Google Scholar 

  8. Budhiraja R, Tuder RM, Hassoun PM (2004) Endothelial dysfunction in pulmonary hypertension. Circulation 109:159–165

    Article  PubMed  Google Scholar 

  9. Toshner M, Voswinckel R, Southwood M, Al-Lamki R, Howard LS, Marchesan D, Yang J, Suntharalingam J, Soon E, Exley A, Stewart S, Hecker M, Zhu Z, Gehling U, Seeger W, Pepke-Zaba J, Morrell NW (2009) Evidence for dysfunction of endothelial progenitors in pulmonary arterial hypertension. Am J Respir Crit Care Med 180:780–787

    Article  PubMed  Google Scholar 

  10. Foussat A, Coulomb-L’Hermine A, Gosling J, Krzysiek R, Durand-Gasselin I, Schall T, Balian A, Richard Y, Galanaud P, Emilie D (2000) Fractalkine receptor expression by T lymphocyte subpopulations and in vivo production of fractalkine in human. Eur J Immunol 30:87–97

    Article  PubMed  CAS  Google Scholar 

  11. Bazan JF, Bacon KB, Hardiman G, Wang W, Soo K, Rossi D, Greaves DR, Zlotnik A, Schall TJ (1997) A new class of membrane bound chemokine with a CX3C motif. Nature 385:640–644

    Article  PubMed  CAS  Google Scholar 

  12. Tuder RM, Groves B, Badesch DB, Voelkel NF (1994) Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am J Pathol 144:275–285

    PubMed  CAS  Google Scholar 

  13. Taraseviciene-Stewart L, Scerbavicius DK, Burns N, Cool CD, Nicolls MR, Voelkel NF (2005) The protective role of T-lymphocytes in pulmonary vascular remodeling. Chest 128:571S–572S

    Article  PubMed  CAS  Google Scholar 

  14. Cupps TR, Fauci AS (1982) Corticosteroid-mediated immunoregulation in man. Immunol Rev 65:133–155

    Article  PubMed  CAS  Google Scholar 

  15. Ramírez F, Fowell DJ, Puklavec M, Simmonds S, Mason D (1996) Glucocorticoids promote a TH2 cytokine response by CD4+ T cells in vitro. J Immunol 156:2406–2412

    PubMed  Google Scholar 

  16. DeKruyff RH, Fang Y, Umetsu DT (1998) Corticosteroids enhance the capacity of macrophages to induce Th2 cytokine synthesis in CD4+ lymphocytes by inhibiting IL-12 production. J Immunol 160:2231–2237

    PubMed  CAS  Google Scholar 

  17. Guo C, Chu X, Shi Y, He W, Li L, Wang L, Wang Y, Peng J, Hou M (2007) Correction of Th1-dominant cytokine profiles by high-dose dexamethasone in patients with chronic idiopathic thrombocytopenic purpura. J Clin Immunol 27:557–562

    Article  PubMed  CAS  Google Scholar 

  18. Romagnani S (1997) The Thl/Th2 paradigm. Immunol Today 18:263–266

    Article  PubMed  CAS  Google Scholar 

  19. Sanchez O, Humbert M, Sitbon O, Simonneau G (1999) Treatment of pulmonary hypertension secondary to connective tissue diseases. Thorax 54:273–277

    Article  PubMed  CAS  Google Scholar 

  20. Bellotto F, Chiavacci P, Laveder F, Angelini A, Thiene G, Marcolongo R (1999) Effective immunosuppressive therapy in a patient with primary pulmonary hypertension. Thorax 54:372–374

    Article  PubMed  CAS  Google Scholar 

  21. Liu SF, Ye X, Malik AB (1999) Inhibition of NF-kB activation by pyrrolidine dithiocarbamate prevents in vivo expression of proinflammatory genes. Circulation 100:1330–1337

    PubMed  CAS  Google Scholar 

  22. Huang J, Kaminski PM, Edwards JG, Yeh A, Wolin MS, Frishman WH, Gewitz MH, Mathew R (2008) Pyrrolidine dithiocarbamate restores endothelial cell membrane integrity and attenuates monocrotaline-induced pulmonary artery hypertension. Am J Physiol Lung Cell Mol Physiol 294:L1250–L1259

    Article  PubMed  CAS  Google Scholar 

  23. Pahl HL (1999) Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene 18:6853–6866

    Article  PubMed  CAS  Google Scholar 

  24. Lee UJ, Choung SR, Prakash KV, Lee EJ, Lee MY, Kim YJ, Han CW, Choi YC (2008) Dual knockdown of p65 and p50 subunits of NF-kappaB by siRNA inhibits the induction of inflammatory cytokines and significantly enhance apoptosis in human primary synoviocytes treated with tumor necrosis factor-alpha. Mol Biol Rep 35:291–298

    Article  PubMed  CAS  Google Scholar 

  25. Schottelius AJ, Mayo MW, Sartor RB, Baldwin AS Jr (1999) Interleukin-10 signaling blocks inhibitor of kappaB kinase activity and nuclear factor kappaB DNA binding. J Biol Chem 274:31868–31874

    Article  PubMed  CAS  Google Scholar 

  26. Scheinman RI, Cogswell PC, Lofquist AK, Baldwin AS Jr (1995) Role of transcriptional activation of I kappa B alpha in mediation of immunosuppression by glucocorticoids. Science 270:283–286

    Article  PubMed  CAS  Google Scholar 

  27. Hilliker KS, Roth RA (1984) Alteration of monocrotaline pyrrole-induced cardiopulmonary effects in rats by hydrallazine, dexamethasone or sulphinpyrazone. Br J Pharmacol 82:375–380

    PubMed  CAS  Google Scholar 

  28. Daley E, Emson C, Guignabert C, de Waal Malefyt R, Louten J, Kurup VP, Hogaboam C, Taraseviciene-Stewart L, Voelkel NF, Rabinovitch M, Grunig E, Grunig G (2008) Pulmonary arterial remodeling induced by a Th2 immune response. J Exp Med 205:361–372

    Article  PubMed  CAS  Google Scholar 

  29. Wilckens T, De Rijk R (1997) Glucocorticoids and immune function: unknown dimensions and new frontiers. Immunol Today 18:418–424

    Article  PubMed  CAS  Google Scholar 

  30. Pinto RF, Higuchi Mde L, Aiello VD (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. Cardiovasc Pathol 13:268–275

    Article  PubMed  Google Scholar 

  31. Sakaguchi S, Yamaguchi T, Nomura T, Ono M (2008) Regulatory T cells and immune tolerance. Cell 133:775–787

    Article  PubMed  CAS  Google Scholar 

  32. Kumaraguru U, Banerjee K, Rouse BT (2005) In vivo rescue of defective memory CD8+ T cells by cognate helper T cells. J Leukoc Biol 78:879–887

    Article  PubMed  CAS  Google Scholar 

  33. Trzonkowski P, Szmit E, Myśliwska J, Myśliwski A (2006) CD4+CD25+ T regulatory cells inhibit cytotoxic activity of CTL and NK cells in humans impact of immunosenescence. Clin Immunol 119:307–316

    Article  PubMed  CAS  Google Scholar 

  34. Imaizumi T, Yoshida H, Satoh K (2004) Regulation of CX3CL1/fractalkine expression in endothelial cells. J Atheroscler Thromb 11:15–21

    PubMed  CAS  Google Scholar 

  35. Perros F, Dorfmüller P, Souza R, Durand-Gasselin I, Godot V, Capel F, Adnot S, Eddahibi S, Mazmanian M, Fadel E, Hervé P, Simonneau G, Emilie D, Humbert M (2007) Fractalkine-induced smooth muscle cell proliferation in pulmonary hypertension. Eur Respir J 29:937–943

    Article  PubMed  CAS  Google Scholar 

  36. Imai T, Hieshima K, Haskell C, Baba M, Nagira M, Nishimura M, Kakizaki M, Takagi S, Nomiyama H, Schall TJ, Yoshie O (1997) Identification and molecular characterization of fractalkine receptor CX3CR1, which mediates both leukocyte migration and adhesion. Cell 91:521–530

    Article  PubMed  CAS  Google Scholar 

  37. Kagoshima M, Ito K, Cosio B, Adcock IM (2003) Glucocorticoid suppression of nuclear factor-kappa B: a role for histone modifications. Biochem Soc Trans 31:60–65

    Article  PubMed  CAS  Google Scholar 

  38. Hayashi R, Wada H, Ito K, Adcock IM (2004) Effects of glucocorticoids on gene transcription. Eur J Pharmacol 500:51–62

    Article  PubMed  CAS  Google Scholar 

  39. Faul JL, Nishimura T, Berry GJ, Benson GV, Pearl RG, Kao PN (2000) Triptolide attenuates pulmonary arterial hypertension and neointimal formation in rats. Am J Respir Crit Care Med 162:2252–2258

    PubMed  CAS  Google Scholar 

  40. Qiu D, Zhao G, Aoki Y, Shi L, Uyei A, Nazarian S, Ng JC, Kao PN (1999) Immunosuppressant PG490 (triptolide) inhibits T-cell interleukin-2 expression at the level of purine-box/nuclear factor of activated T-cells and NF-kappaB transcriptional activation. J Biol Chem 274:13443–13450

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors are grateful to Fengqin Liu and Qingqing Wang for excellent secretarial work. We also greatly appreciate the staff of the Central Laboratory of our hospital.

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Authors and Affiliations

  1. Department of Pediatrics, Shandong Provincial Hospital, Shandong University, 44 Wenxi Road, Ji’nan, 250012, Shandong Province, China

    Wei Wang, Yu-lin Wang, Xiao-ying Chen, Wei Hao, You-peng Jin & Bo Han

  2. Department of Immunology and Microbiology Laboratory, School of Medicine, Shandong University, Ji’nan, China

    Yu-tang Li

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  1. Wei Wang
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  2. Yu-lin Wang
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Correspondence to Yu-lin Wang.

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Fig. S1

Immunohistochemical analysis of macrophages in rat lungs. Sections were from control treatment (a), 1 week post-MCT treatment (b), 2 weeks post-MCT treatment (c), 3 weeks post-MCT treatment (d), PDTC treatment (e), Dex treatment (f). Positive-stained cells are brown. Magnification ×400 (JPEG 1227 kb)

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Wang, W., Wang, Yl., Chen, Xy. et al. Dexamethasone attenuates development of monocrotaline-induced pulmonary arterial hypertension. Mol Biol Rep 38, 3277–3284 (2011). https://doi.org/10.1007/s11033-010-0390-x

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