Chronic intermittent hypobaric hypoxia attenuates monocrotaline-induced pulmonary arterial hypertension via modulating inflammation and suppressing NF-κB /p38 pathway

Document Type : Original Article

Authors

1 Department of Heart Center, the First Hospital of Hebei Medical University, Shijiazhuang, 050031, China

2 Department of Endocrinology, the Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China

3 Department of Physiology, Foundation Medicine School of Hebei Medical University, Shijiazhuang, 050017, China

Abstract

Objective(s): Inflammation is involved in various forms of pulmonary arterial hypertension (PAH). Although the pathophysiology of PAH remains uncertain, NF-κB and p38 mitogen-activated protein kinase (p38 MAPK) has been reportedto be associated with many inflammatory mediators of PAH. This study aimed to evaluate the effect of chronic intermittent hypobaric hypoxia (CIHH) on pulmonary inflammation and remodeling in monocrotaline (MCT) induced PAH in rats.
Materials and Methods: An in vivo model of PAH induced by MCT was employed. Statistical analyses were assessed bydone using one-way analysis of variance (ANOVA) or Fisher's LSD test for multiple comparisons.
Results: Four weeks of CIHH exposure following MCT injection resulted in significant reduction of mean pulmonary artery pressure (mPAP) level and improvement of right ventricular hypertrophy (RVH). Morphometric analyses showed decreased wall thickness of pulmonary arterioles in MCT+CIHH treated rats. These findings are consistent with the decrease in Ki-67 immunostaining. Following CIHH treatments, apoptotic analysis showed a consistent decrease in T lymphocytes together with lower levels of CD4+ T cell subset as measured in spleen and blood samples. Furthermore, CIHH treatment resulted in markedly reduced expression of TNF-α and IL-6 via the inhibition of NF-κB and p38 MAPK activity in rat lungs.
Conclusion: Altogether, these results provide new evidence relating to the mode of action of CIHH in the prevention of PAH induced by MCT.

Keywords

Main Subjects

References

1. Rubin LJ. Primary pulmonary hypertension. N Engl J Med 1997; 336:111-117.
2. Simonneau G, Galie N, Rubin LJ, Langleben D, Seeger W, Domenighetti G, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004; 43:S5-S12.
3. Dorfmüller P, Perros F, Balabanian K, Humbert M. Inflammation in pulmonary arterial hypertension. Eur Respir J 2003; 22:358-363.
4. Humbert M, Monti G, Brenot F, Sitbon O, Portier A, Grangeot-Keros L, et al. Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am J Respir Crit Care Med 1995; 151:1628-1631.
5. Soon E, Holmes AM, Treacy CM, Doughty NJ, Southgate L, Machado RD, et al. Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension. Circulation 2010; 122:920-927.
6. Bhargava A, Kumar A, Yuan N, Gewitz M, Mathew R. Monocrotaline induces interleukin-6 mRNA expression in rat lungs. Heart Dis (Hagerstown, Md) 1998; 1:126-132.
7. Karmochkine M, Wechsler B, Godeau P, Brenot F, Jagot J, Simonneau G. Improvement of severe pulmonary hypertension in a patient with SLE. Ann Rheum Dis 1996; 55:561.
8. Price L, Montani D, Tcherakian C, Dorfmüller P, Souza R, Gambaryan N, et al. Dexamethasone reverses monocrotaline-induced pulmonary arterial hypertension in rats. Eur Respir J 2011; 37:813-822.
9. Bonnet S, Rochefort G, Sutendra G, Archer SL, Haromy A, Webster L, et al. The nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targeted. Proc Natl Acad Sci 2007; 104:11418-11423.
10. Suzuki C, Takahashi M, Morimoto H, Izawa A, Ise H, Hongo M, et al. Mycophenolate mofetil attenuates pulmonary arterial hypertension in rats. Biochem Biophys Res Commun 2006; 349:781-788.
11. Gordon JW, Shaw JA, Kirshenbaum LA. Multiple facets of NF-κB in the heart to be or not to NF-κB. Circ Res 2011; 108:1122-1132.
12. Hall G, Hasday JD, Rogers TB. Regulating the regulator: NF-κB signaling in heart. J Mol Cell Cardiol 2006; 41:580-591.
13. Chen L, Nakano K, Kimura S, Matoba T, Iwata E, Miyagawa M, et al. Nanoparticle-mediated delivery of pitavastatin into lungs ameliorates the development and induces regression of monocrotaline-induced pulmonary artery hypertension. Hypertension 2011; 57:343-350.
14. Kimura S, Egashira K, Chen L, Nakano K, Iwata E, Miyagawa M, et al. Nanoparticle-mediated delivery of nuclear factor κB decoy into lungs ameliorates monocrotaline-induced pulmonary arterial hypertension. Hypertension 2009; 53:877-883.
15. Hassoun PM, Mouthon L, Barberà JA, Eddahibi S, Flores SC, Grimminger F, et al. Inflammation, growth factors, and pulmonary vascular remodeling.            J Am Coll Cardiol 2009; 54:S10-S19.
16. Sugden PH, Clerk A. “Stress-responsive” mitogen-activated protein kinases (c-Jun N-terminal kinases and p38 mitogen-activated protein kinases) in the myocardium. Circ Res 1998; 83:345-352.
17. Rose F, Grimminger F, Appel J, Heller M, Pies V, Weissmann N, et al. Hypoxic pulmonary artery fibroblasts trigger proliferation of vascular smooth muscle cells: role of hypoxia-inducible transcription factors.             FASEB J 2002; 16:1660-1661.
18. Welsh DJ, Scott PH, Peacock AJ. p38 MAP kinase isoform activity and cell cycle regulators in the proliferative response of pulmonary and systemic artery fibroblasts to acute hypoxia. Pulm Pharmacol Ther 2006; 19:128-138.
19. Welsh DJ, Peacock AJ, MacLEAN M, Harnett M. Chronic hypoxia induces constitutive p38 mitogen-activated protein kinase activity that correlates with enhanced cellular proliferation in fibroblasts from rat pulmonary but not systemic arteries. Am J Respir Crit Care Med 2001; 164:282-289.
20. Jin N, Hatton N, Swartz DR, Xia X-l, Harrington MA, Larsen SH, et al. Hypoxia activates un-N-terminal kinase, extracellular Signal–regulated protein kinase, and p38 kinase in pulmonary arteries. Am J Respir Cell Mol Biol 2000; 23:593-601.
21. Scott PH, Paul A, Belham CM, Peacock AJ, Wadsworth RM, Gould GW, et al. Hypoxic stimulation of the stress-activated protein kinases in pulmonary artery fibroblasts. Am J Respir Crit Care Med 1998; 158:958-962.
22. Wang Q, Zuo X-r, Wang Y-y, Xie W-p, Wang H, Zhang M. Monocrotaline-induced pulmonary arterial hypertension is attenuated by TNF-α antagonists via the suppression of TNF-α expression and NF-κB pathway in rats. Vascul Pharmacol 2013; 58:71-77.
23. Hardziyenka M, Campian ME, de Bruin-Bon HR, Michel MC, Tan HL. Sequence of echocardiographic changes during development of right ventricular failure in rat. J Am Soc Echocardiogr 2006; 19:1272-1279.
24. Stenmark KR, Meyrick B, Galie N, Mooi WJ, McMurtry IF. Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure. Am J Physiol Lung Cell Mol Physiol 2009; 297:L1013-L1032.
25. Yuan Y, Liao L, Tulis DA, Xu J. Steroid receptor coactivator-3 is required for inhibition of neointima formation by estrogen. Circulation 2002; 105:2653-2659.
26. Friedrichs K, Gluba S, Eidtmann H, Jonat W. Overexpression of p53 and prognosis in breast cancer. Cancer 1993; 72:3641-3647.
27. Fujita M, Shannon JM, Irvin CG, Fagan KA, Cool C, Augustin A, et al. Overexpression of tumor necrosis factor-α produces an increase in lung volumes and pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2001; 280:L39-L49.
28. Morin C, Hiram R, Rousseau E, Blier PU, Fortin S. Docosapentaenoic acid monoacylglyceride reduces inflammation and vascular remodeling in experimental pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2014:ajpheart. 00814.02013.
29. Takahashi M, Okazaki H, Ogata Y, Takeuchi K, Ikeda U, Shimada K. Lysophosphatidylcholine induces apoptosis in human endothelial cells through a p38-mitogen-activated protein kinase-dependent mechanism. Atherosclerosis 2002; 161:387-394.
30. Weerackody RP, Welsh DJ, Wadsworth RM, Peacock AJ. Inhibition of p38 MAPK reverses hypoxia-induced pulmonary artery endothelial dysfunction. Am J Physiol Lung Cell Mol Physiol 2009; 296:H1312-H1320.
31. Fartoukh M, Emilie D, Le Gall C, Monti G, Simonneau G, Humbert M. Chemokine macrophage inflammatory protein-1α mRNA expression in lung biopsy specimens of primary pulmonary hypertension. Chest J 1998; 114:50S-51S.
32. Cool CD, Kennedy D, Voelkel NF, Tuder RM. Pathogenesis and evolution of plexiform lesions in pulmonary hypertension associated with scleroderma and human immunodeficiency virus infection. Hum Pathol 1997; 28:434-442.
33. Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 2004; 43:S13-S24.
34. Lesprit P, Godeau B, Authier F-J, Soubrier M, Zuber M, Larroche C, et al. Pulmonary hypertension in POEMS syndrome: a new feature mediated by cytokines. Am J Respir Crit Care Med 1998; 157:907-911.
35. Minamino T, Christou H, Hsieh C-M, Liu Y, Dhawan V, Abraham NG, et al. Targeted expression of heme oxygenase-1 prevents the pulmonary inflammatory and vascular responses to hypoxia. Proc Natl Acad Sci 2001; 98:8798-8803.
36. Barst RJ, Loyd JE. Genetics and immunogenetic aspects of primary pulmonary hypertension. Chest J 1998; 114:231S-236S.
37. Voelkel NF, Tuder R. Interleukin‐1 receptor antagonist inhibits pulmonary hypertension induced by inflammationa. Ann N Y Acad Sci 1994; 725:104-109.
38. Tabata T, Ono S, Song C, Noda M, Suzuki S, Tanita T, et al. [Role of leukotriene B4 in monocrotaline-induced pulmonary hypertension]. Nihon Kyobu Shikkan Gakkai Zasshi 1997; 35:160-166.
39. Miyata M, Ueno Y, Sekine H, Ito O, Sakuma F, Koike H,                 et al. Protective effect of beraprost sodium, a stable prostacyclin analogue, in development of monocrotaline-induced pulmonary hypertension. J Cardiovasc Pharmacol 1996; 27:20-26.
40. Sugita T, Hyers TM, Dauber I, Wagner W, McMurtry I, Reeves J. Lung vessel leak precedes right ventricular hypertrophy in monocrotaline-treated rats. J Appl Physiol 1983; 54:371-374.
41. Tuder RM, Groves B, Badesch DB, Voelkel NF. Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am J Pathol 1994; 144:275.
42. Alpert M, Goldberg S, Singsen B, Durham J, Sharp G, Ahmad M, et al. Cardiovascular manifestations of mixed connective tissue disease in adults. Circulation 1983; 68:1182-1193.
43. Ulrich S, Nicolls MR, Taraseviciene L, Speich R, Voelkel N. Increased regulatory and decreased CD8+ cytotoxic T cells in the blood of patients with idiopathic pulmonary arterial hypertension. Respiration 2007; 75:272-280.
44. Daley E, Emson C, Guignabert C, de Waal Malefyt R, Louten J, Kurup VP, et al. Pulmonary arterial remodeling induced by a Th2 immune response. J Exp Med 2008; 205:361-372.
45. Behr T, Berova M, Doe C, Ju H, Angermann CE, Boehm J, et al. p38 mitogen-activated protein kinase inhibitors for the treatment of chronic cardiovascular disease. Curr Opin Investig Drugs 2003; 4:1059-1064.
46. Karin M, Lin A. NF-κB at the crossroads of life and death. Nat Immunol 2002; 3:221-227.
47. Lee JC, Laydon JT, McDonnell PC, Gallagher TF, Kumar S, Green D, et al. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis.  Nature 1994; 372: 739-746.
48. Matsumori A. Anti-inflammatory therapy for heart failure. Curr Opin Pharmacol 2004; 4:171-176.
49. Lee JC, Kumar S, Griswold DE, Underwood DC, Votta BJ, Adams JL. Inhibition of p38 MAP kinase as a therapeutic strategy. Immunopharmacology 2000; 47:185-201.
50. Hosokawa S, Haraguchi G, Sasaki A, Arai H, Muto S, Itai A, et al. Pathophysiological roles of NF-kB in pulmonary arterial hypertension: Effects of synthetic selective NF-kB inhibitor IMD-0354. Cardiovasc Res 2013:cvt105.
51. Kumar S, Wei C, Thomas CM, Kim I-K, Seqqat R, Kumar R, et al. Cardiac-specific genetic inhibition of nuclear factor-κB prevents right ventricular hypertrophy induced by monocrotaline. Am J Physiol Heart Circ Physiol 2012; 302:H1655-H1666.
Iranian Journal of Basic Medical Sciences
Volume 21, Issue 3
March 2018
Pages 244-252

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