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Animal Models with Pulmonary Hypertension

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Diagnosis and Treatment of Pulmonary Hypertension

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Abstract

Pulmonary arterial hypertension (PAH) comprises a multifactorial group of pulmonary vascular disorders that frequently lead to right heart failure and premature death. Histologically, patients with severe PAH have combinations of small pulmonary arterial medial and adventitial thickening, occlusive neointima, and complex plexiform lesions. Despite recent advances in treatments targeting those remodeled pulmonary arteries, the mortality in severe PAH is still high. To explore the novel treatment for severe PAH, better understandings of the pathogenesis of these lesions are needed. Numerous studies to investigate the pathogenic cellular and molecular mechanisms have been done using conventional animal models (i.e., chronically hypoxic and monocrotaline-injected rats) of pulmonary hypertension (PH). Although these animal models have contributed to provide important mechanistic insights for the development of the treatments, they do not develop the histological hallmarks of PAH, plexiform lesions. This chapter provides an overview of the histological characteristics observed in humans with pulmonary hypertension and preclinical models and discusses the better model to be used for investigating the pathogenesis of PAH and preclinical drug evaluations.

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References

  1. Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54:S43–54.

    Article  PubMed  Google Scholar 

  2. Stacher E, Graham BB, Hunt JM, Gandjeva A, Groshong SD, McLaughlin VV, et al. Modern age pathology of pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186:261–72.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Wagenvoort CA. Plexogenic arteriopathy. Thorax. 1994;49:S39–45.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Heath D, Edwards JE. The pathology of hypertensive pulmonary vascular disease: a description of six grades of structural changes in the pulmonary arteries with special reference to congenital cardiac septal defects. Circulation. 1958;18:533–47.

    Article  CAS  PubMed  Google Scholar 

  5. Galiè N, Corris PA, Frost A, Girgis RE, Granton J, Jing ZC, et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D60–72.

    Article  PubMed  Google Scholar 

  6. 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:L1013–32.

    Article  CAS  PubMed  Google Scholar 

  7. Kay JM, Harris P, Heath D. Pulmonary hypertension produced in rats by ingestion of Crotalaria spectabilis seeds. Thorax. 1967;22(2):176–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wilson DW, Segall HJ, Pan LC, Lamé MW, Estep JE, Morin D. Mechanisms and pathology of monocrotaline pulmonary toxicity. Crit Rev Toxicol. 1992;22(5–6):307–25.

    Article  CAS  PubMed  Google Scholar 

  9. Gomez-Arroyo JG, Farkas L, Alhussaini AA, Farkas D, Kraskauskas D, Voelkel NF, Bogaard HJ. The monocrotaline model of pulmonary hypertension in perspective. Am J Physiol Lung Cell Mol Physiol. 2012;302(4):L363–9.

    Article  CAS  PubMed  Google Scholar 

  10. Kurozumi T, Tanaka K, Kido M, Shoyama Y. Monocrotaline-induced renal lesions. Mol Pathol. 1983;39(3):377–86.

    Article  CAS  Google Scholar 

  11. Herget J, Suggett AJ, Leach E, Barer GR. Resolution of pulmonary hypertension and other features induced by chronic hypoxia in rats during complete and intermittent normoxia. Thorax. 1978;33(4):468–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sato K, Webb S, Tucker A, Rabinovitch M, O’Brien RF, McMurtry IF, Stelzner TJ. Factors influencing the idiopathic development of pulmonary hypertension in the fawn hooded rat. Am Rev Respir Dis. 1992;145(4 Pt 1):793–7.

    Article  CAS  PubMed  Google Scholar 

  13. Nagaoka T, Gebb SA, Karoor V, Homma N, Morris KG, McMurtry IF, Oka M. Involvement of RhoA/Rho kinase signaling in pulmonary hypertension of the fawn-hooded rat. J Appl Physiol. 2006;100(3):996–1002.

    Article  CAS  PubMed  Google Scholar 

  14. Ebralidze A, Tulchinsky E, Grigorian M, Afanasyeva A, Senin V, Revazova E, Lukanidin E. Isolation and characterization of a gene specifically expressed in different metastatic cells and whose deduced gene product has a high degree of homology to a Ca2+−binding protein family. Genes Dev. 1989;3:1086–93.

    Article  CAS  PubMed  Google Scholar 

  15. Greenway S, van Suylen RJ, Du Marchie Sarvaas G, Kwan E, Ambartsumian N, Lukanidin E, Rabinovitch M. S100A4/Mts1 produces murine pulmonary artery changes resembling plexogenic arteriopathy and is increased in human plexogenic arteriopathy. Am J Pathol. 2004;164:253–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Humbert M, Monti G, Brenot F, Sitbon O, Portier A, Grangeot-Keros L, Duroux P, Galanaud P, Simonneau G, Emilie D. Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am J Respir Crit Care Med. 1995;151(5):1628–31.

    Article  CAS  PubMed  Google Scholar 

  17. Steiner MK, Syrkina OL, Kolliputi N, Mark EJ, Hales CA, Waxman AB. Interleukin-6 overexpression induces pulmonary hypertension. Circ Res. 2009;104(2):236–44.

    Article  CAS  PubMed  Google Scholar 

  18. Deng Z, Morse JH, Slager SL, Cuervo N, Moore KJ, Venetos G, Kalachikov S, Cayanis E, Fischer SG, Barst RJ, Hodge SE, Knowles JA. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet. 2000;67(3):737–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Elliott CG. Genetics of pulmonary arterial hypertension: current and future implications. Semin Respir Crit Care Med. 2005;26(4):365–71.

    Article  PubMed  Google Scholar 

  20. Beppu H, Ichinose F, Kawai N, Jones RC, Yu PB, Zapol WM, Miyazono K, Li E, Bloch KD. BMPR-II heterozygous mice have mild pulmonary hypertension and an impaired pulmonary vascular remodeling response to prolonged hypoxia. Am J Physiol Lung Cell Mol Physiol. 2004;287(6):L1241–7.

    Article  CAS  PubMed  Google Scholar 

  21. Frank DB, Lowery J, Anderson L, Brink M, Reese J, de Caestecker M. Increased susceptibility to hypoxic pulmonary hypertension in Bmpr2 mutant mice is associated with endothelial dysfunction in the pulmonary vasculature. Am J Physiol Lung Cell Mol Physiol. 2008;294(1):L98–109.

    Article  CAS  PubMed  Google Scholar 

  22. Tanaka Y, Schuster DP, Davis EC, Patterson GA, Botney MD. The role of vascular injury and hemodynamics in rat pulmonary artery remodeling. J Clin Invest. 1996;98(2):434–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. White RJ, Meoli DF, Swarthout RF, Kallop DY, Galaria II, Harvey JL, Miller CM, Blaxall BC, Hall CM, Pierce RA, Cool CD, Taubman MB. Plexiform-like lesions and increased tissue factor expression in a rat model of severe pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol. 2007;293:L583–90.

    Article  CAS  PubMed  Google Scholar 

  24. Tuder RM, Chacon M, Alger L, Wang J, Taraseviciene-Stewart L, Kasahara Y, Cool CD, Bishop AE, Geraci M, Semenza GL, Yacoub M, Polak JM, Voelkel NF. Expression of angiogenesis-related molecules in plexiform lesions in severe pulmonary hypertension: evidence for a process of disordered angiogenesis. J Pathol. 2001;195(3):367–74.

    Article  CAS  PubMed  Google Scholar 

  25. Taraseviciene-Stewart L, Kasahara Y, Alger L, Hirth P, Mc Mahon G, Waltenberger J, Voelkel NF, Tuder RM. Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension. FASEB J. 2001;15:427–38.

    Article  CAS  PubMed  Google Scholar 

  26. Sakao S, Taraseviciene-Stewart L, Lee JD, Wood K, Cool CD, Voelkel NF. Initial apoptosis is followed by increased proliferation of apoptosis-resistant endothelial cells. FASEB J. 2005;19(9):1178–80.

    CAS  PubMed  Google Scholar 

  27. Oka M, Homma N, Taraseviciene-Stewart L, Morris KG, Kraskauskas D, Burns N, Voelkel NF, McMurtry IF. Rho kinase-mediated vasoconstriction is important in severe occlusive pulmonary arterial hypertension in rats. Circ Res. 2007;100:923–9.

    Article  CAS  PubMed  Google Scholar 

  28. Abe K, Toba M, Alzoubi A, Ito M, Fagan KA, Cool CD, Voelkel NF, McMurtry IF, Oka M. Formation of plexiform lesions in experimental severe pulmonary arterial hypertension. Circulation. 2010;121:2747–54.

    Article  PubMed  Google Scholar 

  29. Toba M, Alzoubi A, O’Neill KD, Gairhe S, Matsumoto Y, Oshima K, Abe K, Oka M, McMurtry IF. Temporal hemodynamic and histological progression in Sugen5416/hypoxia/normoxia-exposed pulmonary arterial hypertensive rats. Am J Physiol Heart Circ Physiol. 2014;306(2):H243–50.

    Article  CAS  PubMed  Google Scholar 

  30. Ciuclan L, Bonneau O, Hussey M, Duggan N, Holmes AM, Good R, Stringer R, Jones P, Morrell NW, Jarai G, Walker C, Westwick J, Thomas M. A novel murine model of severe pulmonary arterial hypertension. Am J Respir Crit Care Med. 2011;184(10):1171–82.

    Article  CAS  PubMed  Google Scholar 

  31. Jiang B, Deng Y, Suen C, Taha M, Chaudhary KR, Courtman DW, Stewart DJ. Marked strain-specific differences in the SU5416 rat model of severe pulmonary arterial hypertension. Am J Respir Cell Mol Biol. 2016;54(4):461–8.

    Google Scholar 

  32. Alzoubi A, Almalouf P, Toba M, O’Neill K, Qian X, Francis M, Taylor MS, Alexeyev M, McMurtry IF, Oka M, Stevens T. TRPC4 inactivation confers a survival benefit in severe pulmonary arterial hypertension. Am J Pathol. 2013;183(6):1779–88.

    Article  CAS  PubMed  Google Scholar 

  33. Bogaard HJ, Natarajan R, Mizuno S, Abbate A, Chang PJ, Chau VQ, Hoke NN, Kraskauskas D, Kasper M, Salloum FN, Voelkel NF. Adrenergic receptor blockade reverses right heart remodeling and dysfunction in pulmonary hypertensive rats. Am J Respir Crit Care Med. 2010;182:652–60.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgment and Funding

We thank Dr. Masahiko Oka for helpful editorial comments. This work was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion Science (20588107).

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Authors and Affiliations

  1. Department of Cardiovascular Medicine, Kyushu University Graduate School of Medicine, 3-1-1, Maidashi, Higashi-ku, 812-8582, Fukuoka, Japan

    Kohtaro Abe

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Correspondence to Kohtaro Abe .

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Editors and Affiliations

  1. Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan

    Yoshihiro Fukumoto

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Abe, K. (2017). Animal Models with Pulmonary Hypertension. In: Fukumoto, Y. (eds) Diagnosis and Treatment of Pulmonary Hypertension. Springer, Singapore. https://doi.org/10.1007/978-981-287-840-3_7

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  • DOI: https://doi.org/10.1007/978-981-287-840-3_7

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  • Publisher Name: Springer, Singapore

  • Print ISBN: 978-981-287-839-7

  • Online ISBN: 978-981-287-840-3

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