The monocrotaline model of pulmonary hypertension in perspective

American Journal of Physiology - Lung Cellular and Molecular Physiology

Volumn 302, Issue 4, 2012, Pages

  Gomez Arroyo, Jose G ^a,b   Farkas, Laszlo ^a,b   Alhussaini, Aysar A ^a,b   Farkas, Daniela ^a,b   Kraskauskas, Donatas ^a,b   Voelkel, Norbert F ^a,b   Bogaard, Harm J ^a,b  

^a VIRGINIA COMMONWEALTH UNIVERSITY   (United States)

^b VU UNIVERSITY MEDICAL CENTER   (Netherlands)

Author keywords

Acute lung injury; Hepatic venocclusive disease; Monocrotaline; Myocarditis; Pulmonary hypertension

Indexed keywords

BONE MORPHOGENETIC PROTEIN RECEPTOR 2; MONOCROTALINE; MONOCROTALINE PYRROLE;

ACUTE LUNG INJURY; ARTERY ENDOTHELIUM; CELL DAMAGE; FIBROSING ALVEOLITIS; HEART RIGHT VENTRICLE HYPERTROPHY; HUMAN; HYPOXIA; LIVER TOXICITY; LIVER VEIN OBSTRUCTION; LUNG BLOOD VESSEL; LUNG RESECTION; LUNG TOXICITY; MEGALOCYTOSIS; MYOCARDITIS; NONHUMAN; PRIORITY JOURNAL; PULMONARY HYPERTENSION; PULMONARY VASCULITIS; REVIEW;

ACUTE LUNG INJURY; ANIMALS; DISEASE MODELS, ANIMAL; DRUG-INDUCED LIVER INJURY; HUMANS; HYPERTENSION, PULMONARY; LUNG; MONOCROTALINE; MYOCARDITIS;

EID: 84857027921     PISSN: 10400605     EISSN: 15221504     Source Type: Journal    
DOI: 10.1152/ajplung.00212.2011     Document Type: Review

References (88)

1. Akhavein F, St-Michel EJ, Seifert E, Rohlicek CV. Decreased left ventricular function, myocarditis, and coronary arteriolar medial thickening following monocrotaline administration in adult rats. J Appl Physiol 103: 287-295, 2007.
2. Bastarache JA, Blackwell TS. Development of animal models for the acute respiratory distress syndrome. Dis Model Mech 2: 218-223, 2009.
3. Baybutt RC, Aziz SM, Fagerland JA, Olson JW, Gillespie MN. Monocrotaline alters type II pneumocyte morphology and polyamine regulation. Toxicol Appl Pharmacol 129: 188-195, 1994.
4. Benoist D, Stones R, Drinkhill M, Bernus O, White E. Arrhythmogenic substrate in hearts of rats with monocrotaline-induced pulmonary hypertension and right ventricular hypertrophy. Am J Physiol Heart Circ Physiol 300: H2230-H2237, 2011.
5. Benza RL, Miller DP, Gomberg-Maitland M, Frantz RP, Foreman AJ, Coffey CS, Frost A, Barst RJ, Badesch DB, Elliott CG, Liou TG, McGoon MD. Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation 122: 164-172, 2010.
6. Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M, Legall JR, Morris A, Spragg R. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 149: 818-824, 1994.
7. Bogaard HJ, Abe K, Vonk Noordegraaf A, Voelkel NF. The right ventricle under pressure: cellular and molecular mechanisms of right-heart failure in pulmonary hypertension. Chest 135: 794-804, 2009.
8. 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 182: 652-660, 2010.
9. Bruner LH, Carpenter LJ, Hamlow P, Roth RA. Effect of a mixed function oxidase inducer and inhibitor on monocrotaline pyrrole pneumotoxicity. Toxicol Appl Pharmacol 85: 416-427, 1986.
10. Campian ME, Hardziyenka M, de Bruin K, van Eck-Smit BLF, de Bakker JMT, Verberne HJ, Tan HL. Early inflammatory response during the development of right ventricular heart failure in a rat model. Eur J Heart Fail 12: 653-658, 2010.
11. Casey DB, Badejo AM, Dhaliwal JS, Sikora JL, Fokin A, Golwala NH, Greco AJ, Murthy SN, Nossaman BD, Hyman AL, Kadowitz PJ. Analysis of responses to the Rho-kinase inhibitor Y-27632 in the pulmonary and systemic vascular bed of the rat. Am J Physiol Heart Circ Physiol 299: H184-H192, 2010.
12. Chazova I, Loyd JE, Zhdanov VS, Newman JH, Belenkov Y, Meyrick B. Pulmonary artery adventitial changes and venous involvement in primary pulmonary hypertension. Am J Pathol 146: 389-397, 1995.
13. Copple BL, Ganey PE, Roth RA. Liver inflammation during monocrotaline hepatotoxicity. Toxicology 190: 155-169, 2003.
14. Copple BL, Woolley B, Banes A, Ganey PE, Roth RA. Anticoagulants prevent monocrotaline-induced hepatic parenchymal cell injury but not endothelial cell injury in the rat. Toxicol Appl Pharmacol 180: 186-196, 2002.
15. Copple BL. Modes of cell death in rat liver after monocrotaline exposure. Toxicol Sci 77: 172-182, 2003.
16. Culvenor CC, Dann AT, Dick AT. Alkylation as the mechanism by which the hepatotoxic pyrrolizidine alkaloids act on cell nuclei. Nature 195: 570-573, 1962.
17. Culvenor CC, Edgar JA, Jago MV, Qutteridge A, Peterson JE, Smith LW. Hepato-and pneumotoxicity of pyrrolizidine alkaloids and derivatives in relation to molecular structure. Chem Biol Interact 12: 299-324, 1976.
18. de Wildt SN, Kearns GL, Leeder JS, van den Anker JN. Cytochrome P450 3A: ontogeny and drug disposition. Clin Pharmacokinet 37: 485-505, 1999.
19. DeLeve LD, McCuskey RS, Wang X, Hu L, McCuskey MK, Epstein RB, Kanel GC. Characterization of a reproducible rat model of hepatic veno-occlusive disease. Hepatology 29: 1779-1791, 1999.
20. Dumitrascu R, Koebrich S, Dony E, Weissmann N, Savai R, Pullamsetti SS, Ghofrani HA, Samidurai A, Traupe H, Seeger W, Grimminger F, Schermuly RT. Characterization of a murine model of monocrotaline pyrrole-induced acute lung injury (Abstract). BMC Pulm Med 8: 25, 2008.
21. Epstein RB, Min KW, Anderson SL, Syzek L. A canine model for hepatic venoocclusive disease. Transplantation 54: 12-16, 1992.
22. Estep JE, Lamé MW, Morin D, Jones AD, Wilson DW, Segall HJ. [14C]monocrotaline kinetics and metabolism in the rat. Drug Metab Dispos 19: 135-139, 1991.
23. Fowler AA, Hyers TM, Fisher BJ, Bechard DE, Centor RM, Webster RO. The adult respiratory distress syndrome. Cell populations and soluble mediators in the air spaces of patients at high risk. Am Rev Respir Dis 136: 1225-1231, 1987.
24. Gust R, Schuster DP. Vascular remodeling in experimentally induced subacute canine pulmonary hypertension. Exp Lung Res 27: 1-12, 2001.
25. Handoko ML, de Man FS, Happé CM, Schalij I, Musters RJP, Westerhof N, Postmus PE, Paulus WJ, van der Laarse WJ, Vonk-Noordegraaf A. Opposite effects of training in rats with stable and progressive pulmonary hypertension. Circulation 120: 42-49, 2009.
26. Hardziyenka M, Campian ME, de Bruin-Bon HACMR, Michel MC, Tan HL. Sequence of echocardiographic changes during development of right ventricular failure in rat. J Am Soc Echocardiogr 19: 1272-1279, 2006.
27. Hasegawa M, Kapelyukh Y, Tahara H, Seibler J, Rode A, Krueger S, Lee DN, Wolf CR, Scheer N. Quantitative prediction of human pregnane X receptor and cytochrome P450 3A4 mediated drug-drug interaction in a novel multiple humanized mouse line. Mol Pharmacol doi: 10.1124/mol.111.071845.
28. Hassoun PM, Mouthon L, Barberá JA, Eddahibi S, Flores SC, Grimminger F, Jones PL, Maitland ML, Michelakis ED, Morrell NW, Newman JH, Rabinovitch M, Schermuly R, Stenmark KR, Voelkel NF, Yuan JXJ, Humbert M. Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol 54: S10-S19, 2009.
29. Hayashi S, Mitsumori K, Imaida K, Imazawa T, Yasuhara K, Uneyama C, Hayashi Y. Establishment of an animal model for pulmonary fibrosis in mice using monocrotaline. Toxicol Pathol 23: 63-71, 1995.
30. Huang J, Wolk JH, Gewitz MH, Mathew R. Progressive endothelial cell damage in an inflammatory model of pulmonary hypertension. Exp Lung Res 36: 57-66, 2010.
31. Kasahara Y, Kiyatake K, Tatsumi K, Sugito K, Kakusaka I, Yamagata S, Ohmori S, Kitada M, Kuriyama T. Bioactivation of monocrotaline by P-450 3A in rat liver. J Cardiovasc Pharmacol 30: 124-129, 1997.
32. Kay JM, Harris P, Heath D. Pulmonary hypertension produced in rats by ingestion of Crotalaria spectabilis seeds. Thorax 22: 176-179, 1967.
33. Klein M, Schermuly RT, Ellinghaus P, Milting H, Riedl B, Nikolova S, Pullamsetti SS, Weissmann N, Dony E, Savai R, Ghofrani HA, Grimminger F, Busch AE, Schäfer S. Combined tyrosine and serine/threonine kinase inhibition by sorafenib prevents progression of experimental pulmonary hypertension and myocardial remodeling. Circulation 118: 2081-2090, 2008.
34. Kurozumi T, Tanaka K, Kido M, Shoyama Y. Monocrotaline-induced renal lesions. Exp Mol Pathol 39: 377-386, 1983.
35. Lai YL, Olson JW, Gillespie MN. Ventilatory dysfunction precedes pulmonary vascular changes in monocrotaline-treated rats. J Appl Physiol 70: 561-566, 1991.
36. Lalich JJ, Merkow L. Pulmonary arteritis produced in rat by feeding Crotalaria spectabilis. Lab Invest 10: 744-750, 1961.
37. Lalich JL, Johnson WD, Raczniak TJ, Shumaker RC. Fibrin thrombosis in monocrotaline pyrrole-induced cor pulmonale in rats. Arch Pathol Lab Med 101: 69-73, 1977.
38. Lee J, Reich R, Xu F, Sehgal PB. Golgi, trafficking, and mitosis dysfunctions in pulmonary arterial endothelial cells exposed to monocrotaline pyrrole and NO scavenging. Am J Physiol Lung Cell Mol Physiol 297: L715-L728, 2009.
39. Maioli MA, Alves LC, Perandin D, Garcia AF, Pereira FTV, Mingatto FE. Cytotoxicity of monocrotaline in isolated rat hepatocytes: Effects of dithiothreitol and fructose. Toxicon doi: 10.1016/j.toxicon.2011.04.010.
40. Mingatt OF, Maiol IM, Brach TA, Ishiiwamot OE. Effects of monocrotaline on energy metabolism in the rat liver. Toxicol Lett 182: 115-120, 2008.
41. Mitani Y, Maruyama K, Sakurai M. Prolonged administration of L-arginine ameliorates chronic pulmonary hypertension and pulmonary vascular remodeling in rats. Circulation 96: 689-697, 1997.
42. Miura M, Hirose M, Endoh H, Wakayama Y, Sugai Y, Nakano M, Fukuda K, Shindoh C, Shirato K, Shimokawa H. Acceleration of ca(2+) waves in monocrotaline-induced right ventricular hypertrophy in the rat. Circ J 75: 1343-1349, 2011.
43. Molteni A, Ward WF, Ts'ao CH, Solliday NH, Dunne M. Monocrotaline-induced pulmonary fibrosis in rats: amelioration by captopril and penicillamine. Proc Soc Exp Biol Med 180: 112-120, 1985.
44. Molteni A, Ward WF, Ts'ao CH, Solliday NH. Monocrotaline-induced cardiopulmonary damage in rats: amelioration by the angiotensin-converting enzyme inhibitor CL242817. Proc Soc Exp Biol Med 182: 483-493, 1986.
45. Morrell NW, Adnot S, Archer SL, Dupuis J, Jones PL, MacLean MR, McMurtry IF, Stenmark KR, Thistlethwaite PA, Weissmann N, Yuan JXJ, Weir EK. Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol 54: S20-S31, 2009.
46. Nakayama Wong LS, Lamé MW, Jones AD, Wilson DW. Differential cellular responses to protein adducts of naphthoquinone and monocrotaline pyrrole. Chem Res Toxicol 23: 1504-1513, 2010.
47. Nelson DR, Zeldin DC, Hoffman SMG, Maltais LJ, Wain HM, Nebert DW. Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants. Pharmacogenetics 14: 1-18, 2004.
48. Nicolls MR, Taraseviciene-Stewart L, Rai PR, Badesch DB, Voelkel NF. Autoimmunity and pulmonary hypertension: a perspective. Eur Respir J 26: 1110-1118, 2005.
49. Nishimura T, Faul JL, Berry GJ, Vaszar LT, Qiu D, Pearl RG, Kao PN. Simvastatin attenuates smooth muscle neointimal proliferation and pulmonary hypertension in rats. Am J Respir Crit Care Med 166: 1403-1408, 2002.
50. 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 100: 923-929, 2007.
51. Okada K, Tanaka Y, Bernstein M, Zhang W, Patterson GA, Botney MD. Pulmonary hemodynamics modify the rat pulmonary artery response to injury. A neointimal model of pulmonary hypertension. Am J Pathol 151: 1019-1025, 1997.
52. Overbeek MJ, Mouchaers KTB, Niessen HM, Hadi AM, Kupreishvili K, Boonstra A, Voskuyl AE, Belien JAM, Smit EF, Dijkmans BC, Vonk Noordegraaf A, Grünberg K. Characteristics of interstitial fibrosis and inflammatory cell infiltration in right ventricles of systemic sclerosisassociated pulmonary arterial hypertension. Int J Rheumatol In press.
53. Pan LC, Lamé MW, Morin D, Wilson DW, Segall HJ. Red blood cells augment transport of reactive metabolites of monocrotaline from liver to lung in isolated and tandem liver and lung preparations. Toxicol Appl Pharmacol 110: 336-346, 1991.
54. Perazzo J, Eizayaga F, Romay S, Bengochea L, Pavese A, Lemberg A. An experimental model of liver damage and portal hypertension induced by a single dose of monocrotaline. Hepatogastroenterology 46: 432-435, 1999.
55. Petry TW, Bowden GT, Huxtable RJ, Sipes IG. Characterization of hepatic DNA damage induced in rats by the pyrrolizidine alkaloid monocrotaline. Cancer Res 44: 1505-1509, 1984.
56. Piao L, Fang YH, Cadete VJJ, Wietholt C, Urboniene D, Toth PT, Marsboom G, Zhang HJ, Haber I, Rehman J, Lopaschuk GD, Archer SL. The inhibition of pyruvate dehydrogenase kinase improves impaired cardiac function and electrical remodeling in two models of right ventricular hypertrophy: resuscitating the hibernating right ventricle. J Mol Med 88: 47-60, 2010.
57. Plestina R, Stoner HB, Jones G, Butler WH, Mattocks AR. Vascular changes in the lungs of rats after the intravenous injection of pyrrole carbamates. J Pathol 121: 9-18, 1977.
58. Rabinovitch M. Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest 118: 2372-2379, 2008.
59. Rai PR, Cool CD, King JAC, Stevens T, Burns N, Winn RA, Kasper M, Voelkel NF. The cancer paradigm of severe pulmonary arterial hypertension. Am J Respir Crit Care Med 178: 558-564, 2008.
60. Ramos M, Lamé MW, Segall HJ, Wilson DW. Monocrotaline pyrrole induces Smad nuclear accumulation and altered signaling expression in human pulmonary arterial endothelial cells. Vascul Pharmacol 46: 439-448, 2007.
61. Reid MJ, Lamé MW, Morin D, Wilson DW, Segall HJ. Involvement of cytochrome P450 3A in the metabolism and covalent binding of 14Cmonocrotaline in rat liver microsomes. J Biochem Mol Toxicol 12: 157-166, 1998.
62. Reindel JF, Ganey PE, Wagner JG, Slocombe RF, Roth RA. Development of morphologic, hemodynamic, and biochemical changes in lungs of rats given monocrotaline pyrrole. Toxicol Appl Pharmacol 106: 179-200, 1990.
63. Rosenberg HC, Rabinovitch M. Endothelial injury and vascular reactivity in monocrotaline pulmonary hypertension. Am J Physiol Heart Circ Physiol 255: H1484-H1491, 1988.
64. Sakao S, Taraseviciene-Stewart L, Lee JD, Wood K, Cool CD, Voelkel NF. Initial apoptosis is followed by increased proliferation of apoptosisresistant endothelial cells. FASEB J 19: 1178-1180, 2005.
65. Schermuly RT, Dony E, Ghofrani HA, Pullamsetti S, Savai R, Roth M, Sydykov A, Lai YJ, Weissmann N, Seeger W, Grimminger F. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest 115: 2811-2821, 2005.
66. Schermuly RT, Kreisselmeier KP, Ghofrani HA, Yilmaz H, Butrous G, Ermert L, Ermert M, Weissmann N, Rose F, Guenther A, Walmrath D, Seeger W, Grimminger F. Chronic sildenafil treatment inhibits monocrotaline-induced pulmonary hypertension in rats. Am J Respir Crit Care Med 169: 39-45, 2004.
67. Schwenke DO, Pearson JT, Sonobe T, Ishibashi-Ueda H, Shimouchi A, Kangawa K, Umetani K, Shirai M. Role of Rho-kinase signaling and endothelial dysfunction in modulating blood flow distribution in pulmonary hypertension. J Appl Physiol 110: 901-908, 2011.
68. Sehgal PB, Mukhopadhyay S. Dysfunctional intracellular trafficking in the pathobiology of pulmonary arterial hypertension. Am J Respir Cell Mol Biol 37: 31-37, 2007.
69. Shah SJ, Thenappan T, Rich S, Tian L, Archer SL, Gomberg-Maitland M. Association of serum creatinine with abnormal hemodynamics and mortality in pulmonary arterial hypertension. Circulation 117: 2475-2483, 2008.
70. Shenoy V, Ferreira AJ, Qi Y, Fraga-Silva RA, Díez-Freire C, Dooies A, Jun JY, Sriramula S, Mariappan N, Pourang D, Venugopal CS, Francis J, Reudelhuber T, Santos RA, Patel JM, Raizada MK, Katovich MJ. The angiotensin-converting enzyme 2/angiogenesis-(1-7)/Mas axis confers cardiopulmonary protection against lung fibrosis and pulmonary hypertension. Am J Respir Crit Care Med 182: 1065-1072, 2010.
71. Silva-Neto JP, Barreto RA, Pitanga BPS, Souza CS, Silva VD, Silva AR, Velozo ES, Cunha SD, Batatinha MJM, Tardy M, Ribeiro CSO, Costa MFD, El-Bachá RS, Costa SL. Genotoxicity and morphological changes induced by the alkaloid monocrotaline, extracted from Crotalaria retusa, in a model of glial cells. Toxicon 55: 105-117, 2010.
72. Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, Elliott CG, Gaine SP, Gladwin MT, Jing ZC, Krowka MJ, Langleben D, Nakanishi N, Souza R. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 54: S43-S54, 2009.
73. 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 297: L1013-L1032, 2009.
74. Sugita T, Hyers TM, Dauber IM, Wagner WW, McMurtry IF, Reeves JT. Lung vessel leak precedes right ventricular hypertrophy in monocrotaline-treated rats. J Appl Physiol 54: 371-374, 1983.
75. Taraseviciene-Stewart L, Scerbavicius R, Choe KH, Cool C, Wood K, Tuder RM, Burns N, Kasper M, Voelkel NF. Simvastatin causes endothelial cell apoptosis and attenuates severe pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 291: L668-L676, 2006.
76. Tuder RM, Abman SH, Braun T, Capron F, Stevens T, Thistlethwaite PA, Haworth SG. Development and pathology of pulmonary hypertension. J Am Coll Cardiol 54: S3-S9, 2009.
77. Urboniene D, Haber I, Fang YH, Thenappan T, Archer SL. Validation of high-resolution echocardiography and magnetic resonance imaging vs. high-fidelity catheterization in experimental pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 299: L401-L412, 2010.
78. Voelkel NF, Gómez-Arroyo J. The harmonics of rodent pulmonary hypertension models. Int J Clin Pract 65, Suppl 172: 1-2, 2011.
79. Voelkel NF, Tuder RM. Hypoxia-induced pulmonary vascular remodeling: a model for what human disease? J Clin Invest 106: 733-738, 2000.
80. Wang L, Tamosiuniene R, Voelkel N, Gera L, Nicolls M. Restoration of regulatory T cells (Tregs) prevents autoimmune inflammation (AI) and pulmonary hypertension (PH) in rats (Abstract). Am J Respir Crit Care Med 179: A2355, 2009.
81. Wang YP, Yan J, Beger RD, Fu PP, Chou MW. Metabolic activation of the tumorigenic pyrrolizidine alkaloid, monocrotaline, leading to DNA adduct formation in vivo. Cancer Lett 226: 27-35, 2005.
82. 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 293: L583-L590, 2007.
83. Wilson DW, Lamé MW, Dunston SK, Segall HJ. DNA damage cell checkpoint activities are altered in monocrotaline pyrrole-induced cell cycle arrest in human pulmonary artery endothelial cells. Toxicol Appl Pharmacol 166: 69-80, 2000.
84. Wilson DW, Segall HJ, Pan LC, Lamé MW, Estep JE, Morin D. Mechanisms and Pathology of Monocrotaline Pulmonary Toxicity. Crit Rev Toxicol 22: 307-325, 1992.
85. Woods LW, Wilson DW, Segall HJ. Manipulation of injury and repair of the alveolar epithelium using two pneumotoxicants: 3-methylindole and monocrotaline. Exp Lung Res 25: 165-181, 1999.
86. Yuki H, Sato S, Arisaka Y, Kato S, Tomoike H. Orally administered beraprost sodium inhibits pulmonary hypertension induced by monocrotaline in rats. Tohoku J Exp Med 173: 371-375, 1994.
87. Yuyama H, Fujimori A, Sanagi M, Koakutsu A, Sudoh K, Sasamata M, Miyata K. The orally active nonpeptide selective endothelin ETA receptor antagonist YM598 prevents and reverses the development of pulmonary hypertension in monocrotaline-treated rats. Eur J Pharmacol 496: 129-139, 2004.
88. Zhou Z, Kozlowski J, Schuster DP. Physiologic, biochemical, and imaging characterization of acute lung injury in mice. Am J Respir Crit Care Med 172: 344-351, 2005.