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Semin Respir Crit Care Med 2013; 34(05): 551-559
DOI: 10.1055/s-0033-1356496
DOI: 10.1055/s-0033-1356496
Pathology and Pathobiology of Pulmonary Hypertension
Weitere Informationen
Publikationsverlauf
Publikationsdatum:
13. September 2013 (online)
Abstract
Pulmonary hypertension is a devastating, life-threatening disorder with no curative options, characterized by elevated pulmonary vascular resistance and secondary right ventricular failure. Although the etiologies of pulmonary arterial hypertension are multiple and its pathogenesis is complex, there is growing evidence that inflammation, endothelial dysfunction, aberrant vascular wall cell proliferation, as well as mutations in the bone morphogenetic protein receptor type 2 gene play a crucial role in triggering pathological vascular remodeling. The present article outlines the current understanding of this disease from the point of view of pathology and pathobiology.
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References
- 1 Humbert M, Morrell NW, Archer SL , et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 2004; 43 (12, Suppl S ): 13S-24S
- 2 Morrell NW, Adnot S, Archer SL , et al. Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol 2009; 54 (1, Suppl): S20-S31
- 3 Voelkel NF, Gomez-Arroyo J, Abbate A, Bogaard HJ, Nicolls MR. Pathobiology of pulmonary arterial hypertension and right ventricular failure. Eur Respir J 2012; 40 (6) 1555-1565
- 4 Eddahibi S, Guignabert C, Barlier-Mur AM , et al. Cross talk between endothelial and smooth muscle cells in pulmonary hypertension: critical role for serotonin-induced smooth muscle hyperplasia. Circulation 2006; 113 (15) 1857-1864
- 5 Xu R, Mao JH. Gene transcriptional networks integrate microenvironmental signals in human breast cancer. Integr Biol (Camb) 2011; 3 (4) 368-374
- 6 Amabile N, Guignabert C, Montani D, Yeghiazarians Y, Boulanger CM, Humbert M. Cellular microparticles in the pathogenesis of pulmonary hypertension. Eur Respir J 2013; 42 (1) 272-279
- 7 Shimizu H, Tanabe N, Terada J , et al. Dilatation of bronchial arteries correlates with extent of central disease in patients with chronic thromboembolic pulmonary hypertension. Circ J 2008; 72 (7) 1136-1141
- 8 Frazier AA, Galvin JR, Franks TJ, Rosado-De-Christenson ML. From the archives of the AFIP: pulmonary vasculature: hypertension and infarction. Radiographics 2000; 20 (2) 491-524 , quiz 530–531, 532
- 9 Heath D, Williams D. High-Altitude Medicine and Pathology. London: Butterworths; 1989
- 10 Sakao S, Tatsumi K, Voelkel NF. Reversible or irreversible remodeling in pulmonary arterial hypertension. Am J Respir Cell Mol Biol 2010; 43 (6) 629-634
- 11 Penaloza D, Arias-Stella J. The heart and pulmonary circulation at high altitudes: healthy highlanders and chronic mountain sickness. Circulation 2007; 115 (9) 1132-1146
- 12 Voelkel NF, Tuder RM. Cellular and molecular mechanisms in the pathogenesis of severe pulmonary hypertension. Eur Respir J 1995; 8 (12) 2129-2138
- 13 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 (4) 434-442
- 14 Stacher E, Graham BB, Hunt JM , et al. Modern age pathology of pulmonary arterial hypertension. Am J Respir Crit Care Med 2012; 186 (3) 261-272
- 15 Wagenvoort C, Wagenvoort N. Primary Pulmonary Hypertension: A Pathologic Study of the Lung Vessels in 156 Clinically Diagnosed Cases. Circulation 1970; 42: 1163-1184
- 16 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 (4 Part 1) 533-547
- 17 Krowka MJ, Edwards WD. A spectrum of pulmonary vascular pathology in portopulmonary hypertension. Liver Transpl 2000; 6 (2) 241-242
- 18 Widgren S. [Prolonged survey of cases of pulmonary hypertension in relation to consumption of aminorex. Histological, quantitative and morphometric study of 9 cases]. Schweiz Med Wochenschr 1986; 116 (27-28) 918-924
- 19 Tuder RM, Abman SH, Braun T , et al. Development and pathology of pulmonary hypertension. J Am Coll Cardiol 2009; 54 (1, Suppl): S3-S9
- 20 Moser KM, Bloor CM. Pulmonary vascular lesions occurring in patients with chronic major vessel thromboembolic pulmonary hypertension. Chest 1993; 103 (3) 685-692
- 21 Harrison CV. IV. The pathology of the pulmonary vessels in pulmonary hypertension. Br J Radiol 1958; 31 (364) 217-226
- 22 Piazza G, Goldhaber SZ. Chronic thromboembolic pulmonary hypertension. N Engl J Med 2011; 364 (4) 351-360
- 23 Kucsko L. [Arteriovenous communications in the human lung and their functional significance]. Frankf Z Pathol 1953; 64 (1) 54-83
- 24 Saldaña ME, Harley RA, Liebow AA, Carrington CB. Experimental extreme pulmonary hypertension and vascular disease in relation to polycythemia. Am J Pathol 1968; 52 (5) 935-981
- 25 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 (2) 275-285
- 26 Dorfmüller P, Perros F, Balabanian K, Humbert M. Inflammation in pulmonary arterial hypertension. Eur Respir J 2003; 22 (2) 358-363
- 27 Lee SD, Shroyer KR, Markham NE, Cool CD, Voelkel NF, Tuder RM. Monoclonal endothelial cell proliferation is present in primary but not secondary pulmonary hypertension. J Clin Invest 1998; 101 (5) 927-934
- 28 Yaginuma G, Mohri H, Takahashi T. Distribution of arterial lesions and collateral pathways in the pulmonary hypertension of congenital heart disease: a computer aided reconstruction study. Thorax 1990; 45 (8) 586-590
- 29 Cool CD, Stewart JS, Werahera P , et al. Three-dimensional reconstruction of pulmonary arteries in plexiform pulmonary hypertension using cell-specific markers. Evidence for a dynamic and heterogeneous process of pulmonary endothelial cell growth. Am J Pathol 1999; 155 (2) 411-419
- 30 Dorfmüller P, Zarka V, Durand-Gasselin I , et al. Chemokine RANTES in severe pulmonary arterial hypertension. Am J Respir Crit Care Med 2002; 165 (4) 534-539
- 31 Balabanian K, Foussat A, Dorfmüller P , et al. CX(3)C chemokine fractalkine in pulmonary arterial hypertension. Am J Respir Crit Care Med 2002; 165 (10) 1419-1425
- 32 Sanchez O, Marcos E, Perros F , et al. Role of endothelium-derived CC chemokine ligand 2 in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2007; 176 (10) 1041-1047
- 33 Dorfmüller P, Humbert M, Capron F, Müller KM. Pathology and aspects of pathogenesis in pulmonary arterial hypertension. Sarcoidosis Vasc Diffuse Lung Dis 2003; 20 (1) 9-19
- 34 Perros F, Dorfmüller P, Souza R , et al. Fractalkine-induced smooth muscle cell proliferation in pulmonary hypertension. Eur Respir J 2007; 29 (5) 937-943
- 35 Perros F, Dorfmüller P, Montani D , et al. Pulmonary lymphoid neogenesis in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2012; 185 (3) 311-321
- 36 Carragher DM, Rangel-Moreno J, Randall TD. Ectopic lymphoid tissues and local immunity. Semin Immunol 2008; 20 (1) 26-42
- 37 Aloisi F, Pujol-Borrell R. Lymphoid neogenesis in chronic inflammatory diseases. Nat Rev Immunol 2006; 6 (3) 205-217
- 38 Hogg JC, Chu F, Utokaparch S , et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004; 350 (26) 2645-2653
- 39 Rangel-Moreno J, Carragher DM, de la Luz Garcia-Hernandez M , et al. The development of inducible bronchus-associated lymphoid tissue depends on IL-17. Nat Immunol 2011; 12 (7) 639-646
- 40 Tamby MC, Chanseaud Y, Humbert M , et al. Anti-endothelial cell antibodies in idiopathic and systemic sclerosis associated pulmonary arterial hypertension. Thorax 2005; 60 (9) 765-772
- 41 Terrier B, Tamby MC, Camoin L , et al. Identification of target antigens of antifibroblast antibodies in pulmonary arterial hypertension. Am J Respir Crit Care Med 2008; 177 (10) 1128-1134
- 42 Dib H, Tamby MC, Bussone G , et al. Targets of anti-endothelial cell antibodies in pulmonary hypertension and scleroderma. Eur Respir J 2012; 39 (6) 1405-1414
- 43 Dorfmüller P, Humbert M. Progress in pulmonary arterial hypertension pathology: relighting a torch inside the tunnel. Am J Respir Crit Care Med 2012; 186 (3) 210-212
- 44 Price LC, Wort SJ, Perros F , et al. Inflammation in pulmonary arterial hypertension. Chest 2012; 141 (1) 210-221
- 45 Stevens T. Functional and molecular heterogeneity of pulmonary endothelial cells. Proc Am Thorac Soc 2011; 8 (6) 453-457
- 46 Aird WC. Endothelial cell heterogeneity. Crit Care Med 2003; 31 (4, Suppl): S221-S230
- 47 Tuder RM, Cool CD, Yeager M, Taraseviciene-Stewart L, Bull TM, Voelkel NF. The pathobiology of pulmonary hypertension. Endothelium. Clin Chest Med 2001; 22 (3) 405-418
- 48 Dinh-Xuan AT. Endothelial modulation of pulmonary vascular tone. Eur Respir J 1992; 5 (6) 757-762
- 49 Budhiraja R, Tuder RM, Hassoun PM. Endothelial dysfunction in pulmonary hypertension. Circulation 2004; 109 (2) 159-165
- 50 Masri FA, Xu W, Comhair SA , et al. Hyperproliferative apoptosis-resistant endothelial cells in idiopathic pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 2007; 293 (3) L548-L554
- 51 Tu L, Dewachter L, Gore B , et al. Autocrine fibroblast growth factor-2 signaling contributes to altered endothelial phenotype in pulmonary hypertension. Am J Respir Cell Mol Biol 2011; 45 (2) 311-322
- 52 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) 1178-1180
- 53 Tu L, De Man FS, Girerd B , et al. A critical role for p130Cas in the progression of pulmonary hypertension in humans and rodents. Am J Respir Crit Care Med 2012; 186 (7) 666-676
- 54 Guignabert C, Alvira CM, Alastalo TP , et al. Tie2-mediated loss of peroxisome proliferator-activated receptor-gamma in mice causes PDGF receptor-beta-dependent pulmonary arterial muscularization. Am J Physiol Lung Cell Mol Physiol 2009; 297 (6) L1082-L1090
- 55 Hong KH, Lee YJ, Lee E , et al. Genetic ablation of the BMPR2 gene in pulmonary endothelium is sufficient to predispose to pulmonary arterial hypertension. Circulation 2008; 118 (7) 722-730
- 56 Guignabert C, Raffestin B, Benferhat R, Raoul W, Zadigue P, Rideau D, Hamon M, Adnot S, Eddahibi S. Serotonin transporter inhibition prevents and reverses monocrotaline-induced pulmonary hypertension in rats. Circulation 2005; 111 (21) 2812-2819
- 57 Izikki M, Guignabert C, Fadel E, Humbert M, Tu L, Zadigue P, Dartevelle P, Simonneau G, Adnot S, Maitre B, Raffestin B, Eddahibi S. Endothelial-derived FGF2 contributes to the progression of pulmonary hypertension in humans and rodents. J Clin Invest 2009; 119 (3) 512-523
- 58 de Man FS, Tu L, Handoko ML, Rain S, Ruiter G, François C, Schalij I, Dorfmüller P, Simonneau G, Fadel E, Perros F, Boonstra A, Postmus PE, van der Velden J, Vonk-Noordegraaf A, Humbert M, Eddahibi S, Guignabert C. Dysregulated renin-angiotensin-aldosterone system contributes to pulmonary arterial hypertension. Am J Respir Crit Care Med 2012; 186 (8) 780-789
- 59 Pengo V, Lensing AWA, Prins MH et al; Thromboembolic Pulmonary Hypertension Study Group. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004; 350 (22) 2257-2264
- 60 Pietra GG, Edwards WD, Kay JM , et al. Histopathology of primary pulmonary hypertension. A qualitative and quantitative study of pulmonary blood vessels from 58 patients in the National Heart, Lung, and Blood Institute, Primary Pulmonary Hypertension Registry. Circulation 1989; 80 (5) 1198-1206
- 61 Bjornsson J, Edwards WD. Primary pulmonary hypertension: a histopathologic study of 80 cases. Mayo Clin Proc 1985; 60 (1) 16-25
- 62 Schermuly RT, Ghofrani HA, Wilkins MR, Grimminger F. Mechanisms of disease: pulmonary arterial hypertension. Nat Rev Cardiol 2011; 8 (8) 443-455
- 63 White RJ, Meoli DF, Swarthout RF , et al. 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 (3) L583-L590
- 64 Johnson SR, Granton JT, Mehta S. Thrombotic arteriopathy and anticoagulation in pulmonary hypertension. Chest 2006; 130 (2) 545-552
- 65 Jouve P, Humbert M, Chauveheid MP, Jaïs X, Papo T. POEMS syndrome-related pulmonary hypertension is steroid-responsive. Respir Med 2007; 101 (2) 353-355
- 66 Montani D, Achouh L, Marcelin AG , et al. Reversibility of pulmonary arterial hypertension in HIV/HHV8-associated Castleman's disease. Eur Respir J 2005; 26 (5) 969-972
- 67 Jais X, Launay D, Yaici A , et al. Immunosuppressive therapy in lupus- and mixed connective tissue disease-associated pulmonary arterial hypertension: a retrospective analysis of twenty-three cases. Arthritis Rheum 2008; 58 (2) 521-531
- 68 Sanchez O, Sitbon O, Jaïs X, Simonneau G, Humbert M. Immunosuppressive therapy in connective tissue diseases-associated pulmonary arterial hypertension. Chest 2006; 130 (1) 182-189
- 69 Launay D, Hachulla E, Hatron PY, Jais X, Simonneau G, Humbert M. Pulmonary arterial hypertension: a rare complication of primary Sjögren syndrome: report of 9 new cases and review of the literature. Medicine (Baltimore) 2007; 86 (5) 299-315
- 70 Tamby MC, Humbert M, Guilpain P , et al. Antibodies to fibroblasts in idiopathic and scleroderma-associated pulmonary hypertension. Eur Respir J 2006; 28 (4) 799-807
- 71 Mouthon L, Guillevin L, Humbert M. Pulmonary arterial hypertension: an autoimmune disease?. Eur Respir J 2005; 26 (6) 986-988
- 72 Nicolls MR, Taraseviciene-Stewart L, Rai PR, Badesch DB, Voelkel NF. Autoimmunity and pulmonary hypertension: a perspective. Eur Respir J 2005; 26 (6) 1110-1118
- 73 Huertas A, Tu L, Gambaryan N , et al. Leptin and regulatory T-lymphocytes in idiopathic pulmonary arterial hypertension. Eur Respir J 2012; 40 (4) 895-904
- 74 Pietra GG, Capron F, Stewart S , et al. Pathologic assessment of vasculopathies in pulmonary hypertension. J Am Coll Cardiol 2004; 43 (12, Suppl S ): 25S-32S
- 75 Atkinson C, Stewart S, Upton PD , et al. Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation 2002; 105 (14) 1672-1678
- 76 Teichert-Kuliszewska K, Kutryk MJ, Kuliszewski MA , et al. Bone morphogenetic protein receptor-2 signaling promotes pulmonary arterial endothelial cell survival: implications for loss-of-function mutations in the pathogenesis of pulmonary hypertension. Circ Res 2006; 98 (2) 209-217
- 77 Nasim MT, Ogo T, Chowdhury HM , et al. BMPR-II deficiency elicits pro-proliferative and anti-apoptotic responses through the activation of TGFβ-TAK1-MAPK pathways in PAH. Hum Mol Genet 2012; 21 (11) 2548-2558
- 78 Yang X, Long L, Southwood M , et al. Dysfunctional Smad signaling contributes to abnormal smooth muscle cell proliferation in familial pulmonary arterial hypertension. Circ Res 2005; 96 (10) 1053-1063
- 79 Germain M, Eyries M, Montani D , et al. Genome-wide association analysis identifies a susceptibility locus for pulmonary arterial hypertension. Nat Genet 2013; 45 (5) 518-521