Pulmonary hypertension and idiopathic pulmonary fibrosis: A tale of angiogenesis, apoptosis, and growth factors

American Journal of Respiratory Cell and Molecular Biology

Volumn 45, Issue 1, 2011, Pages 1-15

  Farkas, Laszlo ^a,b   Gauldie, Jack ^a   Voelkel, Norbert F ^b   Kolb, Martin ^a  

^a MCMASTER UNIVERSITY   (Canada)

^b VIRGINIA COMMONWEALTH UNIVERSITY   (United States)

Author keywords

Angiogenesis; Apoptosis; Growth factors; Idiopathic pulmonary fibrosis; Pulmonary hypertension

Indexed keywords

ALPHA CHEMOKINE; ANGIOPOIETIN 1; ANGIOSTATIN; ANGIOTENSIN II; AZATHIOPRINE; BIOLOGICAL MARKER; CORTICOSTEROID; CYCLOPHOSPHAMIDE; ENDOSTATIN; ENDOTHELIN 1; FIBROBLAST GROWTH FACTOR 2; GROWTH FACTOR; METHOTREXATE; NITRIC OXIDE; PIGMENT EPITHELIUM DERIVED FACTOR; PIRFENIDONE; PLATELET DERIVED GROWTH FACTOR; PROSTACYCLIN; SILDENAFIL; TRANSFORMING GROWTH FACTOR BETA; VASCULOTROPIN;

ANGIOGENESIS; APOPTOSIS; FIBROGENESIS; FIBROSING ALVEOLITIS; HISTOPATHOLOGY; HUMAN; LUNG DEVELOPMENT; LUNG SARCOIDOSIS; LUNG TRANSPLANTATION; NONHUMAN; PATHOGENESIS; PULMONARY HYPERTENSION; REVIEW; SARCOIDOSIS; SYSTEMIC SCLEROSIS; VASCULAR SMOOTH MUSCLE;

ANGIOGENESIS INDUCING AGENTS; ANGIOGENESIS INHIBITORS; ANIMALS; APOPTOSIS; BIOLOGICAL MARKERS; EPITHELIAL CELLS; FIBROBLASTS; HUMANS; HYPERTENSION, PULMONARY; IDIOPATHIC PULMONARY FIBROSIS; NEOVASCULARIZATION, PATHOLOGIC; PROGNOSIS; PULMONARY ARTERY; VASOCONSTRICTION;

EID: 80051557093     PISSN: 10441549     EISSN: None     Source Type: Journal    
DOI: 10.1165/rcmb.2010-0365TR     Document Type: Review

References (280)

1. American Thoracic Society/European Respiratory Society international multidisciplinary consensus classification of the idiopathic interstitial pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS Board of Directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med 2002;165:277-304.
2. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American thoracic society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med 2000;161:646-664.
3. Behr J, Ryu JH. Pulmonary hypertension in interstitial lung disease. Eur Respir J 2008;31:1357-1367.
4. Ryu JH, Colby TV, Hartman TE. Idiopathic pulmonary fibrosis: current concepts. Mayo Clin Proc 1998;73:1085-1101. (Pubitemid 28512587)
5. Gross TJ, Hunninghake GW. Idiopathic pulmonary fibrosis. N Engl J Med 2001;345:517-525. (Pubitemid 32758505)
6. Kolb M, Margetts PJ, Anthony DC, Pitossi F, Gauldie J. Transient expression of IL-1beta induces acute lung injury and chronic repair leading to pulmonary fibrosis. J Clin Invest 2001;107:1529-1536. (Pubitemid 32574639)
7. Sime PJ, Xing Z, Graham FL, Csaky KG, Gauldie J. Adenovector-mediated gene transfer of active transforming growth factor-beta 1 induces prolonged severe fibrosis in rat lung. J Clin Invest 1997;100:768-776. (Pubitemid 27371693)
8. Sime PJ, Marr RA, Gauldie D, Xing Z, Hewlett BR, Graham FL, Gauldie J. Transfer of tumor necrosis factor-alpha to rat lung induces severe pulmonary inflammation and patchy interstitial fibrogenesis with induction of transforming growth factor-beta1 and myofibroblasts. Am J Pathol 1998;153:825-832. (Pubitemid 28419035)
9. Bonniaud P, Margetts PJ, Ask K, Flanders K, Gauldie J, Kolb M. TGF-beta and Smad3 signaling link inflammation to chronic fibrogenesis. J Immunol 2005;175:5390-5395. (Pubitemid 41456425)
10. Flaherty KR, Mumford JA, Murray S, Kazerooni EA, Gross BH, Colby TV, Travis WD, Flint A, Toews GB, Lynch JP III, et al. Prognostic implications of physiologic and radiographic changes in idiopathic interstitial pneumonia. Am J Respir Crit Care Med 2003;168:543-548. (Pubitemid 37088596)
11. Collard HR, King TE Jr, Bartelson BB, Vourlekis JS, Schwarz MI, Brown KK. Changes in clinical and physiologic variables predict survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2003;168:538-542. (Pubitemid 37088595)
12. Kawut SM, O'Shea MK, Bartels MN, Wilt JS, Sonett JR, Arcasoy SM. Exercise testing determines survival in patients with diffuse parenchymal lung disease evaluated for lung transplantation. Respir Med 2005;99:1431-1439. (Pubitemid 41487501)
13. Lettieri CJ, Nathan SD, Browning RF, Barnett SD, Ahmad S, Shorr AF. The distance-saturation product predicts mortality in idiopathic pulmonary fibrosis. Respir Med 2006;100:1734-1741. (Pubitemid 44283761)
14. Lama VN, Flaherty KR, Toews GB, Colby TV, Travis WD, Long Q, Murray S, Kazerooni EA, Gross BH, Lynch JP III, et al. Prognostic value of desaturation during a 6-minute walk test in idiopathic interstitial pneumonia. Am J Respir Crit Care Med 2003;168:1084-1090. (Pubitemid 37338937)
15. Hallstrand TS, Boitano LJ, Johnson WC, Spada CA, Hayes JG, Raghu G. The timed walk test as a measure of severity and survival in idiopathic pulmonary fibrosis. Eur Respir J 2005;25:96-103. (Pubitemid 40207737)
16. Lederer DJ, Arcasoy SM, Wilt JS, D'Ovidio F, Sonett JR, Kawut SM. Six-minute-walk distance predicts waiting list survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2006;174:659-664. (Pubitemid 44395333)
17. Lettieri CJ, Nathan SD, Barnett SD, Ahmad S, Shorr AF. Prevalence and outcomes of pulmonary arterial hypertension in advanced idiopathic pulmonary fibrosis. Chest 2006;129:746-752.
18. Patel NM, Lederer DJ, Borczuk AC, Kawut SM. Pulmonary hypertension in idiopathic pulmonary fibrosis. Chest 2007;132:998-1006.
19. D'Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Kernis JT, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 1991;115:343-349.
20. Nathan SD, Noble PW, Tuder RM. Idiopathic pulmonary fibrosis and pulmonary hypertension: connecting the dots. Am J Respir Crit Care Med 2007;175:875-880. (Pubitemid 46684695)
21. Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, Elliott CG, Gaine SP, Gladwin MT, Jing Z-C, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009;54(1 Suppl 1):S43-S54.
22. Nadrous HF, Pellikka PA, Krowka MJ, Swanson KL, Chaowalit N, Decker PA, Ryu JH. The impact of pulmonary hypertension on survival in patients with idiopathic pulmonary fibrosis. Chest 2005;128(6 Suppl):616S-617S. (Pubitemid 43054163)
23. Nadrous HF, Pellikka PA, Krowka MJ, Swanson KL, Chaowalit N, Decker PA, Ryu JH. Pulmonary hypertension in patients with idiopathic pulmonary fibrosis. Chest 2005;128:2393-2399. (Pubitemid 41507585)
24. Nathan SD, Shlobin OA, Ahmad S, Koch J, Barnett SD, Ad N, Burton N, Leslie K. Serial development of pulmonary hypertension in patients with idiopathic pulmonary fibrosis. Respiration 2008;76:288-294.
25. Leuchte HH, Neurohr C, Baumgartner R, Holzapfel M, Giehrl W, Vogeser M, Behr J. Brain natriuretic peptide and exercise capacity in lung fibrosis and pulmonary hypertension. Am J Respir Crit Care Med 2004;170:360-365. (Pubitemid 39214607)
26. Strange C, Highland KB. Pulmonary hypertension in interstitial lung disease. Curr Opin Pulm Med 2005;11:452-455. (Pubitemid 41291091)
27. Shorr AF, Davies DB, Nathan SD. Outcomes for patients with sarcoidosis awaiting lung transplantation. Chest 2002;122:233-238. (Pubitemid 34754168)
28. Ryu JH, Krowka MJ, Pellikka PA, Swanson KL, McGoon MD. Pulmonary hypertension in patients with interstitial lung diseases. Mayo Clin Proc 2007;82:342-350. (Pubitemid 46348935)
29. Farkas L, Farkas D, Ask K, Möller A, Gauldie J, Margetts P, Inman M, Kolb M. VEGF ameliorates pulmonary hypertension through inhibition of endothelial apoptosis in experimental lung fibrosis in rats. J Clin Invest 2009;119:1298-1311.
30. Ms S, Pardo A, Kaminski N. Idiopathic pulmonary fibrosis: aberrant recapitulation of developmental programs? PLoS Med 2008;5:e62.
31. Hislop AA. Airway and blood vessel interaction during lung development. J Anat 2002;201:325-334. (Pubitemid 35244052)
32. Hall SM, Hislop AA, Haworth SG. Origin, differentiation, and maturation of human pulmonary veins. Am J Respir Cell Mol Biol 2002;26:333-340. (Pubitemid 34170059)
33. Hall SM, Hislop AA, Pierce CM, Haworth SG. Prenatal origins of human intrapulmonary arteries: formation and smooth muscle maturation. Am J Respir Cell Mol Biol 2000;23:194-203. (Pubitemid 30656429)
34. Hislop A, Reid L. Fetal and childhood development of the intrapulmonary veins in man - branching pattern and structure. Thorax 1973;28:313-319.
35. Hislop A, Reid L. Intra-pulmonary arterial development during fetal life-branching pattern and structure. J Anat 1972;113:35-48.
36. deMello DE, Sawyer D, Galvin N, Reid LM. Early fetal development of lung vasculature. Am J Respir Cell Mol Biol 1997;16:568-581. (Pubitemid 127498289)
37. Shifren JL, Doldi N, Ferrara N, Mesiano S, Jaffe RB. In the human fetus, vascular endothelial growth factor is expressed in epithelial cells and myocytes, but not vascular endothelium: implications for mode of action. J Clin Endocrinol Metab 1994;79:316-322. (Pubitemid 24221202)
38. Acarregui MJ, Penisten ST, Goss KL, Ramirez K, Snyder JM. Vascular endothelial growth factor gene expression in human fetal lung in vitro. Am J Respir Cell Mol Biol 1999;20:14-23. (Pubitemid 129504838)
39. Healy AM, Morgenthau L, Zhu X, Farber HW, Cardoso WV. VEGF is deposited in the subepithelial matrix at the leading edge of branching airways and stimulates neovascularization in the murine embryonic lung. Dev Dyn 2000;219:341-352.
40. Ng YS, Rohan R, Sunday ME, Demello DE, D'Amore PA. Differential expression of VEGF isoforms in mouse during development and in the adult. Dev Dyn 2001;220:112-121. (Pubitemid 32107812)
41. Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML, Schuh AC. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 1995;376:62-66.
42. Jakkula M, Le Cras TD, Gebb S, Hirth KP, Tuder RM, Voelkel NF, Abman SH. Inhibition of angiogenesis decreases alveolarization in the developing rat lung. Am J Physiol Lung Cell Mol Physiol 2000;279:L600-L607.
43. Sato TN, Tozawa Y, Deutsch U, Wolburg-Buchholz K, Fujiwara Y, Gendron-Maguire M, Gridley T, Wolburg H, Risau W, Qin Y. Distinct roles of the receptor tyrosine kinases TIE-1 and TIE-2 in blood vessel formation. Nature 1995;376:70-74.
44. Zeng X, Gray M, Stahlman MT, Whitsett JA. TGF-beta1 perturbs vascular development and inhibits epithelial differentiation in fetal lung in vivo. Dev Dyn 2001;221:289-301. (Pubitemid 32601827)
45. Folkman J, D'Amore PA. Blood vessel formation: what is its molecular basis? Cell 1996;87:1153-1155. (Pubitemid 27010098)
46. Arciniegas E, Neves CY, Carrillo LM, Zambrano EA, Ramírez R. Endothelial-mesenchymal transition occurs during embryonic pulmonary artery development. Endothelium 2005;12:193-200. (Pubitemid 41600864)
47. Ebina M, Shimizukawa M, Shibata N, Kimura Y, Suzuki T, Endo M, Sasano H, Kondo T, Nukiwa T. Heterogeneous increase in CD34-positive alveolar capillaries in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2004;169:1203-1208. (Pubitemid 38680397)
48. Cosgrove GP, Brown KK, Schiemann WP, Serls AE, Parr JE, Geraci MW, Schwarz MI, Cool CD, Worthen GS. Pigment epithelium-derived factor in idiopathic pulmonary fibrosis: a role in aberrant angiogenesis. Am J Respir Crit Care Med 2004;170:242-251. (Pubitemid 38971408)
49. Simler NR, Brenchley PE, Horrocks AW, Greaves SM, Hasleton PS, Egan JJ. Angiogenic cytokines in patients with idiopathic interstitial pneumonia. Thorax 2004;59:581-585. (Pubitemid 38901516)
50. Tachihara A, Jin E, Matsuoka T, Ghazizadeh M, Yoshino S, Takemura T, Travis WD, Kawanami O. Critical roles of capillary endothelial cells for alveolar remodeling in nonspecific and usual interstitial pneumonias. J Nippon Med Sch 2006;73:203-213. (Pubitemid 44274095)
51. Renzoni EA, Walsh DA, Salmon M, Wells AU, Sestini P, Nicholson AG, Veeraraghavan S, Bishop AE, Romanska HM, Pantelidis P, et al. Interstitial vascularity in fibrosing alveolitis. Am J Respir Crit Care Med 2003;167:438-443. (Pubitemid 36216429)
52. Burdick MD, Murray LA, Keane MP, Xue YY, Zisman DA, Belperio JA, Strieter RM. CXCL11 attenuates bleomycin-induced pulmonary fibrosis via inhibition of vascular remodeling. Am J Respir Crit Care Med 2005;171:261-268.
53. Keane MP, Arenberg DA, Lynch JP III, Whyte RI, Iannettoni MD, Burdick MD, Wilke CA, Morris SB, Glass MC, DiGiovine B, et al. The CXC chemokines, IL-8 and IP-10, regulate angiogenic activity in idiopathic pulmonary fibrosis. J Immunol 1997;159:1437-1443. (Pubitemid 127484123)
54. Keane MP, Belperio JA, Burdick MD, Lynch JP, Fishbein MC, Strieter RM. ENA-78 is an important angiogenic factor in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2001;164:2239-2242. (Pubitemid 34032941)
55. Strieter RM, Gomperts BN, Keane MP. The role of CXC chemokines in pulmonary fibrosis. J Clin Invest 2007;117:549-556. (Pubitemid 46348509)
56. Teng R-J, Eis A, Bakhutashvili I, Arul N, Konduri GG. Increased superoxide production contributes to the impaired angiogenesis of fetal pulmonary arteries with in utero pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2009;297:L184-L195.
57. Fadini GP, Avogaro A, Ferraccioli G, Agostini C. Endothelial progenitors in pulmonary hypertension: new pathophysiology and therapeutic implications. Eur Respir J 2010;35:418-425.
58. Fadini GP, Schiavon M, Rea F, Avogaro A, Agostini C. Depletion of endothelial progenitor cells may link pulmonary fibrosis and pulmonary hypertension. Am J Respir Crit Care Med 2007;176:724-725.
59. Parra ER, David YR, da Costa LR, Ab'Saber A, Sousa R, Kairalla RA, de Carvalho CR, Filho MT, Capelozzi VL. Heterogeneous remodeling of lung vessels in idiopathic pulmonary fibrosis. Lung 2005;183:291-300. (Pubitemid 41428101)
60. Sakao S, Taraseviciene-Stewart L, Wood K, Cool CD, Voelkel NF. Apoptosis of pulmonary microvascular endothelial cells stimulates vascular smooth muscle cell growth. Am J Physiol Lung Cell Mol Physiol 2006;291:L362-L368. (Pubitemid 44343711)
61. Budhiraja R, Tuder RM, Hassoun PM. Endothelial dysfunction in pulmonary hypertension. Circulation 2004;109:159-165. (Pubitemid 38114133)
62. Ask K, Martin GE, Kolb M, Gauldie J. Targeting genes for treatment in idiopathic pulmonary fibrosis: challenges and opportunities, promises and pitfalls. Proc Am Thorac Soc 2006;3:389-393. (Pubitemid 43845418)
63. Perrella MA, Edell ES, Krowka MJ, Cortese DA, Burnett JC Jr. Endothelium-derived relaxing factor in pulmonary and renal circulations during hypoxia. Am J Physiol 1992;263:R45-R50.
64. Dinh-Xuan AT. Endothelial modulation of pulmonary vascular tone. Eur Respir J 1992;5:757-762.
65. Smith AP, Demoncheaux EA, Higenbottam TW. Nitric oxide gas decreases endothelin-1 mRNA in cultured pulmonary artery endothelial cells. Nitric Oxide 2002;6:153-159. (Pubitemid 34848437)
66. Hashimoto N, Phan SH, Imaizumi K, Matsuo M, Nakashima H, Kawabe T, Shimokata K, Hasegawa Y. Endothelial-mesenchymal transition in bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol 2010;43:161-172.
67. Arciniegas E, Frid MG, Douglas IS, Stenmark KR. Perspectives on endothelial-to-mesenchymal transition: potential contribution to vascular remodeling in chronic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2007;293:L1-L8. (Pubitemid 47080705)
68. Frid MG, Kale VA, Stenmark KR. Mature vascular endothelium can give rise to smooth muscle cells via endothelial-mesenchymal transdifferentiation: in vitro analysis. Circ Res 2002;90:1189-1196. (Pubitemid 34786904)
69. + precursor cells and transdifferentiation to smooth muscle-like and neuronal-like cells. FASEB J 2007;21:3640-3652.
70. Koli K, Myllarniemi M, Vuorinen K, Salmenkivi K, Ryynanen MJ, Kinnula VL, Keski-Oja J. Bone morphogenetic protein-4 inhibitor gremlin is overexpressed in idiopathic pulmonary fibrosis. Am J Pathol 2006;169:61-71.
71. Atkinson C, Stewart S, Upton PD, Machado R, Thomson JR, Trembath RC, Morrell NW. Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation 2002;105:1672-1678. (Pubitemid 34298611)
72. Costello CM, Howell K, Cahill E, McBryan J, Konigshoff M, Eickelberg O, Gaine S, Martin F, McLoughlin P. Lung-selective gene responses to alveolar hypoxia: potential role for the bone morphogenetic antagonist gremlin in pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2008;295:L272-L284.
73. Warner JA, Kroegel C. Pulmonary immune cells in health and disease: mast cells and basophils. Eur Respir J 1994;7:1326-1341. (Pubitemid 24235054)
74. Mitani Y, Ueda M, Maruyama K, Shimpo H, Kojima A, Matsumura M, Aoki K, Sakurai M. Mast cell chymase in pulmonary hypertension. Thorax 1999;54:88-90. (Pubitemid 29103760)
75. Zhu YJ, Kradin R, Brandstetter RD, Staton G, Moss J, Hales CA. Hypoxic pulmonary hypertension in the mast cell-deficient mouse. J Appl Physiol 1983;54:680-686. (Pubitemid 13115067)
76. Williams A, Heath D, Kay JM, Smith P. Lung mast cells in rats exposed to acute hypoxia, and chronic hypoxia with recovery. Thorax 1977;32:287-295.
77. Hassoun PM, Mouthon L, Barbera JA, Eddahibi S, Flores SC, Grimminger F, Jones PL, Maitland ML, Michelakis ED, Morrell NW, et al. Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol 2009; 54(1, Suppl)S10-S19.
78. Bournia V, Vlachoyiannopoulos P, Selmi C, Moutsopoulos H, Gershwin M. Recent advances in the treatment of systemic sclerosis. Clin Rev Allergy Immunol 2009;36:176-200.
79. Antoniou KM, Wells AU. Scleroderma lung disease: evolving understanding in light of newer studies. Curr Opin Rheumatol 2008;20:686-691.
80. Bouros D, Wells AU, Nicholson AG, Colby TV, Polychronopoulos V, Pantelidis P, Haslam PL, Vassilakis DA, Black CM, du Bois RM. Histopathologic subsets of fibrosing alveolitis in patients with systemic sclerosis and their relationship to outcome. Am J Respir Crit Care Med 2002;165:1581-1586. (Pubitemid 34693935)
81. du Bois RM. Mechanisms of scleroderma-induced lung disease. Proc Am Thorac Soc 2007;4:434-438.
82. Hachulla E, Gressin V, Guillevin L, Carpentier P, Diot E, Sibilia J, Kahan A, Cabane J, Frances C, Launay D, et al. Early detection of pulmonary arterial hypertension in systemic sclerosis: a French nationwide prospective multicenter study. Arthritis Rheum 2005;52:3792-3800. (Pubitemid 41798217)
83. Mukerjee D, St George D, Coleiro B, Knight C, Denton CP, Davar J, Black CM, Coghlan JG. Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach. Ann Rheum Dis 2003;62:1088-1093. (Pubitemid 37323574)
84. Sgonc R, Gruschwitz MS, Dietrich H, Recheis H, Gershwin ME, Wick G. Endothelial cell apoptosis is a primary pathogenetic event underlying skin lesions in avian and human scleroderma. J Clin Invest 1996;98:785-792. (Pubitemid 26349184)
85. Nicolls MR, Taraseviciene-Stewart L, Rai PR, Badesch DB, Voelkel NF. Autoimmunity and pulmonary hypertension: a perspective. Eur Respir J 2005;26:1110-1118. (Pubitemid 41829945)
86. Okano Y, Medsger TA Jr. Autoantibody to Th ribonucleoprotein (nucleolar 7-2 RNA protein particle) in patients with systemic sclerosis. Arthritis Rheum 1990;33:1822-1828.
87. Negi VS, Tripathy NK, Misra R, Nityanand S. Antiendothelial cell antibodies in scleroderma correlate with severe digital ischemia and pulmonary arterial hypertension. J Rheumatol 1998;25:462-466.
88. Harrison NK, Myers AR, Corrin B, Soosay G, Dewar A, Black CM, Du Bois RM, Turner-Warwick M. Structural features of interstitial lung disease in systemic sclerosis. Am Rev Respir Dis 1991;144:706-713.
89. +T-cell repertoire in the lungs of patients with systemic sclerosis. Hum Immunol 1996;48:84-97.
90. Majumdar S, Li D, Ansari T, Pantelidis P, Black CM, Gizycki M, du Bois RM, Jeffery PK. Different cytokine profiles in cryptogenic fibrosing alveolitis and fibrosing alveolitis associated with systemic sclerosis: a quantitative study of open lung biopsies. Eur Respir J 1999;14:251-257. (Pubitemid 29461285)
91. Cerinic MM, Valentini G, Sorano GG, D'Angelo S, Cuomo G, Fenu L, Generini S, Cinotti S, Morfini M, Pignone A, et al. Blood co-agulation, fibrinolysis, and markers of endothelial dysfunction in systemic sclerosis. Semin Arthritis Rheum 2003;32:285-295. (Pubitemid 36459278)
92. Luzina IG, Atamas SP, Wise R, Wigley FM, Xiao HQ, White B. Gene expression in bronchoalveolar lavage cells from scleroderma patients. Am J Respir Cell Mol Biol 2002;26:549-557. (Pubitemid 34315862)
93. Luzina IG, Atamas SP, Wise R, Wigley FM, Choi J, Xiao HQ, White B. Occurrence of an activated, profibrotic pattern of gene expression in lung CD8+ T cells from scleroderma patients. Arthritis Rheum 2003;48:2262-2274. (Pubitemid 36959208)
94. Scala E, Pallotta S, Frezzolini A, Abeni D, Barbieri C, Sampogna F, De Pita O, Puddu P, Paganelli R, Russo G. Cytokine and chemokine levels in systemic sclerosis: relationship with cutaneous and internal organ involvement. Clin Exp Immunol 2004;138:540-546. (Pubitemid 39573637)
95. Meloni F, Caporali R, Marone Bianco A, Paschetto E, Morosini M, Fietta AM, Bobbio-Pallavicini F, Pozzi E, Montecucco C. Cytokine profile of bronchoalveolar lavage in systemic sclerosis with interstitial lung disease: comparison with usual interstitial pneumonia. Ann Rheum Dis 2004;63:892-894. (Pubitemid 38850472)
96. Le Pavec J, Humbert M, Mouthon L, Hassoun PM. Systemic sclerosis-associated pulmonary arterial hypertension. Am J Respir Crit Care Med 2010;181:1285-1293.
97. Guiducci S, Distler O, Distler JHW, Matucci-Cerinic M. Mechanisms of vascular damage in ssc - implications for vascular treatment strategies. Rheumatology 2008;47(Suppl 5):v18-v20.
98. Laplante P, Raymond MA, Gagnon G, Vigneault N, Sasseville AM, Langelier Y, Bernard M, Raymond Y, Hebert MJ. Novel fibrogenic pathways are activated in response to endothelial apoptosis: implications in the pathophysiology of systemic sclerosis. J Immunol 2005;174:5740-5749. (Pubitemid 40593217)
99. Tamby MC, Humbert M, Guilpain P, Servettaz A, Dupin N, Christner JJ, Simonneau G, Fermanian J, Weill B, Guillevin L, et al. Antibodies to fibroblasts in idiopathic and scleroderma-associated pulmonary hypertension. Eur Respir J 2006;28:799-807. (Pubitemid 46332002)
100. Kahan A, Coghlan G, McLaughlin V. Cardiac complications of systemic sclerosis. Rheumatology (Oxford) 2009;48:iii45-iii48.
101. Steen VD, Follansbee WP, Conte CG, Medsger TA Jr. Thallium perfusion defects predict subsequent cardiac dysfunction in patients with systemic sclerosis. Arthritis Rheum 1996;39:677-681. (Pubitemid 26118047)
102. de Groote P, Gressin V, Hachulla E, Carpentier P, Guillevin L, Kahan A, Cabane J, Frances C, Lamblin N, Diot E, et al. Evaluation of cardiac abnormalities by Doppler echocardiography in a large nationwide multicentric cohort of patients with systemic sclerosis. Ann Rheum Dis 2008;67:31-36.
103. Gerke AK, Hunninghake G. The immunology of sarcoidosis. Clin Chest Med 2008;29:379-390. (Pubitemid 351778215)
104. Agostini C, Facco M, Chilosi M, Semenzato G. Alveolar macrophage-T cell interactions during Th1-type sarcoid inflammation. Microsc Res Tech 2001;53:278-287. (Pubitemid 32467165)
105. Diaz-Guzman E, Farver C, Parambil J, Culver DA. Pulmonary hypertension caused by sarcoidosis. Clin Chest Med 2008;29:549-563. (Pubitemid 351778207)
106. Rosen Y, Moon S, Huang CT, Gourin A, Lyons HA. Granulomatous pulmonary angiitis in sarcoidosis. Arch Pathol Lab Med 1977;101:170-174. (Pubitemid 8187786)
107. Takemura T, Matsui Y, Oritsu M, Akiyama O, Hiraga Y, Omichi M, Hirasawa M, Saiki S, Tamura S, Mochizuki I, et al. Pulmonary vascular involvement in sarcoidosis: granulomatous angiitis and microangiopathy in transbronchial lung biopsies. Virchows Arch A Pathol Anat Histopathol 1991;418:361-368.
108. Hoffstein V, Ranganathan N, Mullen JB. Sarcoidosis simulating pulmonary veno-occlusive disease. Am Rev Respir Dis 1986;134:809-811. (Pubitemid 16008649)
109. Schachter EN, Smith GJ, Cohen GS, Lee SH, Laser A, Gee JB. Pulmonary granulomas in a patient with pulmonary veno-occlusive disease. Chest 1975;67:487-489.
110. Reichenberger F, Schauer J, Kellner K, Sack U, Stiehl P, Winkler J. Different expression of endothelin in the bronchoalveolar lavage in patients with pulmonary diseases. Lung 2001;179:163-174. (Pubitemid 34033112)
111. Koyama S, Sato E, Haniuda M, Numanami H, Nagai S, Izumi T. Decreased level of vascular endothelial growth factor in bronchoalveolar lavage fluid of normal smokers and patients with pulmonary fibrosis. Am J Respir Crit Care Med 2002;166:382-385. (Pubitemid 34864431)
112. Hofmann S, Franke A, Fischer A, Jacobs G, Nothnagel M, Gaede KI, Schurmann M, Muller-Quernheim J, Krawczak M, Rosenstiel P, et al. Genome-wide association study identifies ANXA11 as a new susceptibility locus for sarcoidosis. Nat Genet 2008;40:1103-1106.
113. Wasfi YS, Silveira LJ, Jonth A, Hokanson JE, Fingerlin T, Sato H, Parsons CE, Lympany P, Welsh K, du Bois RM, et al. Fas promoter polymorphisms: genetic predisposition to sarcoidosis in African-Americans. Tissue Antigens 2008;72:39-48. (Pubitemid 351841646)
114. Pierre-Louis B, Prasad A, Frishman WH. Cardiac manifestations of sarcoidosis and therapeutic options. Cardiol Rev 2009;17:153-158.
115. Voelkel NF, Vandivier RW, Tuder RM. Vascular endothelial growth factor in the lung. Am J Physiol Lung Cell Mol Physiol 2006;290:L209-L221.
116. Kasahara Y, Tuder RM, Taraseviciene-Stewart L, Le Cras TD, Abman S, Hirth PK, Waltenberger J, Voelkel NF. Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J Clin Invest 2000;106:1311-1319.
117. Ramirez-Bergeron DL, Runge A, Adelman DM, Gohil M, Simon MC. HIF-dependent hematopoietic factors regulate the development of the embryonic vasculature. Dev Cell 2006;11:81-92. (Pubitemid 43960804)
118. Tuder RM, Yun JH. Vascular endothelial growth factor of the lung: friend or foe. Curr Opin Pharmacol 2008;8:255-260.
119. Meyer KC, Cardoni A, Xiang ZZ. Vascular endothelial growth factor in bronchoalveolar lavage from normal subjects and patients with diffuse parenchymal lung disease. J Lab Clin Med 2000;135:332-338. (Pubitemid 30213549)
120. Hamada N, Kuwano K, Yamada M, Hagimoto N, Hiasa K, Egashira K, Nakashima N, Maeyama T, Yoshimi M, Nakanishi Y. Anti-vascular endothelial growth factor gene therapy attenuates lung injury and fibrosis in mice. J Immunol 2005;175:1224-1231. (Pubitemid 41095011)
121. Moeller A, Ask K, Warburton D, Gauldie J, Kolb M. The bleomycin animal model: a useful tool to investigate treatment options for idiopathic pulmonary fibrosis? Int J Biochem Cell Biol 2008;40:362-382. (Pubitemid 351249887)
122. Borzone G, Moreno R, Urrea R, Meneses M, Oyarzun M, Lisboa C. Bleomycin-induced chronic lung damage does not resemble human idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2001;163:1648-1653. (Pubitemid 32578771)
123. Campbell AI, Zhao Y, Sandhu R, Stewart DJ. Cell-based gene transfer of vascular endothelial growth factor attenuates monocrotaline-induced pulmonary hypertension. Circulation 2001;104:2242-2248. (Pubitemid 33043307)
124. Fujita M, Mason RJ, Cool C, Shannon JM, Hara N, Fagan KA. Pulmonary hypertension in TNF-alpha-overexpressing mice is associated with decreased VEGF gene expression. J Appl Physiol 2002;93:2162-2170. (Pubitemid 35379344)
125. Grover TR, Parker TA, Markham NE, Abman SH. RhVEGF treatment preserves pulmonary vascular reactivity and structure in an experimental model of pulmonary hypertension in fetal sheep. Am J Physiol Lung Cell Mol Physiol 2005;289:L315-L321. (Pubitemid 41008915)
126. Le Cras TD, Markham NE, Tuder RM, Voelkel NF, Abman SH. Treatment of newborn rats with a VEGF receptor inhibitor causes pulmonary hypertension and abnormal lung structure. Am J Physiol Lung Cell Mol Physiol 2002;283:L555-L562.
127. Partovian C, Adnot S, Raffestin B, Louzier V, Levame M, Mavier IM, Lemarchand P, Eddahibi S. Adenovirus-mediated lung vascular endothelial growth factor overexpression protects against hypoxic pulmonary hypertension in rats. Am J Respir Cell Mol Biol 2000;23:762-771. (Pubitemid 32013268)
128. Zhao YD, Courtman DW, Ng DS, Robb MJ, Deng YP, Trogadis J, Han RN, Stewart DJ. Microvascular regeneration in established pulmonary hypertension by angiogenic gene transfer. Am J Respir Cell Mol Biol 2006;35:182-189. (Pubitemid 44175317)
129. Jiang B, Liu L. Chapter 2: PI3K/PTEN signaling in angiogenesis and tumorigenesis. In: George FVW, George K, editors. Advances in cancer research, Volume 102. San Diego, CA: Academic Press; 2009. Pp. 19-65.
130. Vasakova M, Sterclova M, Kolesar L, Slavcev A, Pohunek P, Sulc J, Skibova J, Striz I. Bronchoalveolar lavage fluid cellular characteristics, functional parameters and cytokine and chemokine levels in interstitial lung diseases. Scand J Immunol 2009;69:268-274.
131. Tombran-Tink J, Barnstable CJ. PEDF: a multifaceted neurotrophic factor. Nat Rev Neurosci 2003;4:628-636. (Pubitemid 37280158)
132. Chen L, Zhang SS, Barnstable CJ, Tombran-Tink J. PEDF induces apoptosis in human endothelial cells by activating p38 MAP kinase dependent cleavage of multiple caspases. Biochem Biophys Res Commun 2006;348:1288-1295. (Pubitemid 44291343)
133. Ho TC, Chen SL, Yang YC, Liao CL, Cheng HC, Tsao YP. PEDF induces p53-mediated apoptosis through PPAR gamma signaling in human umbilical vein endothelial cells. Cardiovasc Res 2007;76:213-223.
134. Pignolo RJ, Francis MK, Rotenberg MO, Cristofalo VJ. Putative role for EPC-1/PEDF in the G0 growth arrest of human diploid fibroblasts. J Cell Physiol 2003;195:12-20. (Pubitemid 36292755)
135. Dawson DW, Volpert OV, Gillis P, Crawford SE, Xu H, Benedict W, Bouck NP. Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science 1999;285:245-248. (Pubitemid 29329995)
136. Zhang SX, Wang JJ, Gao G, Parke K, Ma JX. Pigment epithelium-derived factor downregulates vascular endothelial growth factor (VEGF) expression and inhibits VEGF-VEGF receptor 2 binding in diabetic retinopathy. J Mol Endocrinol 2006;37:1-12. (Pubitemid 44288601)
137. Yamagishi S, Inagaki Y, Nakamura K, Abe R, Shimizu T, Yoshimura A, Imaizumi T. Pigment epithelium-derived factor inhibits TNF-alpha-induced interleukin-6 expression in endothelial cells by suppressing NADPH oxidase-mediated reactive oxygen species generation. J Mol Cell Cardiol 2004;37:497-506. (Pubitemid 38953377)
138. Alberdi E, Aymerich MS, Becerra SP. Binding of pigment epithelium-derived factor (PEDF) to retinoblastoma cells and cerebellar granule neurons: evidence for a PEDF receptor. J Biol Chem 1999;274:31605-31612.
139. Bilak MM, Becerra SP, Vincent AM, Moss BH, Aymerich MS, Kuncl RW. Identification of the neuroprotective molecular region of pigment epithelium-derived factor and its binding sites on motor neurons. J Neurosci 2002;22:9378-9386. (Pubitemid 35356181)
140. Aymerich MS, Alberdi EM, Martinez A, Becerra SP. Evidence for pigment epithelium-derived factor receptors in the neural retina. Invest Ophthalmol Vis Sci 2001;42:3287-3293. (Pubitemid 33740692)
141. Bernard A, Gao-Li J, Franco CA, Bouceba T, Huet A, Li Z. Laminin receptor involvement in the anti-angiogenic activity of pigment epithelium-derived factor. J Biol Chem 2009;284:10480-10490.
142. Notari L, Baladron V, Aroca-Aguilar JD, Balko N, Heredia R, Meyer C, Notario PM, Saravanamuthu S, Nueda ML, Sanchez-Sanchez F, et al. Identification of a lipase-linked cell membrane receptor for pigment epithelium-derived factor. J Biol Chem 2006;281:38022-38037. (Pubitemid 46042106)
143. Filleur S, Volz K, Nelius T, Mirochnik Y, Huang H, Zaichuk TA, Aymerich MS, Becerra SP, Yap R, Veliceasa D, et al. Two functional epitopes of pigment epithelial-derived factor block angiogenesis and induce differentiation in prostate cancer. Cancer Res 2005;65:5144-5152. (Pubitemid 40827323)
144. Filleur S, Nelius T, de Riese W, Kennedy RC. Characterization of PEDF: a multi-functional serpin family protein. J Cell Biochem 2009;106:769-775.
145. Maik-Rachline G, Seger R. Variable phosphorylation states of pigment-epithelium-derived factor differentially regulate its function. Blood 2006;107:2745-2752.
146. Maik-Rachline G, Shaltiel S, Seger R. Extracellular phosphorylation converts pigment epithelium-derived factor from a neurotrophic to an antiangiogenic factor. Blood 2005;105:670-678. (Pubitemid 40070751)
147. Hosomichi J, Yasui N, Koide T, Soma K, Morita I. Involvement of the collagen I-binding motif in the anti-angiogenic activity of pigment epithelium-derived factor. Biochem Biophys Res Commun 2005;335:756-761. (Pubitemid 41188263)
148. Meyer C, Notari L, Becerra SP. Mapping the type I collagen-binding site on pigment epithelium-derived factor: implications for its antiangiogenic activity. J Biol Chem 2002;277:45400-45407. (Pubitemid 36159148)
149. Valnickova Z, Petersen SV, Nielsen SB, Otzen DE, Enghild JJ. Heparin binding induces a conformational change in pigment epithelium-derived factor. J Biol Chem 2007;282:6661-6667. (Pubitemid 47100837)
150. Becerra SP, Perez-Mediavilla LA, Weldon JE, Locatelli-Hoops S, Senanayake P, Notari L, Notario V, Hollyfield JG. Pigment epithelium-derived factor binds to hyaluronan: mapping of a hyaluronan binding site. J Biol Chem 2008;283:33310-33320.
151. Bensadoun ES, Burke AK, Hogg JC, Roberts CR. Proteoglycan deposition in pulmonary fibrosis. Am J Respir Crit Care Med 1996;154:1819-1828. (Pubitemid 26424956)
152. Notari L, Miller A, Martinez A, Amaral J, Ju M, Robinson G, Smith LE, Becerra SP. Pigment epithelium-derived factor is a substrate for matrix metalloproteinase type 2 and type 9: implications for downregulation in hypoxia. Invest Ophthalmol Vis Sci 2005;46:2736-2747. (Pubitemid 43086693)
153. Selman M, Ruiz V, Cabrera S, Segura L, Ramirez R, Barrios R, Pardo A. TIMP-1, -2, -3, and -4 in idiopathic pulmonary fibrosis: a prevailing nondegradative lung microenvironment? Am J Physiol Lung Cell Mol Physiol 2000;279:L562-L574.
154. Zamiri P, Masli S, Streilein JW, Taylor AW. Pigment epithelial growth factor suppresses inflammation by modulating macrophage activation. Invest Ophthalmol Vis Sci 2006;47:3912-3918. (Pubitemid 46044306)
155. Zamiri P, Sugita S, Streilein JW. Immunosuppressive properties of the pigmented epithelial cells and the subretinal space. Chem Immunol Allergy 2007;92:86-93. (Pubitemid 47096898)
156. Zhang SX, Wang JJ, Gao G, Shao C, Mott R, Ma JX. Pigment epithelium-derived factor (PEDF) is an endogenous antiinflammatory factor. FASEB J 2006;20:323-325. (Pubitemid 46671158)
157. Wang JJ, Zhang SX, Lu K, Chen Y, Mott R, Sato S, Ma JX. Decreased expression of pigment epithelium-derived factor is involved in the pathogenesis of diabetic nephropathy. Diabetes 2005;54:243-250. (Pubitemid 40105119)
158. Wang JJ, Zhang SX, Mott R, Knapp RR, Cao W, Lau K, Ma JX. Salutary effect of pigment epithelium-derived factor in diabetic nephropathy: evidence for antifibrogenic activities. Diabetes 2006;55:1678-1685. (Pubitemid 44324120)
159. Cao W, Tombran-Tink J, Chen W, Mrazek D, Elias R, McGinnis JF. Pigment epithelium-derived factor protects cultured retinal neurons against hydrogen peroxide-induced cell death. J Neurosci Res 1999;57:789-800. (Pubitemid 29416109)
160. Pang IH, Zeng H, Fleenor DL, Clark AF. Pigment epithelium-derived factor protects retinal ganglion cells. BMC Neurosci 2007;8:11.
161. Cai J, Parr C, Watkins G, Jiang WG, Boulton M. Decreased pigment epithelium-derived factor expression in human breast cancer progression. Clin Cancer Res 2006;12:3510-3517.
162. Uehara H, Miyamoto M, Kato K, Ebihara Y, Kaneko H, Hashimoto H, Murakami Y, Hase R, Takahashi R, Mega S, et al. Expression of pigment epithelium-derived factor decreases liver metastasis and correlates with favorable prognosis for patients with ductal pancreatic adenocarcinoma. Cancer Res 2004;64:3533-3537. (Pubitemid 38657928)
163. Zhang L, Chen J, Ke Y, Mansel RE, Jiang WG. Expression of pigment epithelial derived factor is reduced in non-small cell lung cancer and is linked to clinical outcome. Int J Mol Med 2006;17:937-944.
164. Rychli K, Niessner A, Hohensinner PJ, Mahdy Ali K, Kaun C, Neuhold S, Zorn G, Richter B, Hulsmann M, Berger R, et al. Prognostic value of pigment epithelium-derived factor in advanced heart failure patients. Chest 2010;138:656-664.
165. O'Kane S, Ferguson MW. Transforming growth factor beta S and wound healing. Int J Biochem Cell Biol 1997;29:63-78. (Pubitemid 27096420)
166. Gauldie J, Kolb M, Ask K, Martin G, Bonniaud P, Warburton D. Smad3 signaling involved in pulmonary fibrosis and emphysema. Proc Am Thorac Soc 2006;3:696-702. (Pubitemid 44788227)
167. Prud'homme GJ. Pathobiology of transforming growth factor [beta] in cancer, fibrosis and immunologic disease, and therapeutic considerations. Lab Invest 2007;87:1077-1091. (Pubitemid 47610581)
168. +regulatory T cells and for expansion of these cells. J Immunol 2007;178:2018-2027.
169. + regulatory T cells. J Exp Med 2005;201:1061-1067.
170. Pyzik M, Piccirillo CA. TGF-beta1 modulates FOXP3 expression and regulatory activity in distinct CD4+ T cell subsets. J Leukoc Biol 2007;82:335-346. (Pubitemid 47230645)
171. Selvaraj RK, Geiger TL. A kinetic and dynamic analysis of foxp3 induced in t cells by TGF-beta. J Immunol 2007;179:11 p following 1390.
172. Wahl SM, Hunt DA, Wakefield LM, McCartney-Francis N, Wahl LM, Roberts AB, Sporn MB. Transforming growth factor type beta induces monocyte chemotaxis and growth factor production. Proc Natl Acad Sci USA 1987;84:5788-5792. (Pubitemid 17130416)
173. Pertovaara L, Kaipainen A, Mustonen T, Orpana A, Ferrara N, Saksela O, Alitalo K. Vascular endothelial growth factor is induced in response to transforming growth factor-beta in fibroblastic and epithelial cells. J Biol Chem 1994;269:6271-6274. (Pubitemid 24190991)
174. Carmeliet P. Angiogenesis in health and disease. NatMed 2003;9:653-660. (Pubitemid 36749213)
175. Pollman MJ, Naumovski L, Gibbons GH. Vascular cell apoptosis: cell type-specific modulation by transforming growth factor-β1 in endothelial cells versus smooth muscle cells. Circulation 1999;99:2019-2026. (Pubitemid 29183900)
176. Khalil N, O'Connor R, Unruh H, Warren P, Kemp A, Greenberg A. Enhanced expression and immunohistochemical distribution of transforming growth factor-beta in idiopathic pulmonary fibrosis. Chest 1991;99(3 Suppl):65S-66S.
177. Bergeron A, Soler P, Kambouchner M, Loiseau P, Milleron B, Valeyre D, Hance AJ, Tazi A. Cytokine profiles in idiopathic pulmonary fibrosis suggest an important role for TGF-beta and IL-10. Eur Respir J 2003;22:69-76. (Pubitemid 36896473)
178. Zaiman AL, Podowski M, Medicherla S, Gordy K, Xu F, Zhen L, Shimoda LA, Neptune E, Higgins L, Murphy A, et al. Role of the TGF-{beta}/ALK5 signaling pathway in monocrotaline-induced pulmonary hypertension. Am J Respir Crit Care Med 2008;177:896-905. (Pubitemid 351600668)
179. Bonniaud P, Margetts PJ, Kolb M, Schroeder JA, Kapoun AM, Damm D, Murphy A, Chakravarty S, Dugar S, Higgins L, et al. Progressive transforming growth factor beta1-induced lung fibrosis is blocked by an orally active ALK5 kinase inhibitor. Am J Respir Crit Care Med 2005;171:889-898. (Pubitemid 40562720)
180. Hiwatari N, Shimura S, Yamauchi K, Nara M, Hida W, Shirato K. Significance of elevated procollagen-III-peptide and transforming growth factor-beta levels of bronchoalveolar lavage fluids from idiopathic pulmonary fibrosis patients. Tohoku J Exp Med 1997;181:285-295. (Pubitemid 127471189)
181. Meloni F, Caporali R, Marone Bianco A, Paschetto E, Morosini M, Fietta AM, Patrizio V, Bobbio-Pallavicini F, Pozzi E, Montecucco C. BAL cytokine profile in different interstitial lung diseases: a focus on systemic sclerosis. Sarcoidosis Vasc Diffuse Lung Dis 2004;21:111-118. (Pubitemid 38954751)
182. Otrock ZK, Mahfouz RA, Makarem JA, Shamseddine AI. Understanding the biology of angiogenesis: review of the most important molecular mechanisms. Blood Cells Mol Dis 2007;39:212-220. (Pubitemid 47126926)
183. Thomas KA. Fibroblast growth factors. FASEB J 1987;1:434-440. (Pubitemid 18012078)
184. Cross MJ, Claesson-Welsh L. FGF and VEGF function in angiogenesis: signalling pathways, biological responses and therapeutic inhibition. Trends Pharmacol Sci 2001;22:201-207. (Pubitemid 32244307)
185. Presta M, Tiberio L, Rusnati M, Dell'Era P, Ragnotti G. Basic fibroblast growth factor requires a long-lasting activation of protein kinase C to induce cell proliferation in transformed fetal bovine aortic endothelial cells. Cell Regul 1991;2:719-726.
186. Lappi-Blanco E, Soini Y, Kinnula V, Paakko P. VEGF and BFGF are highly expressed in intraluminal fibromyxoid lesions in bronchiolitis obliterans organizing pneumonia. J Pathol 2002;196:220-227. (Pubitemid 34110904)
187. Benisty JI, McLaughlin VV, Landzberg MJ, Rich JD, Newburger JW, Rich S, Folkman J. Elevated basic fibroblast growth factor levels in patients with pulmonary arterial hypertension. Chest 2004;126:1255-1261. (Pubitemid 39391258)
188. Izikki M. Endothelial-derived FGF2 contributes to the progression of pulmonary hypertension in humans and rodents. J Clin Invest 2009;119:512-523.
189. Belperio JA, Keane MP, Arenberg DA, Addison CL, Ehlert JE, Burdick MD, Strieter RM. CXC chemokines in angiogenesis. J Leukoc Biol 2000;68:1-8.
190. Strieter RM, Polverini PJ, Kunkel SL, Arenberg DA, Burdick MD, Kasper J, Dzuiba J, Van Damme J, Walz A, Marriott D, et al. The functional role of the ELR motif in CXC chemokine-mediated angiogenesis. J Biol Chem 1995;270:27348-27357.
191. Nor JE, Christensen J, Liu J, Peters M, Mooney DJ, Strieter RM, Polverini PJ. Up-regulation of BCL-2 in microvascular endothelial cells enhances intratumoral angiogenesis and accelerates tumor growth. Cancer Res 2001;61:2183-2188. (Pubitemid 32692045)
192. + CXC chemokine-induced angiogenic activity. J Immunol 2000;165:5269-5277.
193. Murdoch C, Monk PN, Finn A. CXC chemokine receptor expression on human endothelial cells. Cytokine 1999;11:704-712. (Pubitemid 29428004)
194. Salcedo R, Resau JH, Halverson D, Hudson EA, Dambach M, Powell D, Wasserman KEN, Oppenheim JJ. Differential expression and responsiveness of chemokine receptors (CXCR1-3) by human microvascular endothelial cells and umbilical vein endothelial cells. FASEB J 2000;14:2055-2064.
195. Schraufstatter IU, Trieu K, Zhao M, Rose DM, Terkeltaub RA, Burger M. IL-8-mediated cell migration in endothelial cells depends on cathepsin B activity and transactivation of the epidermal growth factor receptor. J Immunol 2003;171:6714-6722. (Pubitemid 37532104)
196. Phillips RJ, Burdick MD, Hong K, Lutz MA, Murray LA, Xue YY, Belperio JA, Keane MP, Strieter RM. Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. J Clin Invest 2004;114:438-446. (Pubitemid 39071616)
197. Marcel L, Pius L, Nicole B, Eckart M, Bernhard M. Lymphocyte-specific chemokine receptor CXCR3: regulation, chemokine binding and gene localization. Eur J Immunol 1998;28:3696-3705.
198. Antoniou KM, Tzouvelekis A, Alexandrakis MG, Sfiridaki K, Tsiligianni I, Rachiotis G, Tzanakis N, Bouros D, Milic-Emili J, Siafakas NM. Different angiogenic activity in pulmonary sarcoidosis and idiopathic pulmonary fibrosis. Chest 2006;130:982-988. (Pubitemid 44583725)
199. Belperio JA, Dy M, Murray L, Burdick MD, Xue YY, Strieter RM, Keane MP. The role of the Th2 CC chemokine ligand CCL17 in pulmonary fibrosis. J Immunol 2004;173:4692-4698. (Pubitemid 39280704)
200. Keane MP, Belperio JA, Moore TA, Moore BB, Arenberg DA, Smith RE, Burdick MD, Kunkel SL, Strieter RM. Neutralization of the CXC chemokine, macrophage inflammatory protein-2, attenuates bleomycin-induced pulmonary fibrosis. J Immunol 1999;162:5511-5518. (Pubitemid 29307163)
201. Keane MP, Belperio JA, Arenberg DA, Burdick MD, Xu ZJ, Xue YY, Strieter RM. IFN-{gamma}-inducible protein-10 attenuates bleomycin-induced pulmonary fibrosis via inhibition of angiogenesis. J Immunol 1999;163:5686-5692.
202. Fredriksson L, Li H, Eriksson U. The PDGF family: four gene products form five dimeric isoforms. Cytokine Growth Factor Rev 2004;15:197-204. (Pubitemid 38781045)
203. Lindahl P, Johansson BR, Leveen P, Betsholtz C. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 1997;277:242-245. (Pubitemid 27446080)
204. Hellstrom M, Gerhardt H, Kalen M, Li X, Eriksson U, Wolburg H, Betsholtz C. Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J Cell Biol 2001;153:543-553. (Pubitemid 34280141)
205. Homma S, Nagaoka I, Abe H, Takahashi K, Seyama K, Nukiwa T, Kira S. Localization of platelet-derived growth factor and insulin-like growth factor I in the fibrotic lung. Am J Respir Crit Care Med 1995;152:2084-2089.
206. Antoniades HN, Bravo MA, Avila RE, Galanopoulos T, Neville-Golden J, Maxwell M, Selman M. Platelet-derived growth factor in idiopathic pulmonary fibrosis. J Clin Invest 1990;86:1055-1064. (Pubitemid 20370408)
207. Schermuly RT, Dony E, Ghofrani HA, Pullamsetti S, Savai R, Roth M, Sydykov A, Lai YJ, Weissmann N, Seeger W, et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest 2005;115:2811-2821. (Pubitemid 41434408)
208. Clamp AR, Jayson GC. The clinical potential of antiangiogenic fragments of extracellular matrix proteins. Br J Cancer 2005;93:967-972. (Pubitemid 41548387)
209. Felbor U, Dreier L, Bryant RA, Ploegh HL, Olsen BR, Mothes W. Secreted cathepsin l generates endostatin from collagen XVIII. EMBO J 2000;19:1187-1194. (Pubitemid 30151015)
210. O'Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 1997;88:277-285. (Pubitemid 28015876)
211. Yang IV, Burch LH, Steele MP, Savov JD, Hollingsworth JW, McElvania-Tekippe E, Berman KG, Speer MC, Sporn TA, Brown KK, et al. Gene expression profiling of familial and sporadic interstitial pneumonia. Am J Respir Crit Care Med 2007;175:45-54. (Pubitemid 46105308)
212. Thickett DR, Poole AR, Millar AB. The balance between collagen synthesis and degradation in diffuse lung disease. Sarcoidosis Vasc Diffuse Lung Dis 2001;18:27-33. (Pubitemid 32280534)
213. Paddenberg R, Faulhammer P, Goldenberg A, Kummer W. Hypoxia-induced increase of endostatin in murine aorta and lung. Histochem Cell Biol 2006;125:497-508. (Pubitemid 43673513)
214. Masaki T, Yanagisawa M, Goto K. Physiology and pharmacology of endothelins. Med Res Rev 1992;12:391-421.
215. Giaid A, Polak JM, Gaitonde V, Hamid QA, Moscoso G, Legon S, Uwanogho D, Roncalli M, Shinmi O, Sawamura T, et al. Distribution of endothelin-like immunoreactivity and mRNA in the developing and adult human lung. Am J Respir Cell Mol Biol 1991;4:50-58.
216. Giaid A, Michel RP, Stewart DJ, Sheppard M, Corrin B, Hamid Q. Expression of endothelin-1 in lungs of patients with cryptogenic fibrosing alveolitis. Lancet 1993;341:1550-1554. (Pubitemid 23170459)
217. Saleh D, Furukawa K, Tsao MS, Maghazachi A, Corrin B, Yanagisawa M, Barnes PJ, Giaid A. Elevated expression of endothelin-1 and endothelin- converting enzyme-1 in idiopathic pulmonary fibrosis: possible involvement of proinflammatory cytokines. Am J Respir Cell Mol Biol 1997;16:187-193. (Pubitemid 127498240)
218. Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib H, Kimura S, Masaki T, Duguid WP, Stewart DJ. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993;328:1732-1739. (Pubitemid 23170122)
219. Dupuis J, Prie S. The ET(A)-receptor antagonist LU 135252 prevents the progression of established pulmonary hypertension induced by monocrotaline in rats. J Cardiovasc Pharmacol Ther 1999;4:33-39. (Pubitemid 29111141)
220. Park SH, Saleh D, Giaid A, Michel RP. Increased endothelin-1 in bleomycin-induced pulmonary fibrosis and the effect of an endothelin receptor antagonist. Am J Respir Crit Care Med 1997;156:600-608. (Pubitemid 27352001)
221. Trakada G, Spiropoulos K. Arterial endothelin-1 in interstitial lung disease patients with pulmonary hypertension. Monaldi Arch Chest Dis 2001;56:379-383. (Pubitemid 34134115)
222. Comellas AP, Briva A. Role of endothelin-1 in acute lung injury. Transl Res 2009;153:263-271.
223. Sofia M, Mormile M, Faraone S, Alifano M, Carratu P, Carratu L. Endothelin-1 excretion in urine in active pulmonary sarcoidosis and in other interstitial lung diseases. Sarcoidosis 1995;12:118-123.
224. Jeffery TK, Morrell NW. Molecular and cellular basis of pulmonary vascular remodeling in pulmonary hypertension. Prog Cardiovasc Dis 2002;45:173-202. (Pubitemid 36139815)
225. Morrell N, Higham M, Phillips P, Shakur BH, Robinson P, Beddoes R. Pilot study of losartan for pulmonary hypertension in chronic obstructive pulmonary disease. Respir Res 2005;6:88.
226. Wang R, Zagariya A, Ibarra-Sunga O, Gidea C, Ang E, Deshmukh S, Chaudhary G, Baraboutis J, Filippatos G, Uhal BD. Angiotensin II induces apoptosis in human and rat alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 1999;276:L885-L889. (Pubitemid 29249642)
227. Wang R, Ibarra-Sunga O, Verlinski L, Pick R, Uhal BD. Abrogation of bleomycin-induced epithelial apoptosis and lung fibrosis by captopril or by a caspase inhibitor. Am J Physiol Lung Cell Mol Physiol 2000;279:L143-L151. (Pubitemid 30619534)
228. Maniatis NA, Kotanidou A, Catravas JD, Orfanos SE. Endothelial pathomechanisms in acute lung injury. Vascul Pharmacol 2008;49:119-133.
229. Specks U, Martin WJ II, Rohrbach MS. Bronchoalveolar lavage fluid angiotensin-converting enzyme in interstitial lung diseases. Am Rev Respir Dis 1990;141:117-123. (Pubitemid 20023393)
230. Fiedler U, Augustin HG. Angiopoietins: a link between angiogenesis and inflammation. Trends Immunol 2006;27:552-558. (Pubitemid 44780853)
231. Gale NW, Yancopoulos GD. Growth factors acting via endothelial cell-specific receptor tyrosine kinases: VEGFs, angiopoietins, and ephrins in vascular development. Genes Dev 1999;13:1055-1066. (Pubitemid 29233137)
232. Partanen J, Armstrong E, Makela TP, Korhonen J, Sandberg M, Renkonen R, Knuutila S, Huebner K, Alitalo K. A novel endothelial cell surface receptor tyrosine kinase with extracellular epidermal growth factor homology domains. Mol Cell Biol 1992;12:1698-1707.
233. Iwama A, Hamaguchi I, Hashiyama M, Murayama Y, Yasunaga K, Suda T. Molecular cloning and characterization of mouse TIE and TEK receptor tyrosine kinase genes and their expression in hematopoietic stem cells. Biochem Biophys Res Commun 1993;195:301-309. (Pubitemid 23266532)
234. Sato TN, Qin Y, Kozak CA, Audus KL. TIE-1 and TIE-2 define another class of putative receptor tyrosine kinase genes expressed in early embryonic vascular system. Proc Natl Acad Sci USA 1993;90:9355-9358. (Pubitemid 23315782)
235. Schnurch H, Risau W. Expression of TIE-2, a member of a novel family of receptor tyrosine kinases, in the endothelial cell lineage. Development 1993;119:957-968. (Pubitemid 23337434)
236. Davis S, Aldrich TH, Jones PF, Acheson A, Compton DL, Jain V, Ryan TE, Bruno J, Radziejewski C, Maisonpierre PC, et al. Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell 1996;87:1161-1169. (Pubitemid 27010100)
237. Stratmann A, Risau W, Plate KH. Cell type-specific expression of angiopoietin-1 and angiopoietin-2 suggests a role in glioblastoma angiogenesis. Am J Pathol 1998;153:1459-1466. (Pubitemid 28509902)
238. Sugimachi K, Tanaka S, Taguchi K, Aishima S, Shimada M, Tsuneyoshi M. Angiopoietin switching regulates angiogenesis and progression of human hepatocellular carcinoma. J Clin Pathol 2003;56:854-860. (Pubitemid 37386575)
239. Papapetropoulos A, Fulton D, Mahboubi K, Kalb RG, O'Connor DS, Li F, Altieri DC, Sessa WC. Angiopoietin-1 inhibits endothelial cell apoptosis via the Akt/survivin pathway. J Biol Chem 2000;275:9102-9105. (Pubitemid 30185122)
240. Hegen A, Koidl S, Weindel K, Marme D, Augustin HG, Fiedler U. Expression of angiopoietin-2 in endothelial cells is controlled by positive and negative regulatory promoter elements. Arterioscler Thromb Vasc Biol 2004;24:1803-1809. (Pubitemid 39350295)
241. Oh H, Takagi H, Suzuma K, Otani A, Matsumura M, Honda Y. Hypoxia and vascular endothelial growth factor selectively upregulate angiopoietin-2 in bovine microvascular endothelial cells. J Biol Chem 1999;274:15732-15739.
242. Lobov IB, Brooks PC, Lang RA. Angiopoietin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo. Proc Natl Acad Sci USA 2002;99:11205-11210. (Pubitemid 34920903)
243. Long DA, Price KL, Ioffe E, Gannon CM, Gnudi L, White KE, Yancopoulos GD, Rudge JS, Woolf AS. Angiopoietin-1 therapy enhances fibrosis and inflammation following folic acid-induced acute renal injury. Kidney Int 2008;74:300-309. (Pubitemid 352001243)
244. Kim W, Moon SO, Lee SY, Jang KY, Cho CH, Koh GY, Choi KS, Yoon KH, Sung MJ, Kim DH, et al. Comp-angiopoietin-1 ameliorates renal fibrosis in a unilateral ureteral obstruction model. J Am Soc Nephrol 2006;17:2474-2483. (Pubitemid 44300963)
245. Zhao YD, Campbell AI, Robb M, Ng D, Stewart DJ. Protective role of angiopoietin-1 in experimental pulmonary hypertension. Circ Res 2003;92:984-991. (Pubitemid 36588497)
246. Sullivan CC, Du L, Chu D, Cho AJ, Kido M, Wolf PL, Jamieson SW, Thistlethwaite PA. Induction of pulmonary hypertension by an angiopoietin 1/TIE2/serotonin pathway. Proc Natl Acad Sci USA 2003;100:12331-12336. (Pubitemid 37271560)
247. Dong Z, Kumar R, Yang X, Fidler IJ. Macrophage-derived metalloelastase is responsible for the generation of angiostatin in Lewis lung carcinoma. Cell 1997;88:801-810. (Pubitemid 27164268)
248. Patterson BC, Sang QA. Angiostatin-converting enzyme activities of human matrilysin (MMP-7) and gelatinase B/type IV collagenase (MMP-9). J Biol Chem 1997;272:28823-28825. (Pubitemid 27498157)
249. Stathakis P, Fitzgerald M, Matthias LJ, Chesterman CN, Hogg PJ. Generation of angiostatin by reduction and proteolysis of plasmin: catalysis by a plasmin reductase secreted by cultured cells. J Biol Chem 1997;272:20641- 20645. (Pubitemid 27355624)
250. Cao Y, Xue L. Angiostatin. Semin Thromb Hemost 2004;30:83-93. (Pubitemid 38457303)
251. Cao Y, Ji RW, Davidson D, Schaller J, Marti D, Sohndel S, McCance SG, O'Reilly MS, Llinas M, Folkman J. Kringle domains of human angiostatin: characterization of the anti-proliferative activity on endothelial cells. J Biol Chem 1996;271:29461-29467. (Pubitemid 26382666)
252. Claesson-Welsh L, Welsh M, Ito N, Anand-Apte B, Soker S, Zetter B, O'Reilly M, Folkman J. Angiostatin induces endothelial cell apoptosis and activation of focal adhesion kinase independently of the integrin-binding motif RGD. Proc Natl Acad Sci USA 1998;95:5579-5583. (Pubitemid 28224137)
253. Gupta N, Nodzenski E, Khodarev NN, Yu J, Khorasani L, Beckett MA, Kufe DW, Weichselbaum RR. Angiostatin effects on endothelial cells mediated by ceramide and RhoA. EMBO Rep 2001;2:536-540. (Pubitemid 32611352)
254. Moser TL, Stack MS, Asplin I, Enghild JJ, Hojrup P, Everitt L, Hubchak S, Schnaper HW, Pizzo SV. Angiostatin binds ATP synthase on the surface of human endothelial cells. Proc Natl Acad Sci USA 1999;96:2811-2816. (Pubitemid 29148800)
255. Moser TL, Kenan DJ, Ashley TA, Roy JA, Goodman MD, Misra UK, Cheek DJ, Pizzo SV. Endothelial cell surface F1-F0 ATP synthase is active in ATP synthesis and is inhibited by angiostatin. Proc Natl Acad Sci USA 2001;98:6656-6661. (Pubitemid 32538272)
256. Chavakis E, Dimmeler S. Regulation of endothelial cell survival and apoptosis during angiogenesis. Arterioscler Thromb Vasc Biol 2002;22:887-893. (Pubitemid 34655213)
257. Jurasz P, Ng D, Granton JT, Courtman DW, Stewart DJ. Elevated platelet angiostatin and circulating endothelial microfragments in idiopathic pulmonary arterial hypertension: a preliminary study. Thromb Res 2010;125:53-60.
258. Pascaud M-A, Griscelli F, Raoul W, Marcos E, Opolon P, Raffestin B, Perricaudet M, Adnot S, Eddahibi S. Lung overexpression of angiostatin aggravates pulmonary hypertension in chronically hypoxic mice. Am J Respir Cell Mol Biol 2003;29:449-457. (Pubitemid 37222682)
259. Liu RM. Oxidative stress, plasminogen activator inhibitor 1, and lung fibrosis. Antioxid Redox Signal 2008;10:303-319.
260. Mulligan-Kehoe MJ, Wagner R, Wieland C, Powell R. A truncated plasminogen activator inhibitor-1 protein induces and inhibits angiostatin (kringles 1-3), a plasminogen cleavage product. J Biol Chem 2001;276:8588-8596.
261. Behr J, Kolb M, Cox G. Treating IPF - all or nothing? A pro-con debate. Respirology 2009;14:1072-1081.
262. Gauldie J. Pro: inflammatory mechanisms are a minor component of the pathogenesis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2002;165:1205-1206. (Pubitemid 34461729)
263. Azuma A, Nukiwa T, Tsuboi E, Suga M, Abe S, Nakata K, Taguchi Y, Nagai S, Itoh H, Ohi M, et al. Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2005;171:1040-1047. (Pubitemid 40616955)
264. Taniguchi H, Ebina M, Kondoh Y, Ogura T, Azuma A, Suga M, Taguchi Y, Takahashi H, Nakata K, Sato A, et al. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J 2010;35:821-829.
265. Demedts M, Behr J, Buhl R, Costabel U, Dekhuijzen R, Jansen HM, MacNee W, Thomeer M, Wallaert B, Laurent F, et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2005;353:2229-2242. (Pubitemid 41697286)
266. Kim R, Meyer KC. Review: therapies for interstitial lung disease: past, present and future. Ther Adv Respir Dis 2008;2:319-338.
267. Barst RJ, Gibbs JSR, Ghofrani HA, Hoeper MM, McLaughlin VV, Rubin LJ, Sitbon O, Tapson VF, Galiè N. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol 2009;54(1 Suppl 1)S78-S84.
268. Fisher KA, Serlin DM, Wilson KC, Walter RE, Berman JS, Farber HW. Sarcoidosis-associated pulmonary hypertension: outcome with long-term epoprostenol treatment. Chest 2006;130:1481-1488. (Pubitemid 44786743)
269. Strange C, Bolster M, Mazur J, Taylor M, Gossage JR, Silver R. Hemodynamic effects of epoprostenol in patients with systemic sclerosis and pulmonary hypertension. Chest 2000;118:1077-1082.
270. Archer SL, Weir EK, Wilkins MR. Basic science of pulmonary arterial hypertension for clinicians: new concepts and experimental therapies. Circulation 2010;121:2045-2066.
271. Ghofrani HA, Wiedemann R, Rose F, Schermuly RT, Olschewski H, Weissmann N, Gunther A, Walmrath D, Seeger W, Grimminger F. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet 2002;360:895-900. (Pubitemid 35283832)
272. Olschewski H, Ghofrani HA, Walmrath D, Schermuly R, Temmesfeld-Wollbruck B, Grimminger F, Seeger W. Inhaled prostacyclin and iloprost in severe pulmonary hypertension secondary to lung fibrosis. Am J Respir Crit Care Med 1999;160:600-607. (Pubitemid 29380679)
273. King TE Jr, Behr J, Brown KK, du Bois RM, Raghu G. Bosentan use in idiopathic pulmonary fibrosis (ipf): Results of the placebo-controlled build-1 study [abstract]. Proc Am Thorac Soc 2006;3:A524.
274. Kubo H, Nakayama K, Yanai M, Suzuki T, Yamaya M, Watanabe M, Sasaki H. Anticoagulant therapy for idiopathic pulmonary fibrosis. Chest 2005;128:1475-1482. (Pubitemid 41324435)
275. Chen MW, Ni L, Zhao XG, Niu XY. The inhibition of 20(R)-ginsenoside Rg3 on the expressions of angiogenesis factors proteins in human lung adenocarcinoma cell line A549 and HUVEC304 cell. Zhongguo Zhong Yao Za Zhi 2005;30:357-360. (Pubitemid 44724709)
276. Zhao YD, Courtman DW, Deng Y, Kugathasan L, Zhang Q, Stewart DJ. Rescue of monocrotaline-induced pulmonary arterial hypertension using bone marrow-derived endothelial-like progenitor cells: efficacy of combined cell and eNOS gene therapy in established disease. Circ Res 2005;96:442-450. (Pubitemid 40354538)
277. Turner-Warwick M. Systemic arterial patterns in the lung and clubbing of the fingers. Thorax 1963;18:238-250.
278. Paul D, Samuel SM, Maulik N. Mesenchymal stem cell: present challenges and prospective cellular cardiomyoplasty approaches for myocardial regeneration. Antioxid Redox Signal 2009;11:1841-1855.
279. Polomis D, Runo JR, Meyer KC. Pulmonary hypertension in interstitial lung disease. Curr Opin Pulm Med 2008;14:462-469.
280. Baggiolini M, Walz A, Kunkel SL. Neutrophil-activating peptide-1/interleukin 8, a novel cytokine that activates neutrophils. J Clin Invest 1989;84:1045-1049. (Pubitemid 19247571)