MMPs, inflammation and pulmonary arterial hypertension

  • Marie-Pia d’Ortho
Part of the Progress in Inflammation Research book series (PIR)


Pulmonary arterial hypertension (PAH) is characterised by remodelling of small pulmonary arteries leading to a progressive increase in pulmonary vascular resistance and right ventricular failure [1]. PAH can be idiopathic, familial, or associated with a number of conditions or diseases, such as connective tissue disease. Its prognosis is poor, less than 3 yr from diagnosis. The aetiology of severe unexplained pulmonary hypertension remained largely unknown until a few years ago. The gene underlying familial PAH was identified in 2000, the BMPR-2 gene. However its mutations are not always present, and it probably does not explained the full scope of the disease. PAH is associated with structural alterations in pulmonary arteries including intimal fibrosis, medial hypertrophy and adventitial changes, pointing towards extracellular matrix remodelling which have raised the question of involvement of the matrix degrading enzymes. Among them, serine proteases, such as plasmina and endogenous vascular elastase (EVE), and matrix metalloproteases have been studied. In experimental models, the three of them are increased. Accordingly, their inhibition has preventing and in some cases therapeutic effects. However it should be stressed that opposite consequence of protease inhibition on PAH can be observed depending on the experimental model, either chronic hypoxia-induced PAH (deleterious) or toxic moncrotalin-induced PAH (positive). In humans, only sparse reports exist, that found increase in the MMP inhibitor, TIMP-1, and MMP-2 expression and decreased collagenase (MMP-1). Inflammation is part of the PAH, and accordingly, protease production is a well known part of the inflammatory response. Answering the question whether protease inhibition might represent a therapeutic option in human PAH is however certainly too early.


Pulmonary Hypertension Pulmonary Arterial Hypertension Idiopathic Pulmonary Arterial Hypertension Pulmonary Artery Smooth Muscle Cell Smooth Muscle Cell Migration 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Farber HW, Loscalzo J (2004) Pulmonary arterial hypertension. N Engl J Med 351: 1655–1665PubMedCrossRefGoogle Scholar
  2. 2.
    Simonneau G, Galie N, Rubin LJ, Langleben D, Seeger W, Domenighetti G, Gibbs S, Lebrec D, Speich R, Beghetti M et al (2004) Clinical classification of pulmonary hypertension. J Am Coll Cardiol 43: 5S–12SPubMedCrossRefGoogle Scholar
  3. 3.
    Gaine SP, Rubin LJ (1998) Primary pulmonary hypertension. Lancet 352: 719–725PubMedCrossRefGoogle Scholar
  4. 4.
    Hoeper MM, Galie N, Simonneau G, Rubin LJ (2002) New treatments for pulmonary arterial hypertension. Am J Respir Crit Care Med 165: 1209–1216PubMedCrossRefGoogle Scholar
  5. 5.
    Abenhaim L, Moride Y, Brenot F, Rich S, Benichou J, Kurz X, Higenbottam T, Oakley C, Wouters E, Aubier M et al (1996) Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. N Engl J Med 335: 609–616PubMedCrossRefGoogle Scholar
  6. 6.
    Deng Z, Haghighi F, Helleby L, Vanterpool K, Horn EM, Barst RJ, Hodge SE, Morse JH, Knowles JA (2000) Fine mapping of PPH1, a gene for familial primary pulmonary hypertension, to a 3-cM region on chromosome 2q33. Am J Respir Crit Care Med 161: 1055–1059PubMedGoogle Scholar
  7. 7.
    Deng Z, Morse JH, Slager SL, Cuervo N, Moore KJ, Venetos G, Kalachikov S, Cayanis E, Fischer SG, Barst RJ et al (2000) Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 67: 737–744PubMedCrossRefGoogle Scholar
  8. 8.
    Lane KB, Machado RD, Pauciulo MW, Thomson JR, Phillips JA 3rd, Loyd JE, Nichols WC, Trembath RC (2000) Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. The International PPH Consortium. Nat Genet 26: 81–84PubMedCrossRefGoogle Scholar
  9. 9.
    Nichols WC, Koller DL, Slovis B, Foroud T, Terry VH, Arnold ND, Siemieniak DR, Wheeler L, Phillips JA 3rd, Newman JH et al (1997) Localization of the gene for familial primary pulmonary hypertension to chromosome 2q31–32. Nat Genet 15: 277–280PubMedCrossRefGoogle Scholar
  10. 10.
    Machado RD, Aldred MA, James V, Harrison RE, Patel B, Schwalbe EC, Gruenig E, Janssen B, Koehler R, Seeger W et al (2006) Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. Hum Mutat 27: 121–132PubMedCrossRefGoogle Scholar
  11. 11.
    Thomson JR, Machado RD, Pauciulo MW, Morgan NV, Humbert M, Elliott GC, Ward K, Yacoub M, Mikhail G, Rogers P et al (2000) Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J Med Genet 37: 741–745PubMedCrossRefGoogle Scholar
  12. 12.
    Tuder RM, Marecki JC, Richter A, Fijalkowska I, Flores S (2007) Pathology of pulmonary hypertension. Clin Chest Med 28: 23–42, viiPubMedCrossRefGoogle Scholar
  13. 13.
    Cool CD, Kennedy D, Voelkel NF, Tuder RM (1997) Pathogenesis and evolution of plexiform lesions in pulmonary hypertension associated with scleroderma and human immunodeficiency virus infection. Hum Pathol 28: 434–442PubMedCrossRefGoogle Scholar
  14. 14.
    Santos S, Peinado VI, Ramirez J, Melgosa T, Roca J, Rodriguez-Roisin R, Barbera JA (2002) Characterization of pulmonary vascular remodelling in smokers and patients with mild COPD. Eur Respir J 19: 632–638PubMedCrossRefGoogle Scholar
  15. 15.
    Rabinovitch M, Bothwell T, Hayakawa BN, Williams WG, Trusler GA, Rowe RD, Olley PM, Cutz E (1986) Pulmonary artery endothelial abnormalities in patients with congenital heart defects and pulmonary hypertension. A correlation of light with scanning electron microscopy and transmission electron microscopy. Lab Invest 55: 632–653PubMedGoogle Scholar
  16. 16.
    Todorovitch-Hunter L, Johnson DJ, Ranger P, Keeley FW, Rabinovitsh M (1988) Altered elastin and collagen synthesis associated with progressive pulmonary hypertension induced by monocrotaline: a biochemical and ultrastructural study. Lab Invest 58: 184–195Google Scholar
  17. 17.
    LaBourene JI, Coles JG, Johnson DJ, Mehra A, Keeley FW, Rabinovitch M (1990) Alterations in elastin and collagen related to the mechanism of progressive pulmonary venous obstruction in a piglet model. A hemodynamic, ultrastructural, and biochemical study. Circ Res 66: 438–456PubMedGoogle Scholar
  18. 18.
    Cowan K, Jones P, Rabinovitch M (2000) Elastase and matrix metalloproteinase inhibitors induce regression, and tenascin-C antisense prevents progression, of vascular disease. J Clin Invest 105: 21–34PubMedCrossRefGoogle Scholar
  19. 19.
    Jones P, Cowan K, Rabinovitch M (1997) Tenascin-C, proliferation and subendothelial accumulation of fibronectin in progressive pulmonary vascular disease. Am J Pathol 150: 1349–1360PubMedGoogle Scholar
  20. 20.
    Jones P, Crack J, Rabinovitch M (1997) Regulation of Tenascin-C, a vascular smooth muscle cell survival factor that interacts with the alphaVbeta3 integrin to promote EGF receptor phosphorylation and growth. J Cell Biol 139: 279–293PubMedCrossRefGoogle Scholar
  21. 21.
    Stenmark KR, Davie N, Frid M, Gerasimovskaya E, Das M (2006) Role of the adventitia in pulmonary vascular remodeling. Physiology (Bethesda) 21: 134–145Google Scholar
  22. 22.
    Chazova I, Loyd JE, Zhdanov VS, Newman JH, Belenkov Y, Meyrick B (1995) Pulmonary artery adventitial changes and venous involvement in primary pulmonary hypertension. Am J Pathol 146: 389–397PubMedGoogle Scholar
  23. 23.
    Todorovitch-Hunter L, Dodo H, Ye C, McCready L, Keeley FW, Rabinovitch M (1992) Increased pulmonary artery elastolytic activity in adult rats with monocrotaline-induced progressive hypertensive pulmonary vascular disease compared with infant rats with non-progressive disease. Am Rev Respir Dis 146: 213–233Google Scholar
  24. 24.
    Ye CL, Rabinovitch M (1991) Inhibition of elastolysis by SC-37698 reduces development and progression of monocrotaline pulmonary hypertension. Am J Physiol 261: H1255–1267PubMedGoogle Scholar
  25. 25.
    Maruyama K, Ye CL, Woo M, Venkatacharya H, Lines LD, Silver MM, Rabinovitch M (1991) Chronic hypoxic pulmonary hypertension in rats and increased elastolytic activity. Am J Physiol 261: H1716–1726PubMedGoogle Scholar
  26. 26.
    Jacob MP, Bellon G, Robert L, Hornebeck W, Ayrault-Jarrier M, Burdin J, Polonovski J (1981) Elastase-type activity associated with high density lipoproteins in human serum. Biochem Biophys Res Commun 103: 311–318PubMedCrossRefGoogle Scholar
  27. 27.
    Hornebeck W, Derouette JC, Robert L (1975) Isolation, purification and properties of aortic elastase. FEBS Lett 58: 66–70PubMedCrossRefGoogle Scholar
  28. 28.
    Zhu L, Wigle D, Hinek A, Kobayashi J, Ye C, Zuker M, Dodo H, Keeley FW, Rabinovitch M (1994) The endogenous vascular elastase that governs development and progression of monocrotaline-induced pulmonary hypertension in rats is a novel enzyme related to the serine proteinase adipsin. J Clin Invest 94: 1163–1171PubMedCrossRefGoogle Scholar
  29. 29.
    Rabinovitch M (1999) EVE and beyond, retro and prospective insights. Am J Physiol 277: L5–12PubMedGoogle Scholar
  30. 30.
    Thompson K, Rabinovitch M (1996) Exogenous leukocyte and endogenous elastases can mediate mitogenic activity in pulmonary artery smooth muscle cells by release of extracellular-matrix bound basic fibroblast growth factor. J Cell Physiol 166: 495–505PubMedCrossRefGoogle Scholar
  31. 31.
    Hinek A, Boyle J, Rabinovitch M (1992) Vascular smooth muscle cell detachment from elastin and migration through elastic laminae is promoted by chondroitin sulfate-induced „shedding“ of the 67-kDa cell surface elastin binding protein. Exp Cell Res 203: 344–353PubMedCrossRefGoogle Scholar
  32. 32.
    Hinek A, Molossi S, Rabinovitch M (1996) Functional interplay between interleukin-1 receptor and elastin binding protein regulates fibronectin production in coronary artery smooth muscle cells. Exp Cell Res 225: 122–131PubMedCrossRefGoogle Scholar
  33. 33.
    Fay WP, Garg N, Sunkar M (2007) Vascular functions of the plasminogen activation system. Arterioscler Thromb Vasc Biol 27: 1231–1237PubMedCrossRefGoogle Scholar
  34. 34.
    Zhang L, Seiffert D, Fowler BJ, Jenkins GR, Thinnes TC, Loskutoff DJ, Parmer RJ, Miles LA (2002) Plasminogen has a broad extrahepatic distribution. Thromb Haemost 87: 493–501PubMedGoogle Scholar
  35. 35.
    Kolev K, Machovich R (2003) Molecular and cellular modulation of fibrinolysis. Thromb Haemost 89: 610–621PubMedGoogle Scholar
  36. 36.
    Carmeliet P, Moons L, Ploplis V, Plow E, Collen D (1997) Impaired arterial neointima formation in mice with disruption of the plasminogen gene. J Clin Invest 99: 200–208PubMedCrossRefGoogle Scholar
  37. 37.
    Carmeliet P, Moons L, Herbert JM, Crawley J, Lupu F, Lijnen R, Collen D (1997) Urokinase but not tissue plasminogen activator mediates arterial neointima formation in mice. Circ Res 81: 829–839PubMedGoogle Scholar
  38. 38.
    Quax PH, Lamfers ML, Lardenoye JH, Grimbergen JM, de Vries MR, Slomp J, de Ruiter MC, Kockx MM, Verheijen JH, van Hinsbergh VW (2001) Adenoviral expression of a urokinase receptor-targeted protease inhibitor inhibits neointima formation in murine and human blood vessels. Circulation 103: 562–569PubMedGoogle Scholar
  39. 39.
    Schafer K, Konstantinides S, Riedel C, Thinnes T, Muller K, Dellas C, Hasenfuss G, Loskutoff DJ (2002) Different mechanisms of increased luminal stenosis after arterial injury in mice deficient for urokinase-or tissue-type plasminogen activator. Circulation 106: 1847–1852PubMedCrossRefGoogle Scholar
  40. 40.
    Bansal DD, Klein MR, Hausmann EHS, MacGregor RR (1997) Secretion of cardiac plasminogen activator during hypoxia-induced right ventricular hypertrophy. J Mol Cell Cardiol 29: 310563114CrossRefGoogle Scholar
  41. 41.
    Graham CH, Fitzpatrick TE, McCrae KR (1998) Hypoxia stimulates urokinase receptor expression through a heme protein-dependent pathway. Blood 91: 3300–3307PubMedGoogle Scholar
  42. 42.
    Pinsky DJ, Liao H, Lawson CA, Yan SF, Chen J, Carmeliet P, Loskutoff DJ, Stern DM (1998) Coordinated induction of plasminogen activator inhibitor-1 (PAI-1) and inhibition of plasminogen activator gene expression by hypoxia promotes pulmonary vascular fibrin deposition. J Clin Invest 102: 919–928PubMedCrossRefGoogle Scholar
  43. 43.
    Saksela O, Rifkin DB (1990) Release of basic fibroblast growth factor-heparan sulfate complexes from endothelial cells by plasminogen activator-mediated proteolytic activity. J Cell Biol 110: 767–775PubMedCrossRefGoogle Scholar
  44. 44.
    Overall CM, Lopez-Otin C (2002) Strategies for MMP inhibition in cancer: innovations for the post-trial era. Nat Rev Cancer 2: 657–672PubMedCrossRefGoogle Scholar
  45. 45.
    Nagase H (1997) Activation mechanisms of matrix metalloproteinases. Biol Chem 378: 151–160PubMedGoogle Scholar
  46. 46.
    Okada Y, Nakanishi I (1989) Activation of matrix metalloproteinase 3 (stromelysin) and matrix metalloproteinase 2 (‘gelatinase’) by human neutrophil elastase and cathepsin G. FEBS Lett 249: 353–356PubMedCrossRefGoogle Scholar
  47. 47.
    Butler GS, Butler MJ, Atkinson SJ, Will H, Tamura T, Schade van Westrum S, Crabbe T, Clements J, d’Ortho M-P, Murphy G (1998) The TIMP-2-MT1 MMP ‘receptor’ regulates the concentration and efficient activation of progelatinase A. A kinetic study. J Biol Chem 273: 871–880PubMedCrossRefGoogle Scholar
  48. 48.
    Brew K, Dinakarpandian D, Nagase H (2000) Tissue inhibitors of metalloproteinases: evolution, structure and function. Biochim Biophys Acta 1477: 267–283PubMedGoogle Scholar
  49. 49.
    Hoegy SE, Oh HR, Corcoran ML, Stetler-Stevenson WG (2001) Tissue inhibitor of metalloproteinases-2 (TIMP-2) suppresses TKR-growth factor signaling independent of metalloproteinase inhibition. J Biol Chem 276: 3203–3214PubMedCrossRefGoogle Scholar
  50. 50.
    Frisdal E, Gest V, Vieillard-Baron A, Levame M, Lepetit H, Eddahibi S, Lafuma C, Harf A, Adnot S, Dortho MP (2001) Gelatinase expression in pulmonary arteries during experimental pulmonary hypertension. Eur Respir J 18: 838–845PubMedCrossRefGoogle Scholar
  51. 51.
    Thakker-Varia S, Tozzi CA, Poiani GJ, Barbiaz JP, Tatem L, Wilson FJ, Riley DJ (1998) Expression of matrix degrading enzymes in pulmonary vascular remodeling in the rat. Am J Physiol (Lung Cell Mol Physiol 19) 275: L398–L406PubMedGoogle Scholar
  52. 52.
    Tozzi CA, Thakker-Varia S, Shiu YY, Bannett RF, Peng BW, Poiani GJ, Wilson FJ, Riley DJ (1998) Mast cell colagenase correlates with regression of pulmonary vascular remodeling in the rat. Am J Respir Cell Mol Biol 18: 497–510PubMedGoogle Scholar
  53. 53.
    Vieillard-Baron A, Frisdal E, Eddahibi S, Deprez I, Baker AH, Newby AC, Berger P, Levame M, Raffestin B, Adnot S et al (2000) Inhibition of matrix metalloproteinases by lung TIMP-1 gene transfer or doxycycline aggravates pulmonary hypertension in rats. Circ Res 87: 418–425PubMedGoogle Scholar
  54. 54.
    Levi M, Moons L, Bouche A, Shapiro SD, Collen D, Carmeliet P (2001) Deficiency of urokinase-type plasminogen activator-mediated plasmin generation impairs vascular remodeling during hypoxia-induced pulmonary hypertension in mice. Circulation 103: 2014–2020PubMedGoogle Scholar
  55. 55.
    Partovian C, Adnot S, Eddahibi S, Teiger E, Levame M, Dreyfus P, Raffestin B, Frelin C (1998) Heart and lung VEGF mRNA expression in rats with monocrotaline-or hypoxia-induced pulmonary hypertension. Am J Physiol 275: H1948–1956PubMedGoogle Scholar
  56. 56.
    Partovian C, Adnot S, Raffestin B, Louzier V, Levame M, Mavier IM, Lemarchand P, Eddahibi S (2000) Adenovirus-mediated lung vascular endothelial growth factor overexpression protects against hypoxic pulmonary hypertension in rats. Am J Respir Cell Mol Biol 23: 762–771PubMedGoogle Scholar
  57. 57.
    Cowan K, Heilbut A, Humpl T, Lam C, Ito S, Rabinovitch M (2000) Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor. Nat Med 6: 698–702PubMedCrossRefGoogle Scholar
  58. 58.
    Vieillard-Baron A, Frisdal E, Raffestin B, Baker AH, Eddahibi S, Adnot S, D’Ortho MP (2003) Inhibition of matrix metalloproteinases by lung TIMP-1 gene transfer limits monocrotaline-induced pulmonary vascular remodeling in rats. Hum Gene Ther 14: 861–869PubMedCrossRefGoogle Scholar
  59. 59.
    Miyazono K, Maeda S, Imamura T (2005) BMP receptor signaling: transcriptional targets, regulation of signals, and signaling cross-talk. Cytokine Growth Factor Rev 16: 251–263PubMedCrossRefGoogle Scholar
  60. 60.
    Massague J, Chen YG (2000) Controlling TGF-beta signaling. Genes Dev 14: 627–644PubMedGoogle Scholar
  61. 61.
    Rosenzweig BL, Imamura T, Okadome T, Cox GN, Yamashita H, ten Dijke P, Heldin CH, Miyazono K (1995) Cloning and characterization of a human type II receptor for bone morphogenetic proteins. Proc Natl Acad Sci USA 92: 7632–7636PubMedCrossRefGoogle Scholar
  62. 62.
    Takahashi H, Goto N, Kojima Y, Tsuda Y, Morio Y, Muramatsu M, Fukuchi Y (2006) Downregulation of type II bone morphogenetic protein receptor in hypoxic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 290: L450–458PubMedCrossRefGoogle Scholar
  63. 63.
    Morty RE, Nejman B, Kwapiszewska G, Hecker M, Zakrzewicz A, Kouri FM, Peters DM, Dumitrascu R, Seeger W, Knaus P et al (2007) Dysregulated bone morphogenetic protein signaling in monocrotaline-induced pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol 27: 1072–1078PubMedCrossRefGoogle Scholar
  64. 64.
    Deng H, Makizumi R, Ravikumar TS, Dong H, Yang W, Yang WL (2007) Bone morphogenetic protein-4 is overexpressed in colonic adenocarcinomas and promotes migration and invasion of HCT116 cells. Exp Cell Res 313: 1033–1044PubMedCrossRefGoogle Scholar
  65. 65.
    Lepetit H, Eddahibi S, Fadel E, Frisdal E, Munaut C, Noel A, Humbert M, Adnot S, D’Ortho MP, Lafuma C (2005) Smooth muscle cell matrix metalloproteinases in idiopathic pulmonary arterial hypertension. Eur Respir J 25: 834–842PubMedCrossRefGoogle Scholar
  66. 66.
    Matsui K, Takano Y, Yu ZX, Hi JE, Stetler-Stevenson WG, Travis WD, Ferrans VJ (2002) Immunohistochemical study of endothelin-1 and matrix metalloproteinases in plexogenic pulmonary arteriopathy. Pathol Res Pract 198: 403–412PubMedCrossRefGoogle Scholar
  67. 67.
    Delclaux C, d’Ortho M-P, Delacourt C, Lebargy F, Brun-Buisson C, Brochard L, Lemaire F, Lafuma C, Harf A (1997) Gelatinase in epithelial lining fluid of patients with adult respiratory distress syndrome. Am J Physiol (Lung Cell Mol Physiol 16) 272: L442–L451PubMedGoogle Scholar
  68. 68.
    Kondoh Y, Tanagushi H, Taki F, Takagi K, Satake T (1992) 7S collagen in bronchoalveolar lavage fluid of patients with adult respiratory distress syndrome. Chest 101: 1091–1094PubMedCrossRefGoogle Scholar
  69. 69.
    Emonard H, Hornebeck W (1997) Binding of 92 kDa and 72 kDa progelatinases to insoluble elastin modulates their proteolytic activation. Biol Chem 378: 265–271PubMedCrossRefGoogle Scholar
  70. 70.
    Uzui H, Lee JD, Shimizu H, Tsutani H, Ueda T (2000) The role of protein-tyrosine phosphorylation and gelatinase production in the migration and proliferation of smooth muscle cells. Atherosclerosis 149: 51–59PubMedCrossRefGoogle Scholar
  71. 71.
    Dorfmuller P, Perros F, Balabanian K, Humbert M (2003) Inflammation in pulmonary arterial hypertension. Eur Respir J 22: 358–363PubMedCrossRefGoogle Scholar
  72. 72.
    Frid MG, Brunetti JA, Burke DL, Carpenter TC, Davie NJ, Reeves JT, Roedersheimer MT, van Rooijen N, Stenmark KR (2006) Hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage. Am J Pathol 168: 659–669PubMedCrossRefGoogle Scholar
  73. 73.
    Frid MG, Brunetti JA, Burke DL, Carpenter TC, Davie NJ, Stenmark KR (2005) Circulating mononuclear cells with a dual, macrophage-fibroblast phenotype contribute robustly to hypoxia-induced pulmonary adventitial remodeling. Chest 128: 583S–584SPubMedCrossRefGoogle Scholar
  74. 74.
    Zhao YD, Courtman DW, Deng Y, Kugathasan L, Zhang Q, Stewart DJ (2005) 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 96: 442–450PubMedCrossRefGoogle Scholar
  75. 75.
    Barbera JA, Peinado VI, Santos S (2003) Pulmonary hypertension in chronic obstructive pulmonary disease. Eur Respir J 21: 892–905PubMedCrossRefGoogle Scholar
  76. 76.
    Peinado VI, Barbera JA, Abate P, Ramirez J, Roca J, Santos S, Rodriguez-Roisin R (1999) Inflammatory reaction in pulmonary muscular arteries of patients with mild chronic obstructive pulmonary disease. Am J Respir Crit Care Med 159: 1605–1611PubMedGoogle Scholar
  77. 77.
    Peinado VI, Ramirez J, Roca J, Rodriguez-Roisin R, Barbera JA (2006) Identification of vascular progenitor cells in pulmonary arteries of patients with chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 34: 257–263PubMedCrossRefGoogle Scholar
  78. 78.
    Santos S, Peinado VI, Ramirez J, Morales-Blanhir J, Bastos R, Roca J, Rodriguez-Roisin R, Barbera JA (2003) Enhanced expression of vascular endothelial growth factor in pulmonary arteries of smokers and patients with moderate chronic obstructive pulmonary disease. Am J Respir Crit Care Med 167: 1250–1256PubMedCrossRefGoogle Scholar
  79. 79.
    Shapiro S (1994) Elastolytic metalloproteinases produced by human mononuclear phagocytes. Potential roles in destructive lung disease. Am J Respir Crit Care Med 150: S160–164PubMedGoogle Scholar
  80. 80.
    Weiss SJ, Peppin GJ (1986) Collagenolytic metalloenzymes of the human neutrophil: characteristics, regulation and potential function in vivo. Biochem Pharmacol 35: 3189–3197PubMedCrossRefGoogle Scholar
  81. 81.
    Kazes I, Elalamy I, Sraer JD, Hatmi M, Nguyen G (2000) Platelet release of trimolecular complex components MT1-MMP/TIMP2/MMP2: involvement in MMP2 activation and platelet aggregation. Blood 96: 3064–3069PubMedGoogle Scholar
  82. 82.
    Sawicki G, Salas E, Murat J, Miszta Lane H, Radomski MW (1997) Release of gelatinase A during platelet activation mediates aggregation. Nature 386: 616–619PubMedCrossRefGoogle Scholar
  83. 83.
    Koolwijk P, Sidenius N, Peters E, Sier CF, Hanemaaijer R, Blasi F, van Hinsbergh VW (2001) Proteolysis of the urokinase-type plasminogen activator receptor by metalloproteinase-12: implication for angiogenesis in fibrin matrices. Blood 97: 3123–3131PubMedCrossRefGoogle Scholar
  84. 84.
    Bendeck MP, Zempo N, Clowes AW, Galardy RE, Reidy MA (1994) Smooth muscle cell migration and matrix metalloproteinase expression after arterial injury in the rat. Circ Res 75: 539–545PubMedGoogle Scholar
  85. 85.
    Zaidi SH, You XM, Ciura S, Husain M, Rabinovitch M (2002) Overexpression of the serine elastase inhibitor elafin protects transgenic mice from hypoxic pulmonary hypertension. Circulation 105: 516–521PubMedCrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag Basel/Switzerland 2008

Authors and Affiliations

  • Marie-Pia d’Ortho
    • 1
    • 2
    • 3
  1. 1.Unité U841, IRBM, Département Foie-Coeur-Poumon, équipe 6INSERMFrance
  2. 2.Faculté de Médecine, IFR10Université Paris 12France
  3. 3.AP-HP, Groupe Henri Mondor — Albert ChennevierService de Physiologie — Explorations FonctionnellesCréteilFrance

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