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Impairment and Differential Expression of PR3 and MPO on Peripheral Myelomonocytic Cells with Endothelial Properties in Granulomatosis with Polyangiitis

DOI: 10.1155/2012/715049

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Background. Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are autoimmune-mediated diseases characterized by vasculitic inflammation of respiratory tract and kidneys. Clinical observations indicated a strong association between disease activity and serum levels of certain types of autoantibodies (antineutrophil cytoplasm antibodies with cytoplasmic [cANCA in GPA] or perinuclear [pAN CA in MPA] immunofluorescence). Pathologically, both diseases are characterized by severe microvascular endothelial cell damage. Early endothelial outgrowth cells (eEOCs) have been shown to be critically involved in neovascularization under both physiological and pathological condition. Objectives. The principal aims of our study were (i) to analyze the regenerative activity of the eEOC system and (ii) to determine mPR3 and MPO expression in myelo monocytic cells with endothelial characteristics in GPA and MPA patients. Methods. In 27 GPA and 10 MPA patients, regenerative activity blood-derived eEOCs were analyzed using a culture-forming assay. Flk-1+, CD133+/Flk-1+, mPR3+, and Flk-1+/mPR3+ myelomonocytic cells were quantified by FACS analysis. Serum levels of Angiopoietin-1 and TNF- were measured by ELISA. Results. We found reduced eEOC regeneration, accompanied by lower serum levels of Angiopoietin-1 in GPA patients as compared to healthy controls. In addition, the total numbers of Flk-1+ myelomonocytic cells in the peripheral circulation were decreased. Membrane PR3 expression was significantly higher in total as well as in Flk-1+ myelomonocytic cells. Expression of MPO was not different between the groups. Conclusions. These data suggest impairment of the eEOC system and a possible role for PR3 in this process in patients suffering from GPA. 1. Introduction Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are autoimmune diseases characterized by systemic necrotizing vasculitis mainly affecting the respiratory tract and the kidneys [1]. Histopathological analysis reveals severe structural alterations of microvascular endothelial cells, leading to impaired microcirculation in skin, joints, respiratory tract, and kidneys, respectively. Endothelial damage has been suggested to result from interactions between primed neutrophils and ANCA with the endothelium followed by endothelial detachment from the basement membrane [2]. A number of different studies showed increased levels of both, circulating mature endothelial cells and endothelial microparticles in GPA and MPA [3, 4]. Thus, patients with GPA and MPA suffer from


[1]  G. C. Godman and J. Churg, “Wegener's granulomatosis: pathology and review of the literature,” A. M. A. Archives of Pathology, vol. 58, no. 6, pp. 533–553, 1954.
[2]  B. E. P. B. Ballieux, K. T. Zondervan, P. Kievit et al., “Binding of proteinase 3 and myeloperoxidase to endothelial cells: ANCA-mediated endothelial damage through ADCC?” Clinical and Experimental Immunology, vol. 97, no. 1, pp. 52–60, 1994.
[3]  A. Woywodt, C. Goldberg, T. Kirsch et al., “Circulating endothelial cells in relapse and limited granulomatous disease due to ANCA associated vasculitis,” Annals of the Rheumatic Diseases, vol. 65, no. 2, pp. 164–168, 2006.
[4]  S. Ohlsson, T. Hellmark, K. Pieters, G. Sturfelt, J. Wieslander, and M. Segelmark, “Increased monocyte transcription of the proteinase 3 gene in small vessel vasculitis,” Clinical and Experimental Immunology, vol. 141, no. 1, pp. 174–182, 2005.
[5]  T. Asahara, T. Murohara, A. Sullivan et al., “Isolation of putative progenitor endothelial cells for angiogenesis,” Science, vol. 275, no. 5302, pp. 964–967, 1997.
[6]  T. Asahara, H. Masuda, T. Takahashi et al., “Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization,” Circulation Research, vol. 85, no. 3, pp. 221–228, 1999.
[7]  A. Y. Khakoo and T. Finkel, “Endothelial progenitor cells,” Annual Review of Medicine, vol. 56, pp. 79–101, 2005.
[8]  D. Patschan, M. Plotkin, and M. S. Goligorsky, “Therapeutic use of stem and endothelial progenitor cells in acute renal injury: ?a ira,” Current Opinion in Pharmacology, vol. 6, no. 2, pp. 176–183, 2006.
[9]  C. Urbich and S. Dimmeler, “Endothelial progenitor cells: characterization and role in vascular biology,” Circulation Research, vol. 95, no. 4, pp. 343–353, 2004.
[10]  C. Urbich and S. Dimmeler, “Endothelial progenitor cells: functional characterization,” Trends in Cardiovascular Medicine, vol. 14, no. 8, pp. 318–322, 2004.
[11]  J. Case, L. E. Mead, W. K. Bessler et al., “Human CD34+AC133+VEGFR-2+ cells are not endothelial progenitor cells but distinct, primitive hematopoietic progenitors,” Experimental Hematology, vol. 35, no. 7, pp. 1109–1118, 2007.
[12]  M. C. Yoder, L. E. Mead, D. Prater et al., “Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals,” Blood, vol. 109, no. 5, pp. 1801–1809, 2007.
[13]  K. De Groot, C. Goldberg, F. H. Bahlmann et al., “Vascular endothelial damage and repair in antineutrophil cytoplasmic antibody-associated vasculitis,” Arthritis and Rheumatism, vol. 56, no. 11, pp. 3847–3853, 2007.
[14]  J. Závada, L. Kideryová, R. Pytlík, Z. Vaňková, and V. Tesa?, “Circulating endothelial progenitor cells in patients with ANCA-associated vasculitis,” Kidney and Blood Pressure Research, vol. 31, no. 4, pp. 247–254, 2008.
[15]  J. D. Finkielman, P. A. Merkel, D. Schroeder et al., “Antiproteinase 3 antineutrophil cytoplasmic antibodies and disease activity in Wegener granulomatosis,” Annals of Internal Medicine, vol. 147, no. 9, pp. 611–619, 2007.
[16]  N. Hu, J. Westra, and C. G. M. Kallenberg, “Membrane-bound proteinase 3 and its receptors: relevance for the pathogenesis of Wegener's Granulomatosis,” Autoimmunity Reviews, vol. 8, no. 6, pp. 510–514, 2009.
[17]  P. Lamprecht, “New pathogenetic aspects in primary systemic vasculitides,” Internist, vol. 50, no. 3, pp. 291–297, 2009.
[18]  A. Wikman, A. Fagergren, S. G. O. Johansson, J. Lundahl, and S. H. Jacobson, “Monocyte activation and relationship to anti-proteinase 3 in acute vasculitis,” Nephrology Dialysis Transplantation, vol. 18, no. 9, pp. 1792–1799, 2003.
[19]  R. Y. Leavitt, A. S. Fauci, D. A. Bloch et al., “The American College of Rheumatology 1990 criteria for the classification of Wegener's granulomatosis,” Arthritis and Rheumatism, vol. 33, no. 8, pp. 1101–1107, 1990.
[20]  R. A. Luqmani, P. A. Bacon, R. J. Moots et al., “Birmingham Vasculitis Activity Score (BVAS) in systemic necrotizing vasculitis,” Quarterly Journal of Medicine, vol. 87, no. 11, pp. 671–678, 1994.
[21]  L. Somogyi, N. Cikes, and M. Marusic, “Evaluation of criteria contributions for the classification of systemic lupus erythematosus,” Scandinavian Journal of Rheumatology, vol. 22, no. 2, pp. 58–62, 1993.
[22]  C. Bombardier, D. D. Gladman, M. B. Urowitz, D. Caron, and Chi Hsing Chang, “Derivation of the SLEDAI: a disease activity index for lupus patients,” Arthritis and Rheumatism, vol. 35, no. 6, pp. 630–640, 1992.
[23]  D. W. Cockcroft and M. H. Gault, “Prediction of creatinine clearance from serum creatinine,” Nephron, vol. 16, no. 1, pp. 31–41, 1976.
[24]  D. Patschan, K. Krupincza, S. Patschan, Z. Zhang, C. Hamby, and M. S. Goligorsky, “Dynamics of mobilization and homing of endothelial progenitor cells after acute renal ischemia: modulation by ischemic preconditioning,” American Journal of Physiology, vol. 291, no. 1, pp. F176–F185, 2006.
[25]  P. Romagnani, F. Annunziato, F. Liotta et al., “CD14+ cells with stem cell phenotypic and functional features are the major source of circulating endothelial progenitors,” Circulation Research, vol. 97, no. 4, pp. 314–322, 2005.
[26]  D. Patschan, S. Patschan, J. T. Wessels et al., “Epac-1 activator 8-O-cAMP augments renoprotective effects of allogeneic murine EPCs in acute ischemic kidney injury,” American Journal of Physiology, vol. 298, no. 1, pp. F78–F85, 2010.
[27]  D. Patschan, S. Patschan, E. Henze, J. T. Wessels, M. Koziolek, and G. A. Müller, “LDL lipid apheresis rapidly increases peripheral endothelial progenitor cell competence,” Journal of Clinical Apheresis, vol. 24, no. 5, pp. 180–185, 2009.
[28]  K. De Groot, F. H. Bahlmann, J. Sowa et al., “Uremia causes endothelial progenitor cell deficiency,” Kidney International, vol. 66, no. 2, pp. 641–646, 2004.
[29]  S. Fukuhara, K. Sako, K. Noda, J. Zhang, M. Minami, and N. Mochizuki, “Angiopoietin-1/Tie2 receptor signaling in vascular quiescence and angiogenesis,” Histology and Histopathology, vol. 25, no. 3, pp. 387–396, 2010.
[30]  F. Chen, Z. Tan, C. Dong et al., “Combination of VEGF165/Angiopoietin-1 gene and endothelial progenitor cells for therapeutic neovascularization,” European Journal of Pharmacology, vol. 568, no. 1–3, pp. 222–230, 2007.
[31]  S. Brachemi, A. Mambole, F. Fakhouri et al., “Increased membrane expression of proteinase 3 during neutrophil adhesion in the presence of anti-proteinase 3 antibodies,” Journal of the American Society of Nephrology, vol. 18, no. 8, pp. 2330–2339, 2007.
[32]  I. Kurth, K. Franke, T. Pompe, M. Bornh?user, and C. Werner, “Hematopoietic stem and progenitor cells in adhesive microcavities,” Integrative Biology, vol. 1, no. 5-6, pp. 427–434, 2009.
[33]  B. Schlechta, D. Wiedemann, C. Kittinger et al., “Ex-vivo expanded umbilical cord blood stem cells retain capacity for myocardial regeneration,” Circulation Journal, vol. 74, no. 1, pp. 188–194, 2010.
[34]  A. Tárnok, H. Ulrich, and J. Bocsi, “Phenotypes of stem cells from diverse origin,” Cytometry Part A, vol. 77, no. 1, pp. 6–10, 2010.
[35]  P. Kümpers, S. David, M. Haubitz et al., “The Tie2 receptor antagonist angiopoietin 2 facilitates vascular inflammation in systemic lupus erythematosus,” Annals of the Rheumatic Diseases, vol. 68, no. 10, pp. 1638–1643, 2009.
[36]  N. A. Abdel-Malak, M. Mofarrahi, D. Mayaki, L. M. Khachigian, and S. N. A. Hussain, “Early growth response-1 regulates angiopoietin-1-induced endothelial cell proliferation, migration, and differentiation,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 29, no. 2, pp. 209–216, 2009.
[37]  N. Acquavella, M. F. Quiroga, O. Wittig, and J. E. Cardier, “Effect of simvastatin on endothelial cell apoptosis mediated by Fas and TNF-α,” Cytokine, vol. 49, no. 1, pp. 45–50, 2010.
[38]  F. Wang, H. M. Liu, M. G. Irwin et al., “Role of protein kinase C β2 activation in TNF-α-induced human vascular endothelial cell apoptosis,” Canadian Journal of Physiology and Pharmacology, vol. 87, no. 3, pp. 221–229, 2009.
[39]  X. Wu, R. Guo, P. Chen, Q. Wang, and P. N. Cunningham, “TNF induces caspase-dependent inflammation in renal endothelial cells through a rho- and myosin light chain kinase-dependent mechanism,” American Journal of Physiology, vol. 297, no. 2, pp. F316–F326, 2009.
[40]  Z. Xia, T. Luo, H. M. Liu et al., “L-arginine enhances nitrative stress and exacerbates tumor necrosis factor-α toxicity to human endothelial cells in culture: prevention by propofol,” Journal of Cardiovascular Pharmacology, vol. 55, no. 4, pp. 358–367, 2010.
[41]  P. Lamprecht, J. Holle, and W. L. Gross, “Update on clinical, pathophysiological and therapeutic aspects in ANCA-associated vasculitides,” Current Drug Discovery Technologies, vol. 6, no. 4, pp. 241–251, 2009.
[42]  E. Mauro, G. M. Rigolin, C. Fraulini et al., “Mobilization of endothelial progenitor cells in patients with hematological malignancies after treatment with filgrastim and chemotherapy for autologous transplantation,” European Journal of Haematology, vol. 78, no. 5, pp. 374–380, 2007.
[43]  J. Grisar, D. Aletaha, C. W. Steiner et al., “Endothelial progenitor cells in active rheumatoid arthritis: effects of tumour necrosis factor and glucocorticoid therapy,” Annals of the Rheumatic Diseases, vol. 66, no. 10, pp. 1284–1288, 2007.
[44]  J. U. Holle, Q. J. Wu, F. Moosig, W. L. Gross, and E. Csernok, “Membrane proteinase 3 (mPR3) expression on neutrophils is not increased in localised Wegener's granulomatosis (WG) and Churg-Strauss syndrome (CSS),” Clinical and Experimental Rheumatology, vol. 28, no. 1, pp. S46–S50, 2010.
[45]  D. Patschan, S. Patschan, and G. A. Muller, “Endothelial progenitor cells in acute ischemic kidney injury: strategies for increasing the cells' renoprotective competence,” International Journal of Nephrology, vol. 2011, Article ID 828369, 7 pages, 2011.
[46]  S. Y. Schubert, A. Benarroch, J. Monter-Solans, and E. R. Edelman, “Monocyte activation state regulates monocyte-induced endothelial proliferation through Met signaling,” Blood, vol. 115, no. 16, pp. 3407–3412, 2010.
[47]  C. Kantari, M. Pederzoli-Ribeil, O. Amir-Moazami et al., “Proteinase 3, the Wegener autoantigen, is externalized during neutrophil apoptosis: evidence for a functional association with phospholipid scramblase 1 and interference with macrophage phagocytosis,” Blood, vol. 110, no. 12, pp. 4086–4095, 2007.
[48]  E. C. Hagen, B. E. P. B. Ballieux, L. A. Van Es, M. R. Daha, and F. J. Van der Woude, “Antineutrophil cytoplasmic autoantibodies: a review of the antigens involved, the assays, and the clinical and possible pathogenetic consequences,” Blood, vol. 81, no. 8, pp. 1996–2002, 1993.
[49]  F. J. Van Der Woude, M. R. Daha, and L. A. Van Es, “The current status of neutrophil cytoplasmic antibodies,” Clinical and Experimental Immunology, vol. 78, no. 2, pp. 143–148, 1989.
[50]  F. J. Van der Woude, E. Schrama, L. A. Van Es, F. J. H. Claas, and M. R. Daha, “The role of unconventional alloantigens in interstitial and vascular rejection after renal transplantation,” Transplant Immunology, vol. 2, no. 4, pp. 271–277, 1994.
[51]  W. F. Pendergraft, E. H. Rudolph, R. J. Falk et al., “Proteinase 3 sidesteps caspases and cleaves p21Waf1/Cip1/Sdi1 to induce endothelial cell apoptosis,” Kidney International, vol. 65, no. 1, pp. 75–84, 2004.
[52]  J. J. Yang, R. Kettritz, R. J. Falk, J. C. Jennette, and M. L. Gaido, “Apoptosis of endothelial cells induced by the neutrophil serine proteases proteinase 3 and elastase,” American Journal of Pathology, vol. 149, no. 5, pp. 1617–1626, 1996.


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