Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Fibrosing vasculitis in Wegener's granulomatosis: ultrastructural and immunohistochemical analysis of the vascular lesions

  • 29 Accesses

  • 13 Citations


This study of two cases of pulmonary Wegener's granulomatosis (WG) focuses on the ultrastructural aspects of the vascular wall injury and on the immunohistochemical characterization of the perivascular connective matrix. The iterative waves of endothelial cell necrosis and regeneration are demonstrated by the multiplamellar appearance of the basal lamina. Neutrophils infiltrate the vessel wall and myofibroblasts are recruited to injured vessels. The perivascular connective matrix associates basement-membrane like and fibrillar material with fibrin deposits. The initiation of the fibrosing process was assessed by the visualization of matrix molecules involved in targeting (p-fibronectin), organizing (cellular fibronectin and tenascin) and stabilizing (lysyl-oxidase) the fibrogenic activity. These elementary lesions affect different levels of the vascular tree, and capillaritis is involved in the extension of the pathological process. Lysyl-oxidase labelling reveals the fibrosing front which is located on the border of dense fibrosis. The markers of fibrosing activity disappear in the areas of fibrosis following vasculitis and/or ischaemic necrosis and/or granulomatosis. Vasculitis plays a major role in both the genesis and progression of the fibrosis observed in the late stage of WG.

This is a preview of subscription content, log in to check access.


  1. 1.

    Adler KB, Low RB, Leslie KO, Mitchell J, Evans JN (1989) Contractile cells in normal and fibrotic lung. Lab Invest 60:473–482

  2. 2.

    Aufderheide E, Ekblom P (1988) Tenascin during gut development: appearance in the mesenchyme, shift in molecular forms, and dependence on epithelial-mesenchymal interactions. J Cell Biol 107:2341–2349

  3. 3.

    Aufderheide E, Chiquet-Ehrismann R, Ekblom P (1987) Epithelial mesenchymal interactions in the developing kidney lead to expression of tenascin in the mesenchyme. J Cell Biol 105:599–608

  4. 4.

    Baltaro RJ, Hoffman GS, Sechler JMG, Suffredini AF, Shelhamer JH, Fauci AS, Fleisher TA (1991) Immunoglobulin G antineutrophil cytoplasmic antibodies are produced in the respiratory tract of patients with Wegener's granulomatosis. Am Rev Respir Dis 143:275–278

  5. 5.

    Beer DJ (1992) ANCAs a weigh. Am Rev Respir Dis 146:1128–1130

  6. 6.

    Bosch X, Font J, Mirapeix E, Revert L, Ingelmo M, Urbano-Marquez A (1992) Antimyeloperoxidase autoantibody-associated necrotizing alveolar capillaritis. Am Rev Respir Dis 146:1326–1329

  7. 7.

    Brasile L, Kremer JM, Clarke JL, Cerilli J (1989) Identification of an autoantibody to vascular endothelial cell-specific antigens in patients with systemic vasculitis. Am J Med 87:74–80

  8. 8.

    Braun MG, Csernok E, Gross WL, Muller-Hermelink HK (1991) Proteinase 3, the target antigen of anticytoplasmic antibodies circulating in Wegener's granulomatosis: immunolocalisation in normal and pathologic tissues. Am J Pathol 139:831–838

  9. 9.

    Carrington CB, Liebow AA (1966) Limited form of angeitis and granulomatosis of Wegener's type. Am J Med 41:497–527

  10. 10.

    Chiquet-Ehrismann R, Mackie EJ, Pearson CA, Sakakura T (1986) Tenascin: an extracellular matrix protein involved in tissue interactions during fetal development and oncogenesis. Cell 47:131–139

  11. 11.

    Chuong CM, Chen HM (1991) Exhausted expression of neural cell adhesion molecules and tenascin (cytotactin) during would healing. Am J Pathol 138:427–440

  12. 12.

    Colby TV (1989) Diffuse pulmonary haemorrhage in Wegener's granulomatosis. Semin Respir Med 10:136–140

  13. 13.

    Cordier JF, Valeyre D, Guillevin L, Loire R, Brechot JM (1990) Pulmonary Wegener's granulomatosis. A clinical and imaging study of 77 cases. Chest 97:906–912

  14. 14.

    Csernok H, Lüdemann J, Gross WL, Bainton D (1990) Ultrastructural localization of proteinase 3, the target antigen of anti-cytoplasmic antibodies circulating in Wegener's granulomatosis. Am J Pathol 137:1113–1120

  15. 15.

    DeRemee RA, McDonald TJ, Harrison EG Jr, Coles DT (1976) Wegener's granulomatosis anatomic correlates: a proposed classification. Mayo Clin Proc 51:777–781

  16. 16.

    Donald KJ, Edwards RL, McEvoy JDS (1976) An ultrastructural study of the pathogenesis of tissue injury in limited Wegener's granulomatosis. Pathology 8:161–169

  17. 17.

    Falk RJ, Terell RS, Charles LA, Jennette JC (1990) Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc Natl Acad Sci USA 87:4115–4119

  18. 18.

    Fauci AS, Wolff SM (1973) Wegener's granulomatosis: studies in eighteen patients and a review of literature. Medicine (Baltimore) 52:535–561

  19. 19.

    Fienberg R (1989) Morphological and immunohistologic study of the evolution of the necrotizing palisading granuloma of pathergic (Wegener's) granulomatosis. Semin Respir Med 10:126–132

  20. 20.

    Grinnel F, Feld M, Minter D (1980) Fibroblast adhesion to fibrinogen and fibrin: Requirement for cold insoluble globulin (plasma fibronectin). Cell 19:517–525

  21. 21.

    Gross WL (1989) Wegener's granulomatosis. Sarcoidosis 6:15–29

  22. 22.

    Harrison DJ, Simpson R, Khaebanda R, Abernethy VE, Nimmo G (1989) Antibodies to neutrophil cytoplasmic antigens in Wegener's granulomatosis and other conditions. Thorax 44:373–377

  23. 23.

    Haudenschild CC, Schwartz SM (1979) Endothelial regeneration. II. Restitution of endothelial continuity. Lab Invest 41:405–418

  24. 24.

    Huttner I, Walker C, Gabbiani G (1985) Aortic endothelial cell during regeneration. Remodeling of cell junctions, stress fibers, and stress-fiber membrane attachment domains. Lab Invest 53:287–302

  25. 25.

    Hynes RO (1990) Expression of fibronectins by cells in culture. In: Rich A (ed) Fibronectins. Springer, New York Berlin Heidelberg, pp 65–67

  26. 26.

    Hynes RO (1990) Fibronectin biosynthesis and fibrillogenesis. The role of the cells. In: Rich A (ed) Fibronectins. Springer, New York Berlin Heidelberg, pp 192–194

  27. 27.

    Idell S, James KK, Gillies C, Fair DS, Thrall RS (1989) Abnormalities of pathways of fibrin turnover in lung lavage of rats with oleic acid and bleomycin-induced lung injury support alveolar fibrin deposition. Am J Pathol 135:387–399

  28. 28.

    Imayama S, Ikawa T, Urabe H (1986) Basal lamina of the dermal capillary; concentric multilamination following regeneration processes. J Dermatol 13:456–459

  29. 29.

    Jenne DE (1990) Wegener's autoantigen decoded. Nature 346:520

  30. 30.

    Kagan HM, Trackman PC (1991) Properties and function of lysyl-oxidase. Am J Respir Cell Mol Biol 5:206–210

  31. 31.

    Kelley J (1990) Cytokines of the lung. Am Rev Respir Dis 14:765–788

  32. 32.

    Koch M, Wehrle-Haller B, Baumgartner S, Spring J, Brubacher D, Chiquet M (1991) Epithelial synthesis of tenascin at tips of growing bronchi and graded accumulation in basement membrane and mesenchyme. Exp cell Res 194:297–300

  33. 33.

    Koukoulis GK, Gould VE, Bhattacharyya A, Gould JE, Howeedy AA, Virtanen I (1991) Tenascin in normal, reactive, hyperplastic and neoplastic tissues: biologic and pathologic implications. Hum Pathol 22:636–643

  34. 34.

    Kovacs E (1991) Fibrogenic cytokines: The role of immune mediators in the development of scar tissue. Immunol Today 12:17–23

  35. 35.

    Lien DC, Henson PM, Capen RL, Henson JE, Hanson WL, Wagner WW, Worthen GS (1991) Neutrophil kinetics in the pulmonary microcirculation during acute inflammation. Lab Invest 65:145–159

  36. 36.

    Lightner VA, Gumkowski F, Bigner DD, Erickson HP (1989) Tenascin/Hexabrachion in human skin: biochemical identification and localization by light and electron microscopy. J Cell Biol 108:2483–2493

  37. 37.

    Limper AH, Roman J (1992) Fibronectin: a versatile matrix protein with roles in thoracic development, repair and infection. Chest 101:1663–1673

  38. 38.

    Mackie EJ, Halfer W, Liverani D (1988) Induction of tenascin in healing wounds. J Cell Biol 107:2757–2767

  39. 39.

    Malik AB, Horgan MJ (1987) Mechanisms of thrombin-induced lung vascular injury and edema. Am Rev Respir Dis 136:467–470

  40. 40.

    Mark EJ, Matsubara O, Tan-Liu NS, Fienberg R (1988) The pulmonary biopsy in the early diagnosis of Wegener's (pathergic) granulomatosis. A study based on 35 open lung biopsies. Hum Pathol 19:1065–1071

  41. 41.

    Movat HZ, Wasi S (1985) Severe microvascular injury by lysosomal releasates of human polymorphonuclear leukocytes. Am J Pathol 121:404–417

  42. 42.

    Nölle B, Specks U, Lüdemann J, Rohrbach MS, DeRemee RA, Gross WL (1989) Anticytoplasmic autoantibodies: their immunodiagnostic value in Wegener granulomatosis. Ann Intern Med 111:28–40

  43. 43.

    Peyrol S, Takiya C, Cordier JF, Grimaud JA (1986) Organization of the connective matrix of the sarcoid granuloma: evolution and cell-matrix interactions. Tenth international conference on sarcoidosis and other granulomatous disorder. Ann NY Acad Sci 465:268–285

  44. 44.

    Peyrol S, Cordier JF, Grimaud JA (1990) Intra-alveolar fibrosis of idiopathic bronchiolitis obliterans-organizing pneumonia: cell-matrix patterns. Am J Pathol 137:155–170

  45. 45.

    Reidy MA, Schwartz SM (1981) Endothelial regeneration. III. Time course of intimal changes after small defined injury to rat aortic endothelium. Lab Invest 44:301–308

  46. 46.

    Rennard SI, Hunninghake GW, Bitterman PB, Crystal RG (1985) Production of fibronectin by the human alveolar macrophage: mechanism for recruitment of fibroblasts to sites of tissue injury in interstitial lung diseases. Proc Natl Acad Sci USA 78:7147–7151

  47. 47.

    Sappino AP, Schürch W, Gabbiani G (1990) Differentiation repertoire of fibroblastic cells: expression of cytoskeletal proteins as marker of phenotypic modulations. Lab Invest 63:144–161

  48. 48.

    Savage COS, Pottinger BE, Gaskin G, Pusey CD, Pearson JD (1992) Autoantibodies developing to myeloperoxidase and proteinase 3 in systemic vasculitis stimulate neutrophil cytotoxicity toward cultured endothelial cells. Am J Pathol 141:335–342

  49. 49.

    Schwarz MI, Mortenson RL, Colby TV, Waldron JA, Lynch JA, Hutt MP, Cherniack M, King TE (1993) Pulmonary capillaritis: the association with progressive irreversible airflow limitation and hyperinflation. Am Rev Respir Dis 148:507–511

  50. 50.

    Sommer P, Gleyzal C, Raccurt M, Delbourg M, Serrar M, Joazeiro P, Peyrol S, Kagan H, Trackman PC, Grimaud JA (1993) Transient expression of lysyl-oxidase by liver myofibroblasts in murine schistosomiasis. Lab Invest 69:460–470

  51. 51.

    Specks U, DeRemee R (1989) Significance of antibodies to cytoplasmic components of neutrophils. Thorax 44:369–379

  52. 52.

    Takiya C, Peyrol S, Cordier JF, Grimaud JA (1983) Connective matrix organization in human pulmonary fibrosis. Virchows Arch [B] 44:223–240

  53. 53.

    Tan EML, Glassberg E, Olsen DR, Noveral JP, Unger GA, Peltonen J, Chu ML, Levine E, Sollberg S (1991) Extracellular matrix gene expression by human endothelial and smooth muscle cells. Matrix 11:380–387

  54. 54.

    Travis WD, Hoffman GS, Leavitt RY, Pass HI, Fauci A (1991) Surgical pathology of the lung in Wegener's granulomatosis. Am J Surg Pathol 15:315–333

  55. 55.

    Vracko R, Benditt EP (1970) Capillary basal lamina thickening: Its relationship to endothelial cell death and replacement. J Cell Biol 47:281–291

  56. 56.

    Wegener F (1936) Über generalisierte, septische Gefäßerkrankungen. Verh Dtsch Pathol Ges 29:202–210

  57. 57.

    Weiss SJ (1989) Tissue destruction by neutrophils. N Engl J Med 320:365–376

  58. 58.

    Whitby DJ, Longaker MT, Harrison MR, Adzick NS, Ferguson MW (1991) Rapid epithelialisation of fetal wounds is associated with the early deposition of tenascin. J Cell Sci 99:583–586

  59. 59.

    Wolff SM, Fauci AS, Horn RG, Dale DC (1974) Wegener's granulomatosis. Ann Intern Med 81:513–525

  60. 60.

    Woods A, Couchman JR (1988) Focal adhesions and cell-matrix interactions. Col Rel Res 8:155–182

  61. 61.

    Worthen GS, Haslett C, Rees AJ, Gumbay RS, Henson JE, Henson PM (1987) Neutrophil-mediated pulmonary vascular injury. Am Rev Respir Dis 136:19–28

  62. 62.

    Yoshikawa Y, Watanabe T (1986) Pulmonary lesions in Wegener's granulomatosis: a clinico-pathologic study of 22 autopsy cases. Hum Pathol 17:401–410

Download references

Author information

Correspondence to S. Peyrol.

Additional information

Work supported by a grant of the Association pour la Recherche sur le Cancer (ARC 2057)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Gindre, D., Loire, R., Peyrol, S. et al. Fibrosing vasculitis in Wegener's granulomatosis: ultrastructural and immunohistochemical analysis of the vascular lesions. Vichows Archiv A Pathol Anat 427, 385–393 (1995). https://doi.org/10.1007/BF00199387

Download citation

Key words

  • Wegener's granulomatosis
  • Vasculitis
  • Fibrosis