Skip to main content
PMC home page
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1991 May;138(5):1257–1265.

The roles of the myofibroblast in idiopathic pulmonary fibrosis. Ultrastructural and immunohistochemical features of sites of active extracellular matrix synthesis.

C Kuhn 1, J A McDonald 1
PMCID: PMC1886011  PMID: 2024710

Abstract

The synthesis of collagen and EIIIA-containing cellular fibronectin in certain forms of pulmonary fibrosis occurs in discrete locations: in the Masson bodies in bronchiolitis obliterans with organizing pneumonia and in focal clusters of fibroblasts (fibroblastic foci) within airspaces in usual interstitial pneumonia. These sites were examined by electron microscopy and immunohistochemistry using antibodies against cytoskeletal markers and extracellular matrix components in biopsies from three patients with bronchiolitis obliterans with organizing pneumonia and four patients with usual interstitial pneumonia. Fibroblasts of both Masson bodies and fibroblastic foci expressed vimentin and alpha smooth muscle actin but not desmin, distinguishing them from true smooth muscle. In both structures fibroblasts with well-formed actin filament bundles were aligned parallel to one another, enmeshed in a matrix of fibronectin-containing fibrils (microtendons) that linked cells and collagen bundles. Similar features characterize the phase of contraction during the healing of skin wounds. This suggests that active contractions of fibroblasts plays a role in the remodeling of the lung in pulmonary fibrosis.

Full text

PDF
1258

Images in this article

1259Figure 1
on p.1259
1260Figure 2
on p.1260
1261Figure 3
on p.1261
1262Figure 4
on p.1262
1263Figure 5
on p.1263
1263Figure 6
on p.1263

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adler K. B., Low R. B., Leslie K. O., Mitchell J., Evans J. N. Contractile cells in normal and fibrotic lung. Lab Invest. 1989 Apr;60(4):473–485. [PubMed] [Google Scholar]
  2. Akiyama S. K., Yamada S. S., Chen W. T., Yamada K. M. Analysis of fibronectin receptor function with monoclonal antibodies: roles in cell adhesion, migration, matrix assembly, and cytoskeletal organization. J Cell Biol. 1989 Aug;109(2):863–875. doi: 10.1083/jcb.109.2.863. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Basset F., Ferrans V. J., Soler P., Takemura T., Fukuda Y., Crystal R. G. Intraluminal fibrosis in interstitial lung disorders. Am J Pathol. 1986 Mar;122(3):443–461. [PMC free article] [PubMed] [Google Scholar]
  4. Baur P. S., Jr, Parks D. H. The myofibroblast anchoring strand--the fibronectin connection in wound healing and the possible loci of collagen fibril assembly. J Trauma. 1983 Oct;23(10):853–862. doi: 10.1097/00005373-198310000-00001. [DOI] [PubMed] [Google Scholar]
  5. Burkhardt A. Alveolitis and collapse in the pathogenesis of pulmonary fibrosis. Am Rev Respir Dis. 1989 Aug;140(2):513–524. doi: 10.1164/ajrccm/140.2.513. [DOI] [PubMed] [Google Scholar]
  6. Clark R. A., Folkvord J. M., Hart C. E., Murray M. J., McPherson J. M. Platelet isoforms of platelet-derived growth factor stimulate fibroblasts to contract collagen matrices. J Clin Invest. 1989 Sep;84(3):1036–1040. doi: 10.1172/JCI114227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Darby I., Skalli O., Gabbiani G. Alpha-smooth muscle actin is transiently expressed by myofibroblasts during experimental wound healing. Lab Invest. 1990 Jul;63(1):21–29. [PubMed] [Google Scholar]
  8. Davison A. G., Heard B. E., McAllister W. A., Turner-Warwick M. E. Cryptogenic organizing pneumonitis. Q J Med. 1983 Summer;52(207):382–394. [PubMed] [Google Scholar]
  9. Debus E., Weber K., Osborn M. Monoclonal antibodies to desmin, the muscle-specific intermediate filament protein. EMBO J. 1983;2(12):2305–2312. doi: 10.1002/j.1460-2075.1983.tb01738.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Duband J. L., Nuckolls G. H., Ishihara A., Hasegawa T., Yamada K. M., Thiery J. P., Jacobson K. Fibronectin receptor exhibits high lateral mobility in embryonic locomoting cells but is immobile in focal contacts and fibrillar streaks in stationary cells. J Cell Biol. 1988 Oct;107(4):1385–1396. doi: 10.1083/jcb.107.4.1385. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Epler G. R., Colby T. V., McLoud T. C., Carrington C. B., Gaensler E. A. Bronchiolitis obliterans organizing pneumonia. N Engl J Med. 1985 Jan 17;312(3):152–158. doi: 10.1056/NEJM198501173120304. [DOI] [PubMed] [Google Scholar]
  12. Evans J. N., Kelley J., Low R. B., Adler K. B. Increased contractility of isolated lung parenchyma in an animal model of pulmonary fibrosis induced by bleomycin. Am Rev Respir Dis. 1982 Jan;125(1):89–94. doi: 10.1164/arrd.1982.125.1.89. [DOI] [PubMed] [Google Scholar]
  13. Ffrench-Constant C., Van de Water L., Dvorak H. F., Hynes R. O. Reappearance of an embryonic pattern of fibronectin splicing during wound healing in the adult rat. J Cell Biol. 1989 Aug;109(2):903–914. doi: 10.1083/jcb.109.2.903. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Fukuda Y., Ferrans V. J., Schoenberger C. I., Rennard S. I., Crystal R. G. Patterns of pulmonary structural remodeling after experimental paraquat toxicity. The morphogenesis of intraalveolar fibrosis. Am J Pathol. 1985 Mar;118(3):452–475. [PMC free article] [PubMed] [Google Scholar]
  15. Fukuda Y., Ishizaki M., Masuda Y., Kimura G., Kawanami O., Masugi Y. The role of intraalveolar fibrosis in the process of pulmonary structural remodeling in patients with diffuse alveolar damage. Am J Pathol. 1987 Jan;126(1):171–182. [PMC free article] [PubMed] [Google Scholar]
  16. Harris A. K., Stopak D., Wild P. Fibroblast traction as a mechanism for collagen morphogenesis. Nature. 1981 Mar 19;290(5803):249–251. doi: 10.1038/290249a0. [DOI] [PubMed] [Google Scholar]
  17. Hsu S. M., Raine L., Fanger H. Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem. 1981 Apr;29(4):577–580. doi: 10.1177/29.4.6166661. [DOI] [PubMed] [Google Scholar]
  18. Hølund B., Clausen P. P., Clemmensen I. The influence of fixation and tissue preparation on the immunohistochemical demonstration of fibronectin in human tissue. Histochemistry. 1981;72(2):291–299. doi: 10.1007/BF00517142. [DOI] [PubMed] [Google Scholar]
  19. Kapanci Y., Assimacopoulos A., Irle C., Zwahlen A., Gabbiani G. "Contractile interstitial cells" in pulmonary alveolar septa: a possible regulator of ventilation-perfusion ratio? Ultrastructural, immunofluorescence, and in vitro studies. J Cell Biol. 1974 Feb;60(2):375–392. doi: 10.1083/jcb.60.2.375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Katzenstein A. L. Pathogenesis of "fibrosis" in interstitial pneumonia: an electron microscopic study. Hum Pathol. 1985 Oct;16(10):1015–1024. doi: 10.1016/s0046-8177(85)80279-3. [DOI] [PubMed] [Google Scholar]
  21. Kelley J. Cytokines of the lung. Am Rev Respir Dis. 1990 Mar;141(3):765–788. doi: 10.1164/ajrccm/141.3.765. [DOI] [PubMed] [Google Scholar]
  22. Khalil N., Bereznay O., Sporn M., Greenberg A. H. Macrophage production of transforming growth factor beta and fibroblast collagen synthesis in chronic pulmonary inflammation. J Exp Med. 1989 Sep 1;170(3):727–737. doi: 10.1084/jem.170.3.727. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kuhn C., 3rd, Boldt J., King T. E., Jr, Crouch E., Vartio T., McDonald J. A. An immunohistochemical study of architectural remodeling and connective tissue synthesis in pulmonary fibrosis. Am Rev Respir Dis. 1989 Dec;140(6):1693–1703. doi: 10.1164/ajrccm/140.6.1693. [DOI] [PubMed] [Google Scholar]
  24. Lazenby A. J., Crouch E. C., McDonald J. A., Kuhn C., 3rd Remodeling of the lung in bleomycin-induced pulmonary fibrosis in the rat. An immunohistochemical study of laminin, type IV collagen, and fibronectin. Am Rev Respir Dis. 1990 Jul;142(1):206–214. doi: 10.1164/ajrccm/142.1.206. [DOI] [PubMed] [Google Scholar]
  25. Martinet Y., Rom W. N., Grotendorst G. R., Martin G. R., Crystal R. G. Exaggerated spontaneous release of platelet-derived growth factor by alveolar macrophages from patients with idiopathic pulmonary fibrosis. N Engl J Med. 1987 Jul 23;317(4):202–209. doi: 10.1056/NEJM198707233170404. [DOI] [PubMed] [Google Scholar]
  26. McDonald J. A., Broekelmann T. J., Matheke M. L., Crouch E., Koo M., Kuhn C., 3rd A monoclonal antibody to the carboxyterminal domain of procollagen type I visualizes collagen-synthesizing fibroblasts. Detection of an altered fibroblast phenotype in lungs of patients with pulmonary fibrosis. J Clin Invest. 1986 Nov;78(5):1237–1244. doi: 10.1172/JCI112707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. McDonald J. A. Extracellular matrix assembly. Annu Rev Cell Biol. 1988;4:183–207. doi: 10.1146/annurev.cb.04.110188.001151. [DOI] [PubMed] [Google Scholar]
  28. Mitchell J., Woodcock-Mitchell J., Reynolds S., Low R., Leslie K., Adler K., Gabbiani G., Skalli O. Alpha-smooth muscle actin in parenchymal cells of bleomycin-injured rat lung. Lab Invest. 1989 May;60(5):643–650. [PubMed] [Google Scholar]
  29. Montesano R., Orci L. Transforming growth factor beta stimulates collagen-matrix contraction by fibroblasts: implications for wound healing. Proc Natl Acad Sci U S A. 1988 Jul;85(13):4894–4897. doi: 10.1073/pnas.85.13.4894. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Myers J. L., Katzenstein A. L. Epithelial necrosis and alveolar collapse in the pathogenesis of usual interstitial pneumonia. Chest. 1988 Dec;94(6):1309–1311. doi: 10.1378/chest.94.6.1309. [DOI] [PubMed] [Google Scholar]
  31. Myers J. L., Katzenstein A. L. Ultrastructural evidence of alveolar epithelial injury in idiopathic bronchiolitis obliterans-organizing pneumonia. Am J Pathol. 1988 Jul;132(1):102–109. [PMC free article] [PubMed] [Google Scholar]
  32. Oda D., Gown A. M., Vande Berg J. S., Stern R. Instability of the myofibroblast phenotype in culture. Exp Mol Pathol. 1990 Apr;52(2):221–234. doi: 10.1016/0014-4800(90)90007-z. [DOI] [PubMed] [Google Scholar]
  33. Osborn M., Debus E., Weber K. Monoclonal antibodies specific for vimentin. Eur J Cell Biol. 1984 May;34(1):137–143. [PubMed] [Google Scholar]
  34. Raghow B., Irish P., Kang A. H. Coordinate regulation of transforming growth factor beta gene expression and cell proliferation in hamster lungs undergoing bleomycin-induced pulmonary fibrosis. J Clin Invest. 1989 Dec;84(6):1836–1842. doi: 10.1172/JCI114369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Roman J., LaChance R. M., Broekelmann T. J., Kennedy C. J., Wayner E. A., Carter W. G., McDonald J. A. The fibronectin receptor is organized by extracellular matrix fibronectin: implications for oncogenic transformation and for cell recognition of fibronectin matrices. J Cell Biol. 1989 Jun;108(6):2529–2543. doi: 10.1083/jcb.108.6.2529. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Ryan G. B., Cliff W. J., Gabbiani G., Irlé C., Montandon D., Statkov P. R., Majno G. Myofibroblasts in human granulation tissue. Hum Pathol. 1974 Jan;5(1):55–67. doi: 10.1016/s0046-8177(74)80100-0. [DOI] [PubMed] [Google Scholar]
  37. Scharffetter K., Kulozik M., Stolz W., Lankat-Buttgereit B., Hatamochi A., Söhnchen R., Krieg T. Localization of collagen alpha 1(I) gene expression during wound healing by in situ hybridization. J Invest Dermatol. 1989 Sep;93(3):405–412. [PubMed] [Google Scholar]
  38. Singer I. I., Kawka D. W., Kazazis D. M., Clark R. A. In vivo co-distribution of fibronectin and actin fibers in granulation tissue: immunofluorescence and electron microscope studies of the fibronexus at the myofibroblast surface. J Cell Biol. 1984 Jun;98(6):2091–2106. doi: 10.1083/jcb.98.6.2091. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Singer I. I., Kawka D. W., McNally S. M., Eiermann G. J., Metzger J. M., Peterson L. B. Extensive laminin and basement membrane accumulation occurs at the onset of bleomycin-induced rodent pulmonary fibrosis. Am J Pathol. 1986 Nov;125(2):258–268. [PMC free article] [PubMed] [Google Scholar]
  40. Skalli O., Ropraz P., Trzeciak A., Benzonana G., Gillessen D., Gabbiani G. A monoclonal antibody against alpha-smooth muscle actin: a new probe for smooth muscle differentiation. J Cell Biol. 1986 Dec;103(6 Pt 2):2787–2796. doi: 10.1083/jcb.103.6.2787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Skalli O., Schürch W., Seemayer T., Lagacé R., Montandon D., Pittet B., Gabbiani G. Myofibroblasts from diverse pathologic settings are heterogeneous in their content of actin isoforms and intermediate filament proteins. Lab Invest. 1989 Feb;60(2):275–285. [PubMed] [Google Scholar]
  42. Tamkun J. W., DeSimone D. W., Fonda D., Patel R. S., Buck C., Horwitz A. F., Hynes R. O. Structure of integrin, a glycoprotein involved in the transmembrane linkage between fibronectin and actin. Cell. 1986 Jul 18;46(2):271–282. doi: 10.1016/0092-8674(86)90744-0. [DOI] [PubMed] [Google Scholar]
  43. Torikata C., Villiger B., Kuhn C., 3rd, McDonald J. A. Ultrastructural distribution of fibronectin in normal and fibrotic human lung. Lab Invest. 1985 Apr;52(4):399–408. [PubMed] [Google Scholar]
  44. Tsukada T., McNutt M. A., Ross R., Gown A. M. HHF35, a muscle actin-specific monoclonal antibody. II. Reactivity in normal, reactive, and neoplastic human tissues. Am J Pathol. 1987 May;127(2):389–402. [PMC free article] [PubMed] [Google Scholar]
  45. Vaccaro C. A., Brody J. S., Snider G. L. Alveolar wall basement membranes in bleomycin-induced pulmonary fibrosis. Am Rev Respir Dis. 1985 Oct;132(4):905–912. doi: 10.1164/arrd.1985.132.4.905. [DOI] [PubMed] [Google Scholar]
  46. Van der Meeren A., Levy F., Renier A., Katz A., Jaurand M. C. Effect of epidermal growth factor on rat pleural mesothelial cell growth. J Cell Physiol. 1990 Jul;144(1):137–143. doi: 10.1002/jcp.1041440118. [DOI] [PubMed] [Google Scholar]
  47. Vartio T., Laitinen L., Närvänen O., Cutolo M., Thornell L. E., Zardi L., Virtanen I. Differential expression of the ED sequence-containing form of cellular fibronectin in embryonic and adult human tissues. J Cell Sci. 1987 Nov;88(Pt 4):419–430. doi: 10.1242/jcs.88.4.419. [DOI] [PubMed] [Google Scholar]
  48. Welch M. P., Odland G. F., Clark R. A. Temporal relationships of F-actin bundle formation, collagen and fibronectin matrix assembly, and fibronectin receptor expression to wound contraction. J Cell Biol. 1990 Jan;110(1):133–145. doi: 10.1083/jcb.110.1.133. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

RESOURCES