Advertisement

The Role of Fibrocytes in Lung Repair and Fibrosis

  • Ellen C. Keeley
  • Borna Mehrad
  • Robert M. StrieterEmail author
Chapter
  • 575 Downloads
Part of the Stem Cell Biology and Regenerative Medicine book series (STEMCELL)

Abstract

Regeneration and fibrosis are integral parts of the recovery from tissue injury, and impaired regulation of these mechanisms is a hallmark of many chronic diseases. Traditionally, resident tissue fibroblasts have been thought to proliferate and mediate local fibrosis. However, more recently, data suggest that a circulating bone-marrow-derived progenitor cell, the fibrocyte, plays a critical role in the repair of injured tissue in a diverse set of disease states, including fibrotic lung disease. In this chapter, we describe the unique characteristics of fibrocytes, how they are recruited to the site of lung injury, and experimental results supporting their pivotal role in lung repair and fibrosis.

Keywords

Fibrocytes Pulmonary fibrosis Asthma Hypoxia 

References

  1. 1.
    Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol 2008; 214:199–210.PubMedCrossRefGoogle Scholar
  2. 2.
    Fukuda Y, Ishizaki M, Masuda Y, Kimura G, Kawanami O, and Masugi Y. The role of intraalveolar fibrosis in the process of pulmonary structural remodeling in patients with diffuse alveolar damage. Am J Pathol 1987; 1(26):171–182.Google Scholar
  3. 3.
    Marshall R, Bellingan G, and Laurent G. The acute respiratory distress syndrome: fibrosis in the fast lane. Thorax 1998; 53:815–817.PubMedCrossRefGoogle Scholar
  4. 4.
    Iwano M, Plieth D, Danoff TM, Xue C, Okada H, and Neilson EG. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest 2002; 110:341–350.PubMedGoogle Scholar
  5. 5.
    Kalluri R, and Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest 2003; 112:1776–1784.PubMedGoogle Scholar
  6. 6.
    Kim KK, Kugler MC, Wolters PJ, Robillard L, Galvez MG, Brumwell AN, Sheppard D, and Chapman HA. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci USA 2006; 103:13180–13185.PubMedCrossRefGoogle Scholar
  7. 7.
    Abe R, Donnelly SC, Peng T, Bucala R, and Metz CN. Peripheral blood fibrocytes: differentiation pathway and migration to wound sites. J Immunol 2001; 166:7556–7562.PubMedGoogle Scholar
  8. 8.
    Bucala R, Spiegel LA, Chesney J, Hogan M, and Cerami A. Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol Med 1994; 1:71–81.PubMedGoogle Scholar
  9. 9.
    Metz CN. Fibrocytes: a unique cell population implicated in wound healing. Cell Mol Life Sci 2003; 60:1342–1350.PubMedCrossRefGoogle Scholar
  10. 10.
    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.Google Scholar
  11. 11.
    Bucala R. Circulating fibrocytes: cellular basis for NSF. J Am Coll Radiol 2008; 5:36–39.PubMedCrossRefGoogle Scholar
  12. 12.
    Phillips RJ, Burdick MD, Hong K, Lutz MA, Murray LA, Xue YY, Belperio JA, Keane MP, and Strieter RM. Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. J Clin Invest 2004; 114:438–446.PubMedGoogle Scholar
  13. 13.
    Quan TE, Cowper S, Wu SP, Bockenstedt LK, and Bucala R. Circulating fibrocytes: collagen-secreting cells of the peripheral blood. Int J Biochem Cell Biol 2004; 36:598–606.PubMedCrossRefGoogle Scholar
  14. 14.
    Mehrad B, Burdick MD, Zisman DA, Keane MP, Belperio JA, and Strieter RM. Circulating peripheral blood fibrocytes in human fibrotic interstitial lung disease. Biochem Biophys Res Commun 2007; 353:104–108.PubMedCrossRefGoogle Scholar
  15. 15.
    Andersson-Sjoland A, de Alba CG, Nihlberg K, Becerril C, Ramirez R, Pardo A, Westergren-Thorsson G, and Selman M. Fibrocytes are a potential source of lung fibroblasts in idiopathic pulmonary fibrosis. Int J Biochem Cell Biol 2008; 40:2129–2140.PubMedCrossRefGoogle Scholar
  16. 16.
    Aiba S, and Tagami H. Inverse correlation between CD34 expression and proline-4-hydroxylase immunoreactivity on spindle cells noted in hypertrophic scars and keloids. J Cutan Pathol 1997; 24:65–69.PubMedCrossRefGoogle Scholar
  17. 17.
    Pilling D, Buckley CD, Salmon M, and Gomer RH. Inhibition of fibrocyte differentiation by serum amyloid P. J Immunol 2003; 171:5537–5546.PubMedGoogle Scholar
  18. 18.
    Pilling D, Tucker NM, and Gomer RH. Aggregated IgG inhibits the differentiation of human fibrocytes. J Leukoc Biol 2006; 79:1242–1251.PubMedCrossRefGoogle Scholar
  19. 19.
    Strieter RM, Gomperts BN, and Keane MP. The role of CXC chemokines in pulmonary fibrosis. J Clin Invest 2007; 117:549–556.PubMedCrossRefGoogle Scholar
  20. 20.
    Yang L, Scott PG, Giuffre J, Shankowsky HA, Ghahary A, and Tredget EE. Peripheral blood fibrocytes from burn patients: identification and quantification of fibrocytes in adherent cells cultured from peripheral blood mononuclear cells. Lab Invest 2002; 82:1183–1192.PubMedGoogle Scholar
  21. 21.
    Ebihara Y, Masuya M, Larue AC, Fleming PA, Visconti RP, Minamiguchi H, Drake CJ, and Ogawa M. Hematopoietic origins of fibroblasts: II. In vitro studies of fibroblasts, CFU-F, and fibrocytes. Exp Hematol 2006; 34:219–229.PubMedCrossRefGoogle Scholar
  22. 22.
    Schmidt M, Sun G, Stacey MA, Mori L, and Mattoli S. Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma. J Immunol 2003; 171:380–389.PubMedGoogle Scholar
  23. 23.
    Varcoe RL, Mikhail M, Guiffre AK, Pennings G, Vicaretti M, Hawthorne WJ, Fletcher JP, and Medbury HJ. The role of the fibrocyte in intimal hyperplasia. J Thromb Haemost 2006; 4:1125–1133.PubMedCrossRefGoogle Scholar
  24. 24.
    Gordon S, and Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol 2005; 5:953–964.PubMedCrossRefGoogle Scholar
  25. 25.
    Tacke F, and Randolph GJ. Migratory fate and differentiation of blood monocyte subsets. Immunobiology 2006; 211:609–618.PubMedCrossRefGoogle Scholar
  26. 26.
    Bellini A, and Mattoli S. The role of the fibrocyte, a bone marrow-derived mesenchymal progenitor, in reactive and reparative fibroses. Lab Invest 2007; 87:858–870.PubMedCrossRefGoogle Scholar
  27. 27.
    Balmelli C, Ruggli N, McCullough K, and Summerfield A. Fibrocytes are potent stimulators of anti-virus cytotoxic T cells. J Leukoc Biol 2005; 77:923–933.PubMedCrossRefGoogle Scholar
  28. 28.
    Chesney J, Bacher M, Bender A, and Bucala R. The peripheral blood fibrocyte is a potent antigen-presenting cell capable of priming naive T cells in situ. Proc Natl Acad Sci USA 1997; 94:6307–6312.PubMedCrossRefGoogle Scholar
  29. 29.
    Chesney J, Metz C, Stavitsky AB, Bacher M, and Bucala R. Regulated production of type I collagen and inflammatory cytokines by peripheral blood fibrocytes. J Immunol 1998; 160:419–425.PubMedGoogle Scholar
  30. 30.
    Hong KM, Belperio JA, Keane MP, Burdick MD, and Strieter RM. Differentiation of human circulating fibrocytes as mediated by transforming growth factor-beta and peroxisome proliferator-activated receptor gamma. J Biol Chem 2007; 282:22910–22920.PubMedCrossRefGoogle Scholar
  31. 31.
    Hong KM, Burdick MD, Phillips RJ, Heber D, and Strieter RM. Characterization of human fibrocytes as circulating adipocyte progenitors and the formation of human adipose tissue in SCID mice. FASEB J 2005; 19:2029–2031.PubMedGoogle Scholar
  32. 32.
    Mori L, Bellini A, Stacey MA, Schmidt M, and Mattoli S. Fibrocytes contribute to the myofibroblast population in wounded skin and originate from the bone marrow. Exp Cell Res 2005; 304:81–90.PubMedCrossRefGoogle Scholar
  33. 33.
    Mehrad B, Burdick MD, and Strieter RM. Fibrocyte CXCR4 regulation as a therapeutic target in pulmonary fibrosis. Int J Biochem Cell Biol 2009; 41:1708–1718.PubMedCrossRefGoogle Scholar
  34. 34.
    Chauhan H, Abraham A, Phillips JR, Pringle JH, Walker RA, and Jones JL. There is more than one kind of myofibroblast: analysis of CD34 expression in benign, in situ, and invasive breast lesions. J Clin Pathol 2003; 56:271–276.PubMedCrossRefGoogle Scholar
  35. 35.
    Shao DD, Suresh R, Vakil V, Gomer RH, and Pilling D. Pivotal Advance: Th-1 cytokines inhibit, and Th-2 cytokines promote fibrocyte differentiation. J Leukoc Biol 2008; 83:1323–1333.PubMedCrossRefGoogle Scholar
  36. 36.
    Abdollahi A, Li M, Ping G, Plathow C, Domhan S, Kiessling F, Lee LB, McMahon G, Grone HJ, Lipson KE, and Huber PE. Inhibition of platelet-derived growth factor signaling attenuates pulmonary fibrosis. J Exp Med 2005; 201:925–935.PubMedCrossRefGoogle Scholar
  37. 37.
    Antoniades HN, Bravo MA, Avila RE, Galanopoulos T, Neville-Golden J, Maxwell M, and Selman M. Platelet-derived growth factor in idiopathic pulmonary fibrosis. J Clin Invest 1990; 86:1055–1064.PubMedCrossRefGoogle Scholar
  38. 38.
    Aston C, Jagirdar J, Lee TC, Hur T, Hintz RL, and Rom WN. Enhanced insulin-like growth factor molecules in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1995; 151:1597–1603.PubMedGoogle Scholar
  39. 39.
    Yasuoka H, Jukic DM, Zhou Z, Choi AM, and Feghali-Bostwick CA. Insulin-like growth factor binding protein 5 induces skin fibrosis: a novel murine model for dermal fibrosis. Arthritis Rheum 2006; 54:3001–3010.PubMedCrossRefGoogle Scholar
  40. 40.
    Hartlapp I, Abe R, Saeed RW, Peng T, Voelter W, Bucala R, and Metz CN. Fibrocytes induce an angiogenic phenotype in cultured endothelial cells and promote angiogenesis in vivo. FASEB J 2001; 15:2215–2224.PubMedCrossRefGoogle Scholar
  41. 41.
    Moore BB, Kolodsick JE, Thannickal VJ, Cooke K, Moore TA, Hogaboam C, Wilke CA, and Toews GB. CCR2-mediated recruitment of fibrocytes to the alveolar space after fibrotic injury. Am J Pathol 2005; 166:675–684.PubMedCrossRefGoogle Scholar
  42. 42.
    Murdoch C. CXCR4: chemokine receptor extraordinaire. Immunol Rev 2000; 177:175–184.PubMedCrossRefGoogle Scholar
  43. 43.
    Epperly MW, Guo H, Gretton JE, and Greenberger JS. Bone marrow origin of myofibroblasts in irradiation pulmonary fibrosis. Am J Respir Cell Mol Biol 2003; 29:213–224.PubMedCrossRefGoogle Scholar
  44. 44.
    Ortiz LA, Gambelli F, McBride C, Gaupp D, Baddoo M, Kaminski N, and Phinney DG. Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci USA 2003; 100:8407–8411.PubMedCrossRefGoogle Scholar
  45. 45.
    Rojas M, Xu J, Woods CR, Mora AL, Spears W, Roman J, and Brigham KL. Bone marrow-derived mesenchymal stem cells in repair of the injured lung. Am J Respir Cell Mol Biol 2005; 33:145–152.PubMedCrossRefGoogle Scholar
  46. 46.
    Adamson IY, and Bowden DH. The type 2 cell as progenitor of alveolar epithelial regeneration. A cytodynamic study in mice after exposure to oxygen. Lab Invest 1974; 30:35–42.PubMedGoogle Scholar
  47. 47.
    Chandler DB. Possible mechanisms of bleomycin-induced fibrosis. Clin Chest Med 1990; 11:21–30.PubMedGoogle Scholar
  48. 48.
    Moore BB, Murray L, Das A, Wilke CA, Herrygers AB, and Toews GB. The role of CCL12 in the recruitment of fibrocytes and lung fibrosis. Am J Respir Cell Mol Biol 2006; 35:175–181.PubMedCrossRefGoogle Scholar
  49. 49.
    McMillan TR, Moore BB, Weinberg JB, Vannella KM, Fields WB, Christensen PJ, van Dyk LF, and Toews GB. Exacerbation of established pulmonary fibrosis in a murine model by gammaherpesvirus. Am J Respir Crit Care Med 2008; 177:771–780.PubMedCrossRefGoogle Scholar
  50. 50.
    Sakai N, Wada T, Yokoyama H, Lipp M, Ueha S, Matsushima K, and Kaneko S. Secondary lymphoid tissue chemokine (SLC/CCL21)/CCR7 signaling regulates fibrocytes in renal fibrosis. Proc Natl Acad Sci USA 2006; 103:14098–14103.PubMedCrossRefGoogle Scholar
  51. 51.
    Moeller A, Gilpin SE, Ask K, Cox G, Cook D, Gauldie J, Margetts PJ, Farkas L, Dobranowski J, Boylan C, O’Byrne PM, Strieter RM, and Kolb M. Circulating fibrocytes are an indicator of poor prognosis in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2009; 179:588–594.PubMedCrossRefGoogle Scholar
  52. 52.
    Phillips RJ, Mestas J, Gharaee-Kermani M, Burdick MD, Sica A, Belperio JA, Keane MP, and Strieter RM. Epidermal growth factor and hypoxia-induced expression of CXC chemokine receptor 4 on non-small cell lung cancer cells is regulated by the phosphatidylinositol 3-kinase/PTEN/AKT/mammalian target of rapamycin signaling pathway and activation of hypoxia inducible factor-1alpha. J Biol Chem 2005; 280:22473–22481.PubMedCrossRefGoogle Scholar
  53. 53.
    Staller P, Sulitkova J, Lisztwan J, Moch H, Oakeley EJ, and Krek W. Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL. Nature 2003; 425:307–311.PubMedCrossRefGoogle Scholar
  54. 54.
    Harrison JS, Rameshwar P, Chang V, and Bandari P. Oxygen saturation in the bone marrow of healthy volunteers. Blood 2002; 99:394.PubMedCrossRefGoogle Scholar
  55. 55.
    Parmar K, Mauch P, Vergilio JA, Sackstein R, and Down JD. Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proc Natl Acad Sci USA 2007; 104:5431–5436.PubMedCrossRefGoogle Scholar
  56. 56.
    Schioppa T, Uranchimeg B, Saccani A, Biswas SK, Doni A, Rapisarda A, Bernasconi S, Saccani S, Nebuloni M, Vago L, Mantovani A, Melillo G, and Sica A. Regulation of the chemokine receptor CXCR4 by hypoxia. J Exp Med 2003; 198:1391–1402.PubMedCrossRefGoogle Scholar
  57. 57.
    Nihlberg K, Larsen K, Hultgardh-Nilsson A, Malmstrom A, Bjermer L, and Westergren-Thorsson G. Tissue fibrocytes in patients with mild asthma: a possible link to thickness of reticular basement membrane? Respir Res 2006; 7:50.PubMedCrossRefGoogle Scholar
  58. 58.
    Kaur D, Saunders R, Berger P, Siddiqui S, Woodman L, Wardlaw A, Bradding P, and Brightling CE. Airway smooth muscle and mast cell-derived CC chemokine ligand 19 mediate airway smooth muscle migration in asthma. Am J Respir Crit Care Med 2006; 174:1179–1188.PubMedCrossRefGoogle Scholar
  59. 59.
    Wang CH, Huang CD, Lin HC, Lee KY, Lin SM, Liu CY, Huang KH, Ko YS, Chung KF, and Kuo HP. Increased circulating fibrocytes in asthma with chronic airflow obstruction. Am J Respir Crit Care Med 2008; 178:583–591.PubMedCrossRefGoogle Scholar
  60. 60.
    Saunders R, Siddiqui S, Kaur D, Doe C, Sutcliffe A, Hollins F, Bradding P, Wardlaw A, and Brightling CE. Fibrocyte localization to the airway smooth muscle is a feature of asthma. J Allergy Clin Immunol 2009; 123:376–384.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Ellen C. Keeley
    • 1
  • Borna Mehrad
    • 2
  • Robert M. Strieter
    • 2
    Email author
  1. 1.Division of Cardiology, Department of MedicineUniversity of VirginiaCharlottesvilleUSA
  2. 2.Division of Pulmonary and Critical Care Medicine, Department of MedicineUniversity of VirginiaCharlottesvilleUSA

Personalised recommendations