Pericytes and T Cells in Lung Injury and Fibroproliferation

  • Alexander Birbrair
  • Pedro Henrique Dias Moura Prazeres
  • Daniel Clark Files
  • Osvaldo DelbonoEmail author
Part of the Molecular and Translational Medicine book series (MOLEMED)


The respiratory system is essentially an external organ, constantly exposed to the external environment. As such, it is in contact with any number of antigens and chemical agents that can injure the upper (nasal cavity, pharynx, and larynx) or lower (trachea, bronchi, and lungs) respiratory tract [1]. Injuries to the lung parenchyma are particularly harmful, as the parenchyma is the site of gas (oxygen and carbon dioxide) exchange. Acute or chronic injuries to the lung result in acute or chronic hypoxemic or hypercapnic respiratory failure, respectively. While there are several structural and pathologic mechanisms that contribute to respiratory failure, some lung injuries result in a progressive fibroproliferative response that leads to respiratory failure and death.


Pericytes T cells Lung injury Fibroproliferation 



This work was supported by grants from Pró-reitoria de Pesquisa/Universidade Federal de Minas Gerais (PRPq/UFMG) (Edital 05/2016) to AB and NIH/NIA (R01 AG13934-20) to OD.


The authors indicate no potential conflicts of interest.


  1. 1.
    Katzenstein A-LA, Myers JL. Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am J Respir Crit Care Med. 1998;157:1301–15.PubMedCrossRefGoogle Scholar
  2. 2.
    Matthay MA, Ware LB, Zimmerman GA. The acute respiratory distress syndrome. J Clin Invest. 2012;122:2731–40. Scholar
  3. 3.
    The, A. D. T. F. Acute respiratory distress syndrome: the berlin definition. JAMA. 2012;307:2526–33. Scholar
  4. 4.
    Noble PW, Barkauskas CE, Jiang D. Pulmonary fibrosis: patterns and perpetrators. J Clin Invest. 2012;122:2756–62. Scholar
  5. 5.
    Rubenfeld GD, et al. Incidence and outcomes of acute lung injury. N Engl J Med. 2005;353:1685–93. Scholar
  6. 6.
    Reynolds JH, In JHT t. In: Adam A, Dixon AK, Gillard JH, Schaefer-Prokop C, editors. Grainger & Allison’s diagnostic radiology. London: Churchill Livingstone/Elsevier; 2014. p. 363.Google Scholar
  7. 7.
    Crimlisk J. Lower respiratory problems. In: Ignatavicius DD, Workman ML, Rebar CR, editors. Medical-surgical nursing: assessment and management of clinical problems. 6th ed. St. Louis: Mosby; 2004. p. 592–636.Google Scholar
  8. 8.
    Nagase T, et al. Acute lung injury by sepsis and acid aspiration: a key role for cytosolic phospholipase A2. Nat Immunol. 2000;1:42–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Needham DM, et al. Improving long-term outcomes after discharge from intensive care unit: report from a stakeholders’ conference*. Crit Care Med. 2012;40:502–9. Scholar
  10. 10.
    Haslett C. Granulocyte apoptosis and its role in the resolution and control of lung inflammation. Am J Respir Crit Care Med. 1999;160:S5–S11.PubMedCrossRefGoogle Scholar
  11. 11.
    Strieter RM. What differentiates normal lung repair and fibrosis? Inflammation, resolution of repair, and fibrosis. Proc Am Thorac Soc. 2008;5:305–10.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Wynn TA. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest. 2007;117:524–9.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Rocco P, Dos Santos C, Pelosi P. Lung parenchyma remodeling in acute respiratory distress syndrome. Minerva Anestesiol. 2009;75:730–40.PubMedGoogle Scholar
  14. 14.
    Cabrera-Benitez NE, et al. Mechanical ventilation–associated lung fibrosis in acute respiratory distress syndrome a significant contributor to poor outcome. Anesthesiology. 2014;121:189–98. Scholar
  15. 15.
    Demedts M, et al. Interstitial lung diseases: an epidemiological overview. Eur Respir J. 2001;18:2s–16s.Google Scholar
  16. 16.
    King TE, Pardo A, Selman M. Idiopathic pulmonary fibrosis. Lancet. 2011;378:1949–61. Scholar
  17. 17.
    Noble PW. Idiopathic pulmonary fibrosis: natural history and prognosis. Clin Chest Med. 2006;27:11–6. Scholar
  18. 18.
    Martinez FJ, et al. The clinical course of patients with idiopathic pulmonary fibrosis. Ann Intern Med. 2005;142:963–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Meyer KC, Modi D. New treatments for idiopathic pulmonary fibrosis. Clin Pulm Med. 2016;23:241–51. Scholar
  20. 20.
    Zimmermann KW. Der feinere bau der blutcapillaren. Z Anat Entwicklungsgesch. 1923;68:29–109.CrossRefGoogle Scholar
  21. 21.
    Nag A. Study of non-muscle cells of the adult mammalian heart: a fine structural analysis and distribution. Cytobios. 1979;28:41–61.Google Scholar
  22. 22.
    Epling GP. Electron microscopic observations of pericytes of small blood vessels in the lungs and hearts of normal cattle and swine. Anat Rec. 1966;155:513–29.CrossRefGoogle Scholar
  23. 23.
    Gerhardt H, Betsholtz C. Endothelial-pericyte interactions in angiogenesis. Cell Tissue Res. 2003;314:15–23. Scholar
  24. 24.
    Hirschi KK, D’Amore PA. Pericytes in the microvasculature. Cardiovasc Res. 1996;32:687–98.PubMedCrossRefGoogle Scholar
  25. 25.
    Lv F-J, Tuan RS, Cheung K, Leung VY. Concise review: the surface markers and identity of human mesenchymal stem cells. Stem Cells. 2014;32:1408–19.PubMedCrossRefGoogle Scholar
  26. 26.
    Varela H, et al. Pericytes. Morphofunction, interactions and pathology in a quiescent and activated mesenchymal cell niche. Histol Histopathol. 2009;24:909–69.PubMedGoogle Scholar
  27. 27.
    Bandopadhyay R, et al. Contractile proteins in pericytes at the blood-brain and blood-retinal barriers. J Neurocytol. 2001;30:35–44.PubMedCrossRefGoogle Scholar
  28. 28.
    Shepro D, Morel N. Pericyte physiology. FASEB J Off Publ Fed Am Soc Exp Biol. 1993;7:1031–8.Google Scholar
  29. 29.
    Birbrair A, et al. Pericytes at the intersection between tissue regeneration and pathology. Clin Sci. 2015;128:81–93. Scholar
  30. 30.
    Sims DE. Diversity within pericytes. Clin Exp Pharmacol Physiol. 2000;27:842–6.PubMedCrossRefGoogle Scholar
  31. 31.
    Ligon KL, et al. Development of NG2 neural progenitor cells requires Olig gene function. Proc Natl Acad Sci. 2006;103:7853–8.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Lindahl P, Johansson BR, Leveen P, Betsholtz C. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science. 1997;277:242–5.PubMedCrossRefGoogle Scholar
  33. 33.
    Winkler EA, Bell RD, Zlokovic BV. Pericyte-specific expression of PDGF beta receptor in mouse models with normal and deficient PDGF beta receptor signaling. Mol Neurodegener. 2010;5:32. Scholar
  34. 34.
    Kunz J, Krause D, Kremer M, Dermietzel R. The 140-kDa protein of blood-brain barrier-associated pericytes is identical to aminopeptidase N. J Neurochem. 1994;62:2375–86.PubMedCrossRefGoogle Scholar
  35. 35.
    Ozerdem U, Grako KA, Dahlin-Huppe K, Monosov E, Stallcup WB. NG2 proteoglycan is expressed exclusively by mural cells during vascular morphogenesis. Dev Dyn Off Publ Am Assoc Anat. 2001;222:218–27. Scholar
  36. 36.
    Morikawa S, et al. Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am J Pathol. 2002;160:985–1000. Scholar
  37. 37.
    Bouchard BA, Shatos MA, Tracy PB. Human brain pericytes differentially regulate expression of procoagulant enzyme complexes comprising the extrinsic pathway of blood coagulation. Arterioscler Thromb Vasc Biol. 1997;17:1–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Ribatti D, Nico B, Crivellato E. The role of pericytes in angiogenesis. Int J Dev Biol. 2011;55:261–8.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Kim JA, et al. Brain endothelial hemostasis regulation by pericytes. J Cereb Blood Flow Metab. 2006;26:209–17.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Fisher M. Pericyte signaling in the neurovascular unit. Stroke. 2009;40:S13–5.PubMedCrossRefGoogle Scholar
  41. 41.
    Balabanov R, Washington R, Wagnerova J, Dore-Duffy P. CNS microvascular pericytes express macrophage-like function, cell surface integrin αM, and macrophage marker ED-2. Microvasc Res. 1996;52:127–42.PubMedCrossRefGoogle Scholar
  42. 42.
    Hasan M, Glees P. The fine structure of human cerebral perivascular pericytes and juxtavascular phagocytes: their possible role in hydrocephalic edema resolution. J Hirnforsch. 1989;31:237–49.Google Scholar
  43. 43.
    Jeynes B. Reactions of granular pericytes in a rabbit cerebrovascular ischemia model. Stroke. 1985;16:121–5.PubMedCrossRefGoogle Scholar
  44. 44.
    Balabanov R, Beaumont T, Dore-Duffy P. Role of central nervous system microvascular pericytes in activation of antigen-primed splenic T-lymphocytes. J Neurosci Res. 1999;55:578–87.PubMedCrossRefGoogle Scholar
  45. 45.
    Tu Z, et al. Retinal pericytes inhibit activated T cell proliferation. Invest Ophthalmol Vis Sci. 2011;52:9005–10.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Verbeek MM, Westphal JR, Ruiter DJ, De Waal R. T lymphocyte adhesion to human brain pericytes is mediated via very late antigen-4/vascular cell adhesion molecule-1 interactions. J Immunol. 1995;154:5876–84.PubMedGoogle Scholar
  47. 47.
    Raza A, Franklin MJ, Dudek AZ. Pericytes and vessel maturation during tumor angiogenesis and metastasis. Am J Hematol. 2010;85:593–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Sims DE. Recent advances in pericyte biology – implications for health and disease. Can J Cardiol. 1991;7:431–43.PubMedGoogle Scholar
  49. 49.
    Armulik A, Genove G, Betsholtz C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell. 2011;21:193–215. Scholar
  50. 50.
    Zimmermann KW. Der feinere Bau der Blutkapillaren. Z Anat Entwicklungsgesch. 1923;68:29–109.CrossRefGoogle Scholar
  51. 51.
    Nehls V, Drenckhahn D. Heterogeneity of microvascular pericytes for smooth muscle type alpha-actin. J Cell Biol. 1991;113:147–54.PubMedCrossRefGoogle Scholar
  52. 52.
    Kapanci Y, Ribaux C, Chaponnier C, Gabbiani G. Cytoskeletal features of alveolar myofibroblasts and pericytes in normal human and rat lung. J Histochem Cytochem. 1992;40:1955–63.PubMedCrossRefGoogle Scholar
  53. 53.
    Dias Moura Prazeres, P. H. et al. Pericytes are heterogeneous in their origin within the same tissue. Dev Biol. 2017. Scholar
  54. 54.
    Simon C, Lickert H, Gotz M, Dimou L. Sox10-iCreERT2: a mouse line to inducibly trace the neural crest and oligodendrocyte lineage. Genesis. 2012;50:506–15. Scholar
  55. 55.
    Winkler EA, Bell RD, Zlokovic BV. Central nervous system pericytes in health and disease. Nat Neurosci. 2011;14:1398–405. [pii].
  56. 56.
    Asahina K, Zhou B, Pu WT, Tsukamoto H. Septum transversum-derived mesothelium gives rise to hepatic stellate cells and perivascular mesenchymal cells in developing mouse liver. Hepatology. 2011;53:983–95. Scholar
  57. 57.
    Bergwerff M, Verberne ME, DeRuiter MC, Poelmann RE, Gittenberger-de Groot AC. Neural crest cell contribution to the developing circulatory system: implications for vascular morphology? Circ Res. 1998;82:221–31.PubMedCrossRefGoogle Scholar
  58. 58.
    Etchevers HC, Vincent C, Le Douarin NM, Couly GF. The cephalic neural crest provides pericytes and smooth muscle cells to all blood vessels of the face and forebrain. Development. 2001;128:1059–68.PubMedGoogle Scholar
  59. 59.
    Korn J, Christ B, Kurz H. Neuroectodermal origin of brain pericytes and vascular smooth muscle cells. J Comp Neurol. 2002;442:78–88. [pii].CrossRefPubMedGoogle Scholar
  60. 60.
    Que J, et al. Mesothelium contributes to vascular smooth muscle and mesenchyme during lung development. Proc Natl Acad Sci U S A. 2008;105:16626–30. [pii].
  61. 61.
    Wilm B, Ipenberg A, Hastie ND, Burch JB, Bader DM. The serosal mesothelium is a major source of smooth muscle cells of the gut vasculature. Development. 2005;132:5317–28. Scholar
  62. 62.
    Yamanishi E, Takahashi M, Saga Y, Osumi N. Penetration and differentiation of cephalic neural crest-derived cells in the developing mouse telencephalon. Develop Growth Differ. 2012;54:785–800. Scholar
  63. 63.
    Nehls V, Denzer K, Drenckhahn D. Pericyte involvement in capillary sprouting during angiogenesis in situ. Cell Tissue Res. 1992;270:469–74.PubMedCrossRefGoogle Scholar
  64. 64.
    Bondjers C, et al. Microarray analysis of blood microvessels from PDGF-B and PDGF-Rbeta mutant mice identifies novel markers for brain pericytes. FASEB J Off Publ Fed Am Soc Exp Biol. 2006;20:1703–5. Scholar
  65. 65.
    Goritz C, et al. A pericyte origin of spinal cord scar tissue. Science. 2011;333:238–42. Scholar
  66. 66.
    Kunisaki Y, et al. Arteriolar niches maintain haematopoietic stem cell quiescence. Nature. 2013;502:637–43. Scholar
  67. 67.
    Birbrair A, et al. Skeletal muscle pericyte subtypes differ in their differentiation potential. Stem Cell Res. 2013;10:67–84. [pii].
  68. 68.
    Birbrair A, et al. Type-1 pericytes accumulate after tissue injury and produce collagen in an organ-dependent manner. Stem Cell Res Ther. 2014;5:122. Scholar
  69. 69.
    West J. Regional differences in gas exchange in the lung of erect man. J Appl Physiol. 1962;17:893–8.PubMedCrossRefGoogle Scholar
  70. 70.
    Schreider JP, Raabe OG. Structure of the human respiratory acinus. Am J Anat. 1981;162:221–32.PubMedCrossRefGoogle Scholar
  71. 71.
    Daniels CB, Orgeig S. Pulmonary surfactant: the key to the evolution of air breathing. Physiology. 2003;18:151–7.CrossRefGoogle Scholar
  72. 72.
    Haagmans BL, et al. Pegylated interferon-α protects type 1 pneumocytes against SARS coronavirus infection in macaques. Nat Med. 2004;10:290–3.PubMedCrossRefGoogle Scholar
  73. 73.
    Castranova V, Rabovsky J, Tucker J, Miles P. The alveolar type II epithelial cell: a multifunctional pneumocyte. Toxicol Appl Pharmacol. 1988;93:472–83.PubMedCrossRefGoogle Scholar
  74. 74.
    Nielsen S, King LS, Christensen BM, Agre P. Aquaporins in complex tissues. II. Subcellular distribution in respiratory and glandular tissues of rat. Am J Phys Cell Phys. 1997;273:C1549–61.CrossRefGoogle Scholar
  75. 75.
    Novick RJ, Gehman KE, Ali IS, Lee J. Lung preservation: the importance of endothelial and alveolar type II cell integrity. Ann Thorac Surg. 1996;62:302–14. Scholar
  76. 76.
    Witschi H, C○té MG, Cross CE. Primary pulmonary responses to toxic agents. CRC Crit Rev Toxicol. 1977;5:23–66. Scholar
  77. 77.
    Mason RJ. Biology of alveolar type II cells. Respirology. 2006;11:S12–5.PubMedCrossRefGoogle Scholar
  78. 78.
    Marshall B, Hanson C, Frasch F, Marshall C. Role of hypoxic pulmonary vasoconstriction in pulmonary gas exchange and blood flow distribution. Intensive Care Med. 1994;20:379–89.PubMedCrossRefGoogle Scholar
  79. 79.
    Smith JJ, Porth CM, Erickson M. Hemodynamic response to the upright posture. J Clin Pharmacol. 1994;34:375–86.PubMedCrossRefGoogle Scholar
  80. 80.
    Ohkuda K, Nakahara K, Weidner WJ, Binder A, Staub NC. Lung fluid exchange after uneven pulmonary artery obstruction in sheep. Circ Res. 1978;43:152–61.PubMedCrossRefGoogle Scholar
  81. 81.
    Euler USV, Liljestrand G. Observations on the pulmonary arterial blood pressure in the cat. Acta Physiol Scand. 1946;12:301–20. Scholar
  82. 82.
    Fishman AP. Respiratory gases in the regulation of the pulmonary circulation. Physiol Rev. 1961;41:214–80.PubMedCrossRefGoogle Scholar
  83. 83.
    Wagner PD. Diffusion and chemical reaction in pulmonary gas exchange. Physiol Rev. 1977;57:257–312.PubMedCrossRefGoogle Scholar
  84. 84.
    Boström H, Gritli-Linde A, Betsholtz C. PDGF-a/PDGF alpha-receptor signaling is required for lung growth and the formation of alveoli but not for early lung branching morphogenesis. Dev Dyn. 2002;223:155–62.PubMedCrossRefGoogle Scholar
  85. 85.
    Lindblom P, et al. Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes Dev. 2003;17:1835–40.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Birbrair A, et al. Role of pericytes in skeletal muscle regeneration and fat accumulation. Stem Cells Dev. 2013;22:2298–314. Scholar
  87. 87.
    Burri PH. Lung development. New York: Springer; 1999. p. 122–51.CrossRefGoogle Scholar
  88. 88.
    Dexter L, et al. Studies of the pulmonary circulation in man at rest. Normal variations and the interrelations between increased pulmonary blood flow, elevated pulmonary arterial pressure, and high pulmonary “capillary” pressures. J Clin Investig. 1950;29:602.PubMedCrossRefGoogle Scholar
  89. 89.
    West J, Dollery C, Naimark A. Distribution of blood flow in isolated lung; relation to vascular and alveolar pressures. J Appl Physiol. 1964;19:713–24.PubMedCrossRefGoogle Scholar
  90. 90.
    AgustI AG, et al. Hypoxic pulmonary vasoconstriction and gas exchange during exercise in chronic obstructive pulmonary disease. Chest. 1990;97:268–75.PubMedCrossRefGoogle Scholar
  91. 91.
    Weibel ER. Morphometric estimation of pulmonary diffusion capacity: I. Model and method. Respir Physiol. 1970;11:54–75.PubMedCrossRefGoogle Scholar
  92. 92.
    Weibel ER. What makes a good lung. Swiss Med Wkly. 2009;139:375–86.PubMedGoogle Scholar
  93. 93.
    Dejana E. Endothelial adherens junctions: implications in the control of vascular permeability and angiogenesis. J Clin Investig. 1996;98:1949.PubMedCrossRefGoogle Scholar
  94. 94.
    Roberts WG, Palade GE. Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. J Cell Sci. 1995;108:2369–79.PubMedGoogle Scholar
  95. 95.
    Pober JS, Sessa WC. Evolving functions of endothelial cells in inflammation. Nat Rev Immunol. 2007;7:803–15.PubMedCrossRefGoogle Scholar
  96. 96.
    Sims DE, Westfall JA. Analysis of relationships between pericytes and gas exchange capillaries in neonatal and mature bovine lungs. Microvasc Res. 1983;25:333–42.PubMedCrossRefGoogle Scholar
  97. 97.
    Tsukimoto K, Mathieu-Costello O, Prediletto R, Elliott A, West J. Ultrastructural appearances of pulmonary capillaries at high transmural pressures. J Appl Physiol. 1991;71:573–82.PubMedCrossRefGoogle Scholar
  98. 98.
    Vanhoutte PM, Rubanyi GM, Miller VM, Houston DS. Modulation of vascular smooth muscle contraction by the endothelium. Annu Rev Physiol. 1986;48:307–20.PubMedCrossRefGoogle Scholar
  99. 99.
    Edelman DA, Jiang Y, Tyburski J, Wilson RF, Steffes C. Pericytes and their role in microvasculature homeostasis. J Surg Res. 2006;135:305–11.PubMedCrossRefGoogle Scholar
  100. 100.
    Soderblom C, et al. Perivascular fibroblasts form the fibrotic scar after contusive spinal cord injury. J Neurosci. 2013;33:13882–7. Scholar
  101. 101.
    Crisan M, Corselli M, Chen WC, Peault B. Perivascular cells for regenerative medicine. J Cell Mol Med. 2012; Scholar
  102. 102.
    Bechmann I, et al. Immune surveillance of mouse brain perivascular spaces by blood-borne macrophages. Eur J Neurosci. 2001;14:1651–8.CrossRefGoogle Scholar
  103. 103.
    Guillemin GJ, Brew BJ. Microglia, macrophages, perivascular macrophages, and pericytes: a review of function and identification. J Leukoc Biol. 2004;75:388–97. Scholar
  104. 104.
    Hoyles RK, et al. An essential role for resident fibroblasts in experimental lung fibrosis is defined by lineage-specific deletion of high-affinity type II transforming growth factor β receptor. Am J Respir Crit Care Med. 2011;183:249–61.PubMedCrossRefGoogle Scholar
  105. 105.
    Hung C, et al. Role of lung pericytes and resident fibroblasts in the pathogenesis of pulmonary fibrosis. Am J Respir Crit Care Med. 2013;188:820–30. Scholar
  106. 106.
    Darby I, Skalli O, Gabbiani G. a-Smooth muscle actin is transiently expressed by myofibroblasts during experimental wound healing. Lab Investig. 1990;63:21–9.PubMedPubMedCentralGoogle Scholar
  107. 107.
    Spitzer TL, et al. Perivascular human endometrial mesenchymal stem cells express pathways relevant to self-renewal, lineage specification, and functional phenotype. Biol Reprod. 2012;86:58. Scholar
  108. 108.
    Yotsumoto F, et al. NG2 proteoglycan-dependent recruitment of tumor macrophages promotes pericyte-endothelial cell interactions required for brain tumor vascularization. Oncoimmunology. 2015;4:e1001204. Scholar
  109. 109.
    Stark K, et al. Capillary and arteriolar pericytes attract innate leukocytes exiting through venules and ‘instruct’ them with pattern-recognition and motility programs. Nat Immunol. 2013;14:41–51. Scholar
  110. 110.
    Allsopp G, Gamble HJ. An electron microscopic study of the pericytes of the developing capillaries in human fetal brain and muscle. J Anat. 1979;128:155–68.PubMedPubMedCentralGoogle Scholar
  111. 111.
    Lefrancais E, et al. The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors. Nature. 2017;544:105–9. Scholar
  112. 112.
    Kiel MJ, Yilmaz OH, Iwashita T, Terhorst C, Morrison SJ. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell. 2005;121:1109–21. Scholar
  113. 113.
    Rock JR, et al. Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition. Proc Natl Acad Sci. 2011;108:E1475–83. Scholar
  114. 114.
    Desmoulière A, Chaponnier C, Gabbiani G. Tissue repair, contraction, and the myofibroblast. Wound Repair Regen. 2005;13:7–12.PubMedCrossRefGoogle Scholar
  115. 115.
    Bissell MJ, Rizki A, Mian IS. Tissue architecture: the ultimate regulator of breast epithelial function. Curr Opin Cell Biol. 2003;15:753.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Powell D, et al. Myofibroblasts. I. Paracrine cells important in health and disease. Am J Phys Cell Phys. 1999;277:C1–C19.CrossRefGoogle Scholar
  117. 117.
    Kramann R, et al. Perivascular Gli1+ progenitors are key contributors to injury-induced organ fibrosis. Cell Stem Cell. 2015;16:51–66.PubMedCrossRefGoogle Scholar
  118. 118.
    Marriott S, et al. ABCG2pos lung mesenchymal stem cells are a novel pericyte subpopulation that contributes to fibrotic remodeling. Am J Phys Cell Phys. 2014;307:C684–98.CrossRefGoogle Scholar
  119. 119.
    Cox TR, Erler JT. Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer. Dis Model Mech. 2011;4:165–78.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Lieber CS. Alcoholic fatty liver: its pathogenesis and mechanism of progression to inflammation and fibrosis. Alcohol. 2004;34:9–19.PubMedCrossRefGoogle Scholar
  121. 121.
    Munger JS, et al. A mechanism for regulating pulmonary inflammation and fibrosis: the integrin αvβ6 binds and activates latent TGF β1. Cell. 1999;96:319–28.PubMedCrossRefGoogle Scholar
  122. 122.
    Rockey DC, Bell PD, Hill JA. Fibrosis – a common pathway to organ injury and failure. N Engl J Med. 2015;372:1138–49.PubMedCrossRefGoogle Scholar
  123. 123.
    Hastie AT, et al. Asthmatic epithelial cell proliferation and stimulation of collagen production: human asthmatic epithelial cells stimulate collagen type III production by human lung myofibroblasts after segmental allergen challenge. Am J Respir Crit Care Med. 2002;165:266–72.PubMedCrossRefGoogle Scholar
  124. 124.
    Hinz B, Gabbiani G. Fibrosis: recent advances in myofibroblast biology and new therapeutic perspectives. F1000 Biol Rep. 2010;2:78. Scholar
  125. 125.
    Khalil N, O’Connor RN, Flanders KC, Unruh H. TGF-beta 1, but not TGF-beta 2 or TGF-beta 3, is differentially present in epithelial cells of advanced pulmonary fibrosis: an immunohistochemical study. Am J Respir Cell Mol Biol. 1996;14:131–8.PubMedCrossRefGoogle Scholar
  126. 126.
    Hinz B, Celetta G, Tomasek JJ, Gabbiani G, Chaponnier C. Alpha-smooth muscle actin expression upregulates fibroblast contractile activity. Mol Biol Cell. 2001;12:2730–41.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Verrecchia F, Mauviel A. Transforming growth factor-beta and fibrosis. World J Gastroenterol. 2007;13:3056–62.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Friedman SL, Sheppard D, Duffield JS, Violette S. Therapy for fibrotic diseases: nearing the starting line. Sci Transl Med. 2013;5:167sr161. Scholar
  129. 129.
    Hinz B, et al. The myofibroblast: one function, multiple origins. Am J Pathol. 2007;170:1807–16.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Zeisberg EM, et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat Med. 2007;13:952–61. Scholar
  131. 131.
    Markwald R, Eisenberg C, Eisenberg L, Trusk T, Sugi Y. Epithelial-mesenchymal transformations in early avian heart development. Acta Anat (Basel). 1996;156:173–86.CrossRefGoogle Scholar
  132. 132.
    Iwano M, et al. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest. 2002;110:341–50. Scholar
  133. 133.
    Kim KK, et al. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci U S A. 2006;103:13180–5. Scholar
  134. 134.
    Poulsom R, et al. Bone marrow contributes to renal parenchymal turnover and regeneration. J Pathol. 2001;195:229–35. Scholar
  135. 135.
    Fathke C, et al. Contribution of bone marrow-derived cells to skin: collagen deposition and wound repair. Stem Cells. 2004;22:812–22. Scholar
  136. 136.
    Hashimoto N, Jin H, Liu T, Chensue SW, Phan SH. Bone marrow-derived progenitor cells in pulmonary fibrosis. J Clin Invest. 2004;113:243–52. Scholar
  137. 137.
    Strieter RM, Keeley EC, Hughes MA, Burdick MD, Mehrad B. The role of circulating mesenchymal progenitor cells (fibrocytes) in the pathogenesis of pulmonary fibrosis. J Leukoc Biol. 2009;86:1111–8. Scholar
  138. 138.
    Forbes SJ, et al. A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis. Gastroenterology. 2004;126:955–63.PubMedCrossRefGoogle Scholar
  139. 139.
    Scholten D, et al. Migration of fibrocytes in fibrogenic liver injury. Am J Pathol. 2011;179:189–98. Scholar
  140. 140.
    Barnes JL, Glass WF 2nd. Renal interstitial fibrosis: a critical evaluation of the origin of myofibroblasts. Contrib Nephrol. 2011;169:73–93. [pii].
  141. 141.
    Lin S-L, Kisseleva T, Brenner DA, Duffield JS. Pericytes and perivascular fibroblasts are the primary source of collagen-producing cells in obstructive fibrosis of the kidney. Am J Pathol. 2008;173:1617–27.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Dore-Duffy P, Cleary K. Morphology and properties of pericytes. In: Sukriti Nag. The blood-brain and other neural barriers: reviews and protocols. New York: Humana Press; 2011. p. 49–68.Google Scholar
  143. 143.
    Fries KM, et al. Evidence of fibroblast heterogeneity and the role of fibroblast subpopulations in fibrosis. Clin Immunol Immunopathol. 1994;72:283–92.PubMedCrossRefGoogle Scholar
  144. 144.
    Stratman AN, Davis GE. Endothelial cell-pericyte interactions stimulate basement membrane matrix assembly: influence on vascular tube remodeling, maturation, and stabilization. Microsc Microanal. 2012;18:68–80.PubMedCrossRefGoogle Scholar
  145. 145.
    Garibaldi BT, et al. Regulatory T cells reduce acute lung injury fibroproliferation by decreasing fibrocyte recruitment. Am J Respir Cell Mol Biol. 2013;48:35–43. Scholar
  146. 146.
    Friedman SL, Roll FJ, Boyles J, Bissell DM. Hepatic lipocytes: the principal collagen-producing cells of normal rat liver. Proc Natl Acad Sci. 1985;82:8681–5.PubMedCrossRefGoogle Scholar
  147. 147.
    Leeuw M, De A, Mccarthy SP, Geerts A, Knook DL. Purified rat liver fat-storing cells in culture divide and contain collagen. Hepatology. 1984;4:392–403.PubMedCrossRefGoogle Scholar
  148. 148.
    Mederacke I, et al. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat Commun. 2013;4:2823.PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Dulauroy S, Di Carlo SE, Langa F, Eberl G, Peduto L. Lineage tracing and genetic ablation of ADAM12+ perivascular cells identify a major source of profibrotic cells during acute tissue injury. Nat Med. 2012;18:1262–70.PubMedCrossRefGoogle Scholar
  150. 150.
    Faulkner JL, Szcykalski LM, Springer F, Barnes JL. Origin of interstitial fibroblasts in an accelerated model of angiotensin II-induced renal fibrosis. Am J Pathol. 2005;167:1193–205.PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Humphreys BD, et al. Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am J Pathol. 2010;176:85–97.PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    LeBleu VS, et al. Origin and function of myofibroblasts in kidney fibrosis. Nat Med. 2013;19:1047–53.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Birbrair A, et al. Type-2 pericytes participate in normal and tumoral angiogenesis. Am J Phys Cell Phys. 2014;307:C25–38.CrossRefGoogle Scholar
  154. 154.
    Tiddens H, Silverman M, Bush A. The role of inflammation in airway disease: remodeling. Am J Respir Crit Care Med. 2000;162:S7–S10.PubMedCrossRefGoogle Scholar
  155. 155.
    Bardales RH, Xie S-S, Schaefer R, Hsu S-M. Apoptosis is a major pathway responsible for the resolution of type II pneumocytes in acute lung injury. Am J Pathol. 1996;149:845.PubMedPubMedCentralGoogle Scholar
  156. 156.
    Hermanns MI, Unger RE, Kehe K, Peters K, Kirkpatrick CJ. Lung epithelial cell lines in coculture with human pulmonary microvascular endothelial cells: development of an alveolo-capillary barrier in vitro. Lab Investig. 2004;84:736–52.PubMedCrossRefGoogle Scholar
  157. 157.
    Laycock H, Rajah A. Acute lung injury and acute respiratory distress syndrome: a review article. BJMP. 2010;3:324.Google Scholar
  158. 158.
    Medzhitov R. Origin and physiological roles of inflammation. Nature. 2008;454:428–35.PubMedCrossRefGoogle Scholar
  159. 159.
    Ryan GB, Majno G. Acute inflammation. A review. Am J Pathol. 1977;86:183.PubMedPubMedCentralGoogle Scholar
  160. 160.
    Lamme EN, Van Leeuwen RT, Brandsma K, Van Marle J, Middelkoop E. Higher numbers of autologous fibroblasts in an artificial dermal substitute improve tissue regeneration and modulate scar tissue formation. J Pathol. 2000;190:595–603.PubMedCrossRefPubMedCentralGoogle Scholar
  161. 161.
    Rustenhoven J, Jansson D, Smyth LC, Dragunow M, Brain Pericytes A. Mediators of neuroinflammation. Trends Pharmacol Sci. 2016;38:291–304.PubMedCrossRefPubMedCentralGoogle Scholar
  162. 162.
    Wallez Y, Huber P. Endothelial adherens and tight junctions in vascular homeostasis, inflammation and angiogenesis. Biochim Biophys Acta (BBA) Biomembr. 2008;1778:794–809.CrossRefGoogle Scholar
  163. 163.
    Miller FN, Sims DE, Schuschke DA, Abney DL. Differentiation of light-dye effects in the microcirculation. Microvasc Res. 1992;44:166–84. Scholar
  164. 164.
    Guijarro-Muñoz I, Compte M, Álvarez-Cienfuegos A, Álvarez-Vallina L, Sanz L. Lipopolysaccharide activates Toll-like receptor 4 (TLR4)-mediated NF-κB signaling pathway and proinflammatory response in human pericytes. J Biol Chem. 2014;289:2457–68.PubMedCrossRefGoogle Scholar
  165. 165.
    Abraham E. Neutrophils and acute lung injury. Crit Care Med. 2003;31:S195–9.PubMedCrossRefGoogle Scholar
  166. 166.
    Maekawa M, et al. Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science. 1999;285:895–8.PubMedCrossRefGoogle Scholar
  167. 167.
    Johnson ER, Matthay MA. Acute lung injury: epidemiology, pathogenesis, and treatment. J Aerosol Med Pulm Drug Deliv. 2010;23:243–52.PubMedPubMedCentralCrossRefGoogle Scholar
  168. 168.
    Jordan S, Mitchell J, Quinlan G, Goldstraw P, Evans T. The pathogenesis of lung injury following pulmonary resection. Eur Respir J. 2000;15:790–9.PubMedCrossRefGoogle Scholar
  169. 169.
    Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol. 2008;8:349–61.PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Serhan CN, et al. Resolution of inflammation: state of the art, definitions and terms. FASEB J. 2007;21:325–32.PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Varga J, Haustein U, Creech RH, Dwyer JP, Jimenez SA. Exaggerated radiation-induced fibrosis in patients with systemic sclerosis. JAMA. 1991;265:3292–5.PubMedCrossRefGoogle Scholar
  172. 172.
    Meshi B, et al. Emphysematous lung destruction by cigarette smoke: the effects of latent adenoviral infection on the lung inflammatory response. Am J Respir Cell Mol Biol. 2002;26:52–7.PubMedCrossRefGoogle Scholar
  173. 173.
    Meduri GU, et al. Fibroproliferative phase of ARDS: clinical findings and effects of corticosteroids. Chest. 1991;100:943–52.PubMedCrossRefGoogle Scholar
  174. 174.
    Jiménez SA, et al. Dialysis-associated systemic fibrosis (nephrogenic fibrosing dermopathy): study of inflammatory cells and transforming growth factor β1 expression in affected skin. Arthritis Rheumatol. 2004;50:2660–6.CrossRefGoogle Scholar
  175. 175.
    Selman M, et al. TIMP-1,-2,-3, and-4 in idiopathic pulmonary fibrosis. A prevailing nondegradative lung microenvironment? Am J Physiol Lung Cell Mol Physiol. 2000;279:L562–74.PubMedCrossRefGoogle Scholar
  176. 176.
    Wynn TA. Fibrotic disease and the TH1/TH2 paradigm. Nat Rev Immunol. 2004;4:583–94.PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Stadelmann WK, Digenis AG, Tobin GR. Physiology and healing dynamics of chronic cutaneous wounds. Am J Surg. 1998;176:26S–38S.PubMedCrossRefGoogle Scholar
  178. 178.
    Kisseleva T, Brenner DA. Role of hepatic stellate cells in fibrogenesis and the reversal of fibrosis. J Gastroenterol Hepatol. 2007;22:S73–8.PubMedCrossRefGoogle Scholar
  179. 179.
    Marshall BG, Shaw RJ. Immunological mechanisms in asthma and allergic diseases, vol. 78. Basel: Karger Publishers; 2000. p. 148–58.CrossRefGoogle Scholar
  180. 180.
    Luzina IG, Todd NW, Iacono AT, Atamas SP. Roles of T lymphocytes in pulmonary fibrosis. J Leukoc Biol. 2008;83:237–44.PubMedCrossRefGoogle Scholar
  181. 181.
    Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature. 1996;383:787.PubMedCrossRefGoogle Scholar
  182. 182.
    Berner B, Akça D, Jung T, Muller GA, Reuss-Borst MA. Analysis of Th1 and Th2 cytokines expressing CD4+ and CD8+ T cells in rheumatoid arthritis by flow cytometry. J Rheumatol. 2000;27:1128–35.PubMedGoogle Scholar
  183. 183.
    Schroeder JT, MacGlashan D, Kagey-Sobotka A, White JM, Lichtenstein LM. IgE-dependent IL-4 secretion by human basophils. The relationship between cytokine production and histamine release in mixed leukocyte cultures. J Immunol. 1994;153:1808–17.PubMedGoogle Scholar
  184. 184.
    Trinchieri G. Interleukin-12: a cytokine produced by antigen-presenting cells with immunoregulatory functions in the generation of T-helper cells type 1 and cytotoxic lymphocytes. Blood. 1994;84:4008–27.PubMedGoogle Scholar
  185. 185.
    Macatonia SE, et al. Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells. J Immunol. 1995;154:5071–9.PubMedGoogle Scholar
  186. 186.
    Ong C, Wong C, Roberts CR, Teh HS, Jirik FR. Anti-IL-4 treatment prevents dermal collagen deposition in the tight-skin mouse model of scleroderma. Eur J Immunol. 1998;28:2619–29.PubMedCrossRefPubMedCentralGoogle Scholar
  187. 187.
    Chiaramonte MG, Donaldson DD, Cheever AW, Wynn TA. An IL-13 inhibitor blocks the development of hepatic fibrosis during a T-helper type 2–dominated inflammatory response. J Clin Invest. 1999;104:777–85.PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Demols A, et al. Endogenous interleukin-10 modulates fibrosis and regeneration in experimental chronic pancreatitis. Am J Physiol Gastrointest Liver Physiol. 2002;282:G1105–12.PubMedCrossRefGoogle Scholar
  189. 189.
    D’Alessio FR, et al. CD4(+)CD25(+)Foxp3(+) Tregs resolve experimental lung injury in mice and are present in humans with acute lung injury. J Clin Invest. 2009;119:2898–913. Scholar
  190. 190.
    Rubenfeld GD, Herridge MS. Epidemiology and outcomes of acute lung injury. Chest J. 2007;131:554–62.CrossRefGoogle Scholar
  191. 191.
    Network, T. A. R. D. S. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342:1301–8. Scholar
  192. 192.
    Guérin C, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013;368:2159–68. Scholar
  193. 193.
    Papazian L, et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010;363:1107–16. Scholar
  194. 194.
    Richeldi L, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2071–82. Scholar
  195. 195.
    King TE, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2083–92. Scholar
  196. 196.
    Lydon NB, Druker BJ. Lessons learned from the development of imatinib. Leuk Res. 2004;28(Suppl 1):S29–38. Scholar
  197. 197.
    Schneider RK, et al. Gli1+ mesenchymal stromal cells are a key driver of bone marrow fibrosis and an important cellular therapeutic target. Cell Stem Cell. 2017; Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Alexander Birbrair
    • 1
  • Pedro Henrique Dias Moura Prazeres
    • 1
  • Daniel Clark Files
    • 2
    • 3
  • Osvaldo Delbono
    • 2
    Email author
  1. 1.Department of PathologyFederal University of Minas GeraisBelo HorizonteBrazil
  2. 2.Department of Internal Medicine, Gerontology and GeriatricsWake Forest School of MedicineWinston-SalemUSA
  3. 3.Pulmonary, Critical Care, Allergy and Immunology and the Critical Illness Injury and Recovery Research CenterWake Forest School of MedicineWinston-SalemUSA

Personalised recommendations