Purinergic Signaling in Wound Healing and Airway Remodeling

Part of the Subcellular Biochemistry book series (SCBI, volume 55)


Airway epithelia are continuously damaged by airborne pollutants, pathogens and allergens, and they rely on intrinsic mechanisms to restore barrier integrity. Epithelial repair is a multi-step process including cell migration into the wounded area, proliferation, differentiation and matrix deposition. Each step requires the secretion of various molecules, including growth factors, integrins and matrix metalloproteinases. Evidence is emerging that purinergic signaling promotes repair in human airway epithelia. An injury induces ATP release, which binds P2Y2 receptors (P2Y2Rs) to initiate protein kinase C (PKC)-dependent oxidative activation of TNFα-converting enzyme (TACE), which then releases the membrane-bound ligands of the epidermal growth factor receptor (EGFR). The P2Y2R- and EGFR-dependent signaling cascades converge to induce mediator release, whereas the latter also induces cytoskeletal rearrangement for cell migration and proliferation. Similar roles for purinergic signaling are reported in pulmonary endothelial cells, smooth muscle cells and fibroblasts. In chronic airway diseases, the aberrant regulation of extracellular purines is implicated in the development of airway remodeling by mucus cell metaplasia and hypersecretion, excess collagen deposition, fibrosis and neovascularization. This chapter describes the crosstalk between these signaling cascades and discusses the impact of deregulated purinergic signaling in chronic lung diseases.


Airway remodeling EGFR P2Y2 receptors Migration Wound healing 


  1. 1.
    Kato A, Schleimer RP (2007) Beyond inflammation: airway epithelial cells are at the interface of innate and adaptive immunity. Curr Opin Immunol 19:711–720PubMedCrossRefGoogle Scholar
  2. 2.
    Bartlett JA, Fischer AJ, McCray PBJ (2008) Innate immune functions of the airway epithelium. Contrib Microbiol 15:147–163PubMedCrossRefGoogle Scholar
  3. 3.
    Erjefalt JS, Persson CG (1997) Airway epithelial repair: breathtakingly quick and multipotentially pathogenic. Thorax 52:1010–1012PubMedCrossRefGoogle Scholar
  4. 4.
    Knight DA, Holgate ST (2003) The airway epithelium: structural and functional properties in health and disease. Respirology 8:432–446PubMedCrossRefGoogle Scholar
  5. 5.
    Park KS, Wells JM, Zorn AM, Wert SE, Laubach VE, Fernandez LG, Whitsett JA (2006) Transdifferentiation of ciliated cells during repair of the respiratory epithelium. Am J Respir Cell Mol Biol 34:151–157PubMedCrossRefGoogle Scholar
  6. 6.
    Heguy A, Harvey BG, Leopold PL, Dolgalev I, Raman T, Crystal RG (2007) Responses of the human airway epithelium transcriptome to in vivo injury. Physiol Genomics 29:139–148PubMedGoogle Scholar
  7. 7.
    Coraux C, Roux J, Jolly T, Birembaut P (2008) Epithelial cell-extracellular matrix interactions and stem cells in airway epithelial regeneration. Proc Am Thorac Soc 5:689–694PubMedCrossRefGoogle Scholar
  8. 8.
    Rawlins EL, Ostrowski LE, Randell SH, Hogan BL (2007) Lung development and repair: contribution of the ciliated lineage. Proc Natl Acad Sci USA 104:410–417PubMedCrossRefGoogle Scholar
  9. 9.
    Burgel PR, Nadel JA (2008) Epidermal growth factor receptor-mediated innate immune responses and their roles in airway diseases. Eur Respir J 32:1068–1081PubMedCrossRefGoogle Scholar
  10. 10.
    Ahmad S, Ahmad A, White CW (2006) Purinergic signaling and kinase activation for survival in pulmonary oxidative stress and disease. Free Radic Biol Med 41:29–40PubMedCrossRefGoogle Scholar
  11. 11.
    Lazarowski ER, Boucher RC, Harden TK (2003) Mechanisms of release of nucleotides and integration of their action as P2X- and P2Y-receptor activating molecules. Mol Pharmacol 64:785–795PubMedCrossRefGoogle Scholar
  12. 12.
    Schwiebert EM, Zsembery A (2003) Extracellular ATP as a signaling molecule for epithelial cells. Biochim Biophys Acta 1615:7–32PubMedCrossRefGoogle Scholar
  13. 13.
    Caruso M, Holgate ST, Polosa R (2006) Adenosine signaling in airways. Curr Opin Pharmacol 6:251–256PubMedCrossRefGoogle Scholar
  14. 14.
    Dignass AU, Becker A, Spiegler S, Goebell H (1998) Adenine nucleotides modulate epithelial wound healing in vitro. Eur J Clin Invest 28:554–561PubMedCrossRefGoogle Scholar
  15. 15.
    Klepeis VE, Weinger I, Kaczmarek E, Trinkaus-Randall V (2004) P2Y receptors play a critical role in epithelial cell communication and migration. J Cell Biochem 93:1115–1133PubMedCrossRefGoogle Scholar
  16. 16.
    Yin J, Xu K, Zhang J, Kumar A, Yu FS (2007) Wound-induced ATP release and EGF receptor activation in epithelial cells. J Cell Sci 120:815–825PubMedCrossRefGoogle Scholar
  17. 17.
    Wesley UV, Bove PF, Hristova M, McCarthy S, van der Vliet A (2007) Airway epithelial cell migration and wound repair by ATP-mediated activation of dual Oxidase 1. J Biol Chem 282:3213–3220PubMedCrossRefGoogle Scholar
  18. 18.
    Schafer R, Sedehizade F, Welte T, Reiser G (2003) ATP- and UTP-activated P2Y receptors differently regulate proliferation of human lung epithelial tumor cells. Am J Physiol 285:L376–L385Google Scholar
  19. 19.
    Communi D, Paindavoine P, Place GA, Parmentier M, Boeynaems JM (1999) Expression of P2Y receptors in cell lines derived from the human lung. Br J Pharmacol 127:562–568PubMedCrossRefGoogle Scholar
  20. 20.
    Schafer R, Hartig R, Sedehizade F, Welte T, Reiser G (2006) Adenine nucleotides inhibit proliferation of the human lung adenocarcinoma cell line LXF-289 by activation of nuclear factor kappaB1 and mitogen-activated protein kinase pathways. FEBS J 273:3756–3767PubMedCrossRefGoogle Scholar
  21. 21.
    Communi D, Robaye B, Boeynaems J-M (1999) Pharmacological characterization of the human P2Y11 receptor. Br J Pharmacol 128:1199–1206PubMedCrossRefGoogle Scholar
  22. 22.
    Marteau F, Le Poul E, Communi D, Communi D, Labouret C, Savi P, Boeynaems J-M, Gonzalez NS (2003) Pharmacological characterization of the human P2Y13 receptor. Mol Pharmacol 64:104–112PubMedCrossRefGoogle Scholar
  23. 23.
    Gerasimovskaya EV, Davie NJ, Ahmad S, Tucker DA, White CW, Stenmark KR (2005) Extracellular adenosine triphosphate: a potential regulator of vasa vasorum neovascularization in hypoxia-induced pulmonary vascular remodeling. Chest 128:608S–610SPubMedCrossRefGoogle Scholar
  24. 24.
    Dart RA, Gollub S, Lazar J, Nair C, Schroeder D, Woolf SH (2003) Treatment of systemic hypertension in patients with pulmonary disease: COPD and asthma. Chest 123:222–243PubMedCrossRefGoogle Scholar
  25. 25.
    Chaulet H, Desgranges C, Renault MA, Dupuch F, Ezan G, Peiretti F, Loirand G, Pacaud P, Gadeau AP (2001) Extracellular nucleotides induce arterial smooth muscle cell migration via osteopontin. Circ Res 89:772–778PubMedCrossRefGoogle Scholar
  26. 26.
    Seye CI, Kong Q, Erb L, Garrad RC, Krugh B, Wang M, Turner JT, Sturek M, Gonzalez FA, Weisman GA (2002) Functional P2Y2 nucleotide receptors mediate uridine 5′-triphosphate-induced intimal hyperplasia in collared rabbit carotid arteries. Circulation 106:2720–2726PubMedCrossRefGoogle Scholar
  27. 27.
    Gerasimovskaya EV, Woodward HN, Tucker DA, Stenmark KR (2008) Extracellular ATP is a pro-angiogenic factor for pulmonary artery vasa vasorum endothelial cells. Angiogenesis 11:169–182PubMedCrossRefGoogle Scholar
  28. 28.
    Gerasimovskaya EV, Ahmad S, White CW, Jones PL, Carpenter TC, Stenmark KR (2002) Extracellular ATP is an autocrine/paracrine regulator of hypoxia-induced adventitial fibroblast growth. Signaling through extracellular signal-regulated kinase-1/2 and the Egr-1 transcription factor. J Biol Chem 277:44638–44650PubMedCrossRefGoogle Scholar
  29. 29.
    Communi D, Janssens R, Suarez-Huerta N, Robaye B, Boeynaems JM (2000) Advances in signaling by extracellular nucleotides. The role and transduction mechanisms of P2Y receptors. Cell Signal 12:351–360PubMedCrossRefGoogle Scholar
  30. 30.
    Ralevic V, Burnstock G (1998) Receptors for purines and pyrimidines. Pharmacol Rev 50:413–492PubMedGoogle Scholar
  31. 31.
    Muller T, Bayer H, Myrtek D, Ferrari D, Sorichter S, Ziegenhagen MW, Zissel G, Virchow JC Jr, Luttmann W, Norgauer J, Di Virgilio F, Idzko M (2005) The P2Y14 receptor of airway epithelial cells: coupling to intracellular Ca2+ and IL-8 secretion. Am J Respir Cell Mol Biol 33:601–609PubMedCrossRefGoogle Scholar
  32. 32.
    Chodniewicz D, Klemke RL (2004) Guiding cell migration through directed extension and stabilization of pseudopodia. Exp Cell Res 301:31–37PubMedCrossRefGoogle Scholar
  33. 33.
    Ridley AJ, Schwartz MA, Burridge K, Firtel RA, Ginsberg MH, Borisy G, Parsons JT, Horwitz AR (2003) Cell migration: integrating signals from front to back. Science 302:1704–1709PubMedCrossRefGoogle Scholar
  34. 34.
    Chorna NE, Chevres M, Santos-Berrios C, Orellano EA, Erb L, Gonzalez FA (2007) P2Y2 receptors induced cell surface redistribution of alpha(v) integrin is required for activation of ERK 1/2 in U937 cells. J Cell Physiol 211:410–422PubMedCrossRefGoogle Scholar
  35. 35.
    Bagchi S, Liao Z, Gonzalez FA, Chorna NE, Seye CI, Weisman GA, Erb L (2005) The P2Y2 nucleotide receptor interacts with alpha v integrins to activate Go and induce cell migration. J Biol Chem 280:39050–39057PubMedCrossRefGoogle Scholar
  36. 36.
    Liao Z, Seye CI, Weisman GA, Erb L (2007) The P2Y2 nucleotide receptor requires interaction with alpha v integrins to access and activate G12. J Cell Sci 120:1654–1662PubMedCrossRefGoogle Scholar
  37. 37.
    Yu N, Erb L, Shivaji R, Weisman GA, Seye CI (2008) Binding of the P2Y2 nucleotide receptor to filamin A regulates migration of vascular smooth muscle cells. Circ Res 102:581–588PubMedCrossRefGoogle Scholar
  38. 38.
    Fox JW, Lamperti ED, YZ Ek_io lu, Hong SE, Feng Y, Graham DA, Scheffer IE, Dobyns WB, Hirsch BA, Radtke RA, Berkovic SF, Huttenlocher PR, Walsh CA (1998) Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia. Neuron 21:1315–1325PubMedCrossRefGoogle Scholar
  39. 39.
    Gerasimovskaya EV, Tucker DA, Weiser-Evans M, Wenzlau JM, Klemm DJ, Banks M, Stenmark KR (2005) Extracellular ATP-induced proliferation of adventitial fibroblasts requires phosphoinositide 3-kinase, Akt, mammalian target of rapamycin, and p70 S6 kinase signaling pathways. J Biol Chem 280:1838–1848PubMedCrossRefGoogle Scholar
  40. 40.
    Pullikuth AK, Catling AD (2007) Scaffold mediated regulation of MAPK signaling and cytoskeletal dynamics: a perspective. Cell Signal 19:1621–1632PubMedCrossRefGoogle Scholar
  41. 41.
    Coraux C, Martinella-Catusse C, Nawrocki-Raby B, Hajj R, Burlet H, Escotte S, Laplace V, Birembaut P, Puchelle E (2005) Differential expression of matrix metalloproteinases and interleukin-8 during regeneration of human airway epithelium in vivo. J Pathol 206:160–169PubMedCrossRefGoogle Scholar
  42. 42.
    Legrand C, Gilles C, Zahm JM, Polette M, Buisson AC, Kaplan H, Birembaut P, Tournier JM (1999) Airway epithelial cell migration dynamics. MMP-9 role in cell-extracellular matrix remodeling. J Cell Biol 146:517–529CrossRefGoogle Scholar
  43. 43.
    Bove PF, Wesley UV, Greul AK, Hristova M, Dostmann WR, van der Vliet A (2007) Nitric oxide promotes airway epithelial wound repair through enhanced activation of MMP-9. Am J Respir Cell Mol Biol 36:138–146PubMedCrossRefGoogle Scholar
  44. 44.
    Adiseshaiah P, Vaz M, Machireddy N, Kalvakolanu DV, Reddy SP (2008) A Fra-1-dependent, matrix metalloproteinase driven EGFR activation promotes human lung epithelial cell motility and invasion. J Cell Physiol 216:405–412PubMedCrossRefGoogle Scholar
  45. 45.
    Okamoto T, Valacchi G, Gohil K, Akaike T, van der Vliet A (2002) S-nitrosothiols inhibit cytokine-mediated induction of matrix metalloproteinase-9 in airway epithelial cells. Am J Respir Cell Mol Biol 27:463–473PubMedGoogle Scholar
  46. 46.
    McNamara N, Gallup M, Sucher A, Maltseva I, McKemy D, Basbaum C (2006) AsialoGM1 and TLR5 cooperate in flagellin-induced nucleotide signaling to activate Erk1/2. Am J Respir Cell Mol Biol 34:653–660PubMedCrossRefGoogle Scholar
  47. 47.
    Fu Z, Bettega K, Carroll S, Buchholz KR, Machen TE (2007) Role of Ca2+ in responses of airway epithelia to Pseudomonas aeruginosa, flagellin, ATP, and thapsigargin. Am J Physiol 292:L353–L364Google Scholar
  48. 48.
    Gillitzer R, Goebeler M (2001) Chemokines in cutaneous wound healing. J Leukoc Biol 69:513–521PubMedGoogle Scholar
  49. 49.
    Marcet B, Libert F, Boeynaems JM, Communi D (2007) Extracellular nucleotides induce COX-2 up-regulation and prostaglandin E2 production in human A549 alveolar type II epithelial cells. Eur J Pharmacol 566:167–171PubMedCrossRefGoogle Scholar
  50. 50.
    Savla U, Appel HJ, Sporn PH, Waters CM (2001) Prostaglandin E(2) regulates wound closure in airway epithelium. Am J Physiol 280:L421–L431Google Scholar
  51. 51.
    Boucher I, Yang L, Mayo C, Klepeis V, Trinkaus-Randall V (2007) Injury and nucleotides induce phosphorylation of epidermal growth factor receptor: MMP and HB-EGF dependent pathway. Exp Eye Res 85:130–141PubMedCrossRefGoogle Scholar
  52. 52.
    Koff JL, Shao MX, Kim S, Ueki IF, Nadel JA (2006) Pseudomonas lipopolysaccharide accelerates wound repair via activation of a novel epithelial cell signaling cascade. J Immunol 177:8693–8700PubMedGoogle Scholar
  53. 53.
    Block ER, Matela AR, SundarRaj N, Iszkula ER, Klarlund JK (2004) Wounding induces motility in sheets of corneal epithelial cells through loss of spatial constraints: role of heparin-binding epidermal growth factor-like growth factor signaling. J Biol Chem 279:24307–24312PubMedCrossRefGoogle Scholar
  54. 54.
    Vermeer PD, Panko L, Welsh MJ, Zabner J (2006) erbB1 functions as a sensor of airway epithelial integrity by regulation of protein phosphatase 2A activity. J Biol Chem 281:1725–1730PubMedCrossRefGoogle Scholar
  55. 55.
    Vermeer PD, Einwalter LA, Moninger TO, Rokhlina T, Kern JA, Zabner J, Welsh MJ (2003) Segregation of receptor and ligand regulates activation of epithelial growth factor receptor. Nature 422:322–326PubMedCrossRefGoogle Scholar
  56. 56.
    Luttrell LM, Daaka Y, Lefkowitz RJ (1999) Regulation of tyrosine kinase cascades by G-protein-coupled receptors. Curr Opin Cell Biol 11:177–183PubMedCrossRefGoogle Scholar
  57. 57.
    Rozengurt E (2007) Mitogenic signaling pathways induced by G protein-coupled receptors. J Cell Physiol 213:589–602PubMedCrossRefGoogle Scholar
  58. 58.
    Liu J, Liao Z, Camden J, Griffin KD, Garrad RC, Santiago-Perez LI, Gonzalez FA, Seye CI, Weisman GA, Erb L (2004) Src homology 3 binding sites in the P2Y2 nucleotide receptor interact with Src and regulate activities of Src, proline-rich tyrosine kinase 2, and growth factor receptors. J Biol Chem 279:8212–8218PubMedCrossRefGoogle Scholar
  59. 59.
    Block ER, Klarlund JK (2008) Wounding sheets of epithelial cells activates the epidermal growth factor receptor through distinct short- and long-range mechanisms. Mol Biol Cell 19:4909–4917PubMedCrossRefGoogle Scholar
  60. 60.
    Homolya L, Steinberg TH, Boucher RC (2000) Cell to cell communication in response to mechanical stress via bilateral release of ATP and UTP in polarized epithelia. J Cell Biol 150:1349–1360PubMedCrossRefGoogle Scholar
  61. 61.
    Ohtsu H, Dempsey PJ, Eguchi S (2006) ADAMs as mediators of EGF receptor transactivation by G protein-coupled receptors. Am J Physiol 291:C1–C10CrossRefGoogle Scholar
  62. 62.
    Boots AW, Hristova M, Kasahara DI, Haenen GR, Bast A, van der Vliet A (2009) ATP-mediated activation of the NADPH oxidase DUOX1 mediates airway epithelial responses to bacterial stimuli. J Biol Chem 284:17858–17867PubMedCrossRefGoogle Scholar
  63. 63.
    van der Vliet A (2008) NADPH oxidases in lung biology and pathology: host defense enzymes, and more. Free Radic Biol Med 44:938–955PubMedCrossRefGoogle Scholar
  64. 64.
    Terada LS (2006) Specificity in reactive oxidant signaling: think globally, act locally. J Cell Biol 174:615–623PubMedCrossRefGoogle Scholar
  65. 65.
    Forteza R, Salathe M, Miot F, Conner GE (2005) Regulated hydrogen peroxide production by Duox in human airway epithelial cells. Am J Respir Cell Mol Biol 32:462–469PubMedCrossRefGoogle Scholar
  66. 66.
    Shao MXG, Nadel JA (2005) Neutrophil elastase induces MUC5AC mucin production in human airway epithelial cells via a cascade involving protein kinase C, reactive oxygen species, and TNF-alpha-converting enzyme. J Immunol 175:4009–4016PubMedGoogle Scholar
  67. 67.
    Shao MXG, Nakanaga T, Nadel JA (2004) Cigarette smoke induces MUC5AC mucin overproduction via tumor necrosis factor-alpha-converting enzyme in human airway epithelial (NCI-H292) cells. Am J Physiol 287:L420–L427Google Scholar
  68. 68.
    Shao MXG, Nadel JA (2005) Dual oxidase 1-dependent MUC5AC mucin expression in cultured human airway epithelial cells. Proc Natl Acad Sci 102:767–772PubMedCrossRefGoogle Scholar
  69. 69.
    Nakanaga T, Nadel JA, Ueki IF, Koff JL, Shao MX (2007) Regulation of interleukin-8 via an airway epithelial signaling cascade. Am J Physiol 292:L1289–L1296Google Scholar
  70. 70.
    Cruz CM, Rinna A, Forman HJ, Ventura AL, Persechini PM, Ojcius DM (2007) ATP activates a reactive oxygen species-dependent oxidative stress response and secretion of proinflammatory cytokines in macrophages. J Biol Chem 282:2871–2879PubMedCrossRefGoogle Scholar
  71. 71.
    Pines A, Perrone L, Bivi N, Romanello M, Damante G, Gulisano M, Kelley MR, Quadrifoglio F, Tell G (2005) Activation of APE1/Ref-1 is dependent on reactive oxygen species generated after purinergic receptor stimulation by ATP. Nucleic Acids Res 33:4379–4394PubMedCrossRefGoogle Scholar
  72. 72.
    Dichmann S, Idzko M, Zimpfer U, Hofmann C, Ferrari D, Luttmann W, Virchow C Jr, Di Virgilio F, Norgauer J (2000) Adenosine triphosphate-induced oxygen radical production and CD11b up-regulation: Ca2+ mobilization and actin reorganization in human eosinophils. Blood 95:973–978PubMedGoogle Scholar
  73. 73.
    Chen Y, Corriden R, Inoue Y, Yip L, Hashiguchi N, Zinkernagel A, Nizet V, Insel PA, Junger WG (2006) ATP release guides neutrophil chemotaxis via P2Y2 and A3 receptors. Science 314:1792–1795PubMedCrossRefGoogle Scholar
  74. 74.
    Song CJ, Steinebrunner I, Wang X, Stout SC, Roux SJ (2006) Extracellular ATP induces accumulation of superoxide via NADPH oxidases in Arabidopsis. Plant Physiol 140:1222–1232PubMedCrossRefGoogle Scholar
  75. 75.
    Jeter CR, Roux SJ (2006) Plant responses to extracellular nucleotides: cellular processes and biological effects. Purinergic Signal 2:443–449PubMedCrossRefGoogle Scholar
  76. 76.
    Kim SY, Sivaguru M, Stacey G (2006) Extracellular ATP in plants. Visualization, localization, and analysis of physiological significance in growth and signaling. Plant Physiol 142:984–992PubMedCrossRefGoogle Scholar
  77. 77.
    Cheung KK, Ryten M, Burnstock G (2003) Abundant and dynamic expression of G protein-coupled P2Y receptors in mammalian development. Dev Dyn 228:254–266PubMedCrossRefGoogle Scholar
  78. 78.
    Fischer H, Gonzales LK, Kolla V, Schwarzer C, Miot F, Illek B, Ballard PL (2007) Developmental regulation of DUOX1 expression and function in human fetal lung epithelial cells. Am J Physiol 292:L1506–L1514Google Scholar
  79. 79.
    Burch LH, Picher M (2006) E-NTPDases in human airways: regulation and relevance for chronic lung diseases. Purinergic Signal 2:399–408PubMedCrossRefGoogle Scholar
  80. 80.
    Mohsenin A, Blackburn MR (2006) Adenosine signaling in asthma and chronic obstructive pulmonary disease. Curr Opin Pulm Med 12:54–59PubMedCrossRefGoogle Scholar
  81. 81.
    Brown RA, Spina D, Page CP (2008) Adenosine receptors and asthma. Br J Pharmacol 153(1):S446–S456PubMedCrossRefGoogle Scholar
  82. 82.
    Fredholm BB (2007) Adenosine, an endogenous distress signal, modulates tissue damage and repair. Cell Death Differ 14:1315–1323PubMedCrossRefGoogle Scholar
  83. 83.
    Allen-Gipson DS, Spurzem K, Kolm N, Spurzem JR, Wyatt TA (2007) Adenosine promotion of cellular migration in bronchial epithelial cells is mediated by the activation of cyclic adenosine monophosphate-dependent protein kinase A. J Investig Med 55:378–385PubMedCrossRefGoogle Scholar
  84. 84.
    Michoud M-C, Napolitano G, Maghni K, Govindaraju V, Cogo A, Martin JG (2002) Effects of extracellular triphosphate nucleotides and nucleosides on airway smooth muscle cell proliferation. Am J Respir Cell Mol Biol 27:732–738PubMedGoogle Scholar
  85. 85.
    Szkotak AJ, Ng AM, Man SF, Baldwin SA, Cass CE, Young JD, Duszyk M (2003) Coupling of CFTR-mediated anion secretion to nucleoside transporters and adenosine homeostasis in Calu-3 cells. J Membr Biol 192:169–179PubMedCrossRefGoogle Scholar
  86. 86.
    Rollins BM, Burn M, Coakley RD, Chambers LA, Hirsh AJ, Clunes MT, Lethem MI, Donaldson SH, Tarran R (2008) A2B adenosine receptors regulate the mucus clearance component of the lung’s innate defense system. Am J Respir Cell Mol Biol 39:190–197PubMedCrossRefGoogle Scholar
  87. 87.
    Allen-Gipson DS, Wong J, Spurzem JR, Sisson JH, Wyatt TA (2006) Adenosine A2A receptors promote adenosine-stimulated wound healing in bronchial epithelial cells. Am J Physiol 290:L849–L855Google Scholar
  88. 88.
    Spurzem JR, Gupta J, Veys T, Kneifl KR, Rennard SI, Wyatt TA (2002) Activation of protein kinase A accelerates bovine bronchial epithelial cell migration. Am J Physiol 282:L1108–L1116Google Scholar
  89. 89.
    Roman J, Rivera HN, Roser-Page S, Sitaraman SV, Ritzenthaler JD (2006) Adenosine induces fibronectin expression in lung epithelial cells: implications for airway remodeling. Am J Physiol 290:L317–L325Google Scholar
  90. 90.
    Han SW, Roman J (2006) Fibronectin induces cell proliferation and inhibits apoptosis in human bronchial epithelial cells: pro-oncogenic effects mediated by PI3-kinase and NF-kappaB. Oncogene 25:4341–4349PubMedCrossRefGoogle Scholar
  91. 91.
    Feoktistov I, Biaggioni I, Cronstein BN (2009) Adenosine receptors in wound healing, fibrosis and angiogenesis. Handb Exp Pharmacol 193:383–397PubMedCrossRefGoogle Scholar
  92. 92.
    Montesinos MC, Desai A, Chen JF, Yee H, Schwarzschild MA, Fink JS, Cronstein BN (2002) Adenosine promotes wound healing and mediates angiogenesis in response to tissue injury via occupancy of A2A receptors. Am J Pathol 160:2009–2018PubMedCrossRefGoogle Scholar
  93. 93.
    Jones MC, Caswell PT, Norman JC (2006) Endocytic recycling pathways: emerging regulators of cell migration. Curr Opin Cell Biol 18:549–557PubMedCrossRefGoogle Scholar
  94. 94.
    Farber K, Markworth S, Pannasch U, Nolte C, Prinz V, Kronenberg G, Gertz K, Endres M, Bechmann I, Enjyoji K, Robson SC, Kettenmann H (2008) The ectonucleotidase CD39/NTPDase1 modulates purinergic-mediated microglial migration. Glia 56:331–341PubMedCrossRefGoogle Scholar
  95. 95.
    Corriden R, Chen Y, Inoue Y, Beldi G, Robson S, Insel PA, Junger WG (2008) Ecto-nucleoside triphosphate-diphosphohydrolase 1 (NTPDASE1/CD39) regulates neutrophil chemotaxis by hydrolyzing released ATP to adenosine. J Biol Chem 283(42):28480–28486PubMedCrossRefGoogle Scholar
  96. 96.
    Goepfert C, Sundberg C, Sevigny J, Enjyoji K, Hoshi T, Csizmadia E, Robson S (2001) Disordered cellular migration and angiogenesis in cd39-null mice. Circulation 104:3109–3115PubMedCrossRefGoogle Scholar
  97. 97.
    Holgate ST (2008) The airway epithelium is central to the pathogenesis of asthma. Allergol Int 57:1–10PubMedCrossRefGoogle Scholar
  98. 98.
    Fedorov IA, Wilson SJ, Davies DE, Holgate ST (2005) Epithelial stress and structural remodelling in childhood asthma. Thorax 60:389–394PubMedCrossRefGoogle Scholar
  99. 99.
    Jeffery PK (2004) Remodeling and inflammation of bronchi in asthma and chronic obstructive pulmonary disease. Proc Am Thorac Soc 1:176–183PubMedCrossRefGoogle Scholar
  100. 100.
    Scotton CJ, Chambers R (2007) Molecular targets in pulmonary fibrosis: the myofibroblast in focus. Chest 132:1311–1321PubMedCrossRefGoogle Scholar
  101. 101.
    Horowitz JC, Thannickal VJ (2006) Epithelial-mesenchymal interactions in pulmonary fibrosis. Semin Respir Crit Care Med 27:600–612PubMedCrossRefGoogle Scholar
  102. 102.
    Willis BC, Borok Z (2007) TGF-beta-induced EMT: mechanisms and implications for fibrotic lung disease. Am J Physiol 293:L525–L534Google Scholar
  103. 103.
    Driver AG, Kukoly CA, Ali S, Mustafa SJ (1993) Adenosine in the bronchoalveolar lavage fluid in asthma. Am Rev Respir Dis 148:91–97PubMedGoogle Scholar
  104. 104.
    Esther CR Jr, Alexis NE, Clas ML, Lazarowski ER, Donaldson SH, Pedrosa Ribeiro CM, Moore CG, Davis SD, Boucher RC (2008) Extracellular purines are biomarkers of neutrophilic airway inflammation. Eur Respir J 31:949–956PubMedCrossRefGoogle Scholar
  105. 105.
    Esther CR Jr, Boysen G, Olsen BM, Collins LB, Ghio AJ, Swenberg JW, Boucher RC (2009) Mass spectrometric analysis of biomarkers and dilution markers in exhaled breath condensate reveals elevated purines in asthma and cystic fibrosis. Am J Physiol 296:L987–L993Google Scholar
  106. 106.
    Adriaensen D, Timmermans JP (2004) Purinergic signaling in the lung: important in asthma and COPD? Curr Opin Pharmacol 4:207–214PubMedCrossRefGoogle Scholar
  107. 107.
    Davis CW, Lazarowski E (2008) Coupling of airway ciliary activity and mucin secretion to mechanical stresses by purinergic signaling. Respir Physiol Neurobiol 163:208–213PubMedCrossRefGoogle Scholar
  108. 108.
    Chen Y, Zhao YH, Wu R (2001) Differential regulation of airway mucin gene expression and mucin secretion by extracellular nucleotide triphosphates. Am J Respir Cell Mol Biol 25:409–417PubMedGoogle Scholar
  109. 109.
    Song KS, Lee TJ, Kim KT, Chung KC, Yoon JH (2008) cAMP-responding element-binding protein and c-Ets1 interact in the regulation of ATP-dependent MUC5AC gene expression. J Biol Chem 283:26869–26878PubMedCrossRefGoogle Scholar
  110. 110.
    Blackburn MR, Datta SK, Kellems RE (1998) Adenosine deaminase-deficient mice generated using a two-stage genetic engineering strategy exhibit a combined immunodeficiency. J Biol Chem 273:5093–5100PubMedCrossRefGoogle Scholar
  111. 111.
    Blackburn MR, Datta SK, Wakamiya M, Vartabedian BS, Kellems RE (1996) Metabolic and immunologic consequences of limited adenosine deaminase expression in mice. J Biol Chem 271:15203–15210PubMedCrossRefGoogle Scholar
  112. 112.
    Chunn JL, Young HW, Banerjee SK, Colasurdo GN, Blackburn MR (2001) Adenosine-dependent airway inflammation and hyperresponsiveness in partially adenosine deaminase-deficient mice. J Immunol 167:4676–4685PubMedGoogle Scholar
  113. 113.
    Chunn JL, Mohsenin A, Young HWJ, Lee CG, Elias JA, Kellems RE, Blackburn MR (2006) Partially adenosine deaminase-deficient mice develop pulmonary fibrosis in association with adenosine elevations. Am J Physiol 290:L579–L587Google Scholar
  114. 114.
    Blackburn K, Lee CG, Young HWJ, Zhu Z, Chunn JL, Kang MJ, Banerjee SK, Elias JA (2003) Adenosine mediates IL-13-induced inflammation and remodeling in the lung and interacts in an IL-13-adenosine amplification pathway. J Clin Invest 112:332–344PubMedGoogle Scholar
  115. 115.
    Kuperman DA, Schleimer RP (2008) Interleukin-4, interleukin-13, signal transducer and activator of transcription factor 6, and allergic asthma. Curr Mol Med 8:384–392PubMedCrossRefGoogle Scholar
  116. 116.
    Tesfaigzi Y (2008) Regulation of mucous cell metaplasia in bronchial asthma. Curr Mol Med 8:408–415PubMedCrossRefGoogle Scholar
  117. 117.
    Laoukili J, Perret E, Willems T, Minty A, Parthoens E, Houcine O, Coste A, Jorissen M, Marano F, Caput D, Tournier F (2001) IL-13 alters mucociliary differentiation and ciliary beating of human respiratory epithelial cells. J Clin Invest 108:1817–1824PubMedGoogle Scholar
  118. 118.
    Okada SF, Zhang L, Kreda SM, Abdullah LH, Davis CW, Pickles RJ, Lazarowski ER, Boucher RC (2010) Coupled nucleotide and mucin hypersecretion from goblet cell metaplastic human airway epithelium. Am J Respir Cell Mol Biol (in press)Google Scholar
  119. 119.
    Hirsh AJ, Stonebraker J, van Heusden CA, Lazarowski ER, Boucher RC, Picher M (2007) Adenosine deaminase 1 and concentrative nucleoside transporters 2 and 3 regulate adenosine on the apical surface of human airway epithelia: implications for inflammatory lung diseases. Biochemistry 46:10373–10383PubMedCrossRefGoogle Scholar
  120. 120.
    Wilson MS, Wynn TA (2009) Pulmonary fibrosis: pathogenesis, etiology and regulation. Mucosal Immunol 2:103–121PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  1. 1.Department of PathologyUniversity of VermontBurlingtonUSA
  2. 2.Cystic Fibrosis Pulmonary Research and Treatment CenterUniversity of North CarolinaChapel HillUSA

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