Abstract
Pulmonary emphysema is a major manifestation of chronic obstructive pulmonary disease (COPD), which is characterized by progressive destruction of alveolar parenchyma with persistent inflammation of the small airways. Such destruction in the distal respiratory tract is irreversible and irreparable. All-trans-retinoic acid was suggested as a novel therapy for regeneration of lost alveoli in emphysema. However, profound discrepancies were evident between studies. At present, no effective therapeutic options are available that allow for the regeneration of lost alveoli in emphysematous human lungs. Recently, some reports on rodent’s models have suggested the beneficial effects of various growth factors toward alveolar maintenance and repair processes.
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Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS (2001) Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) workshop summary. Am J Respir Crit Care Med 163:1256–1276
Lopez AD, Murray CC (1998) The global burden of disease, 1990–2020. Nat Med 4:1241–1243
Mannino DM, Buist AS (2007) Global burden of COPD: risk factors, prevalence, and future trends. Lancet 370:765–773
Halbert RJ, Natoli JL, Gano A, Badamgarav E, Buist AS, Mannino DM (2006) Global burden of COPD: systematic review and meta-analysis. Eur Respir J 28:523–532
Barnes PJ (1999) Molecular genetics of chronic obstructive pulmonary disease. Thorax 54:245–252
Snider GL, Kleinerman J, Thurlbeck WM, Bengali ZH (1985) The definition of emphysema. Am Rev Respir Dis 132:181–185
Massaro GDC, Massaro D (1997) Retinoic acid treatment abrogates elastase induced pulmonary emphysema in rats. Nat Med 3:675–677
Chinoy MR (2003) Lung growth and development. Front Biosci 8:D392–D415
Kimura Y, Suzuki T, Kaneko C, Darnel AD, Moriya T, Suzuki S, Handa M, Ebina M, Nukiwa T, Sasano H (2002) Retinoid receptors in the developing human lung. Clin Sci 103:613–621
Veness-Meehan KA, Bottone FG Jr, Stiles AD (2000) Effects of retinoic acid on air space development and lung collagen in hyperoxia-exposed newborn rats. Pediatr Res 48:434–444
Randell SH, Mercer RR, Young SL (1989) Postnatal growth of pulmonary acini and alveoli in normal and oxygen-exposed rats studied by serial section reconstructions. Am J Anat 186:55–68
Paiva SA, Godoy I, Vannucchi H, Favaro RM, Geraldo RR, Campana AO (1996) Assessment of vitamin A status in chronic obstructive pulmonary disease patients and healthy smokers. Am J Clin Nutr 64:928–934
Mao JT, Goldin JG, Dermand J, Ibrahim G, Brown MS, Emerick A, McNitt-Gray MF, Gjertson DW, Estrada F, Tashkin DP, Roth MD (2002) A pilot study of all-trans-retinoic acid for the treatment of human emphysema. Am J Respir Crit Care Med 165:718–723
Meshi B, Vitalis TZ, Ionescu D, Elliott WM, Liu C, Wang XD, Hayashi S, Hogg JC (2002) Emphysematous lung destruction by cigarette smoke. The effects of latent adenoviral infection on the lung inflammatory response. Am J Respir Cell Mol Biol 26:52–57
Fujita M, Ye Q, Ouchi H, Nakashima N, Hamada N, Hagimoto N, Kuwano K, Mason RJ, Nakanishi Y (2004) Retinoic acid fails to reverse emphysema in adult mouse models. Thorax 59:224–230
March TH, Cossey PY, Esparza DC, Dix KJ, McDonald JD, Bowen LE (2004) Inhalation administration of all-trans-retinoic acid for treatment of elastase induced pulmonary emphysema in Fischer 344 rats. Exp Lung Res 30:383–404
Seifart C, Muyal JP, Plagens A, Yildirim AÖ, Kohse K, Grau V, Sandu S, Reinke C, Tschernig T, Vogelmeier C, Fehrenbach H (2011) All-trans retinoic acid results in irregular repair of septa and fails to inhibit proinflammatory macrophages. Eur Respir J 38(2):425–439
Takahashi S, Nakamura H, Seki M, Shiraishi Y, Yamamoto M, Furuuchi M, Nakajima T, Tsujimura S, Shirahata T, Nakamura M, Minematsu N, Yamasaki M, Tateno H, Ishizaka A (2008) Reversal of elastase-induced pulmonary emphysema and promotion of alveolar epithelial cell proliferation by simvastatin in mice. Am J Physiol Lung Cell Mol Physiol 294:L882–L890
Johnson BA, Iacono AT, Zeevi A, McCurry KR, Duncan SR (2003) Statin use is associated with improved function and survival of lung allografts. Am J Respir Crit Care Med 167:1271–1278
Weis M, Pehlivanli S, Meiser BM, von Scheidt W (2001) Simvastatin treatment is associated with improvement in coronary endothelial function and decreased cytokine activation in patients after heart transplantation. J Am Coll Cardiol 38:814–818
Fehrenbach H (2001) Alveolar epithelial type II cell: defender of the alveolus revisited. Respir Res 2:33–46
Witschi H (1976) Proliferation of type II alveolar cells: a review of common responses in toxic lung injury. Toxicology 5:267–277
Kheradmand F, Folkesson HG, Shum L, Derynk R, Pytela R, Matthay MA (1994) Transforming growth factor-α enhances alveolar epithelial cell repair in a new in vitro model. Am J Physiol 267:L728–L738
Garat C, Kheradmand F, Albertine KH, Folkesson HG, Matthay MA (1996) Soluble and insoluble fibronectin increases alveolar epithelial wound healing in vitro. Am J Physiol 271:L844–L853
Warburton D, Bellusci S (2004) The molecular genetics of lung morphogenesis repair. Paediatr Respir Rev 5(Suppl 1):S283–S287
Shannon JM, Deterding RR (1997) Epithelial-mesenchymal interactions in lung development. In: McDonald JA (ed) Lung growth and development. Marcel Dekker, Inc., New York, pp 81–118
O’Reilly MA, Stripp BR, Pryhuber GS (1997) Epithelial-mesenchymal interactions in the alteration of gene expression and morphology following lung injury. Microsc Res Tech 38:473–479
Ware LB, Matthay MA (2002) Keratinocyte and hepatocyte growth factors in the lung: roles in lung development, inflammation, and repair. Am J Physiol Lung Cell Mol Physiol 282:L924–L940
Bussolino F, Di Renzo MF, Ziche M, Bocchietto E, Olivero M, Naldini L, Gaudino G, Tamagnone L, Coffer A, Comoglio PM (1992) Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth. J Cell Biol 119:629–641
Kaza AK, Laubach VE, Kern JA, Long SM, Fiser SM, Tepper JA, Nguyen RP, Shockey KS, Tribble CG, Kron IL (2000) Epidermal growth factor augments postpneumonectomy lung growth. J Thorac Cardiovasc Surg 120:916–921
Ross R, Glomset JA, Kariya B, Harker L (1974) A platelet-dependent serum factor that stimulates the proliferation of arterial smooth muscle cells in vitro. Proc Natl Acad Sci USA 71:1207–1210
Kohler N, Lipton A (1974) Platelets as a source of fibroblast growth-promoting activity. Exp Cell Res 87:297–301
Maeda S, Suzuki S, Suzuki T, Endo M, Moriya T, Chida M, Kondo T, Sasano H (2002) Analysis of intrapulmonary vessels and epithelial–endothelial interactions in the human developing lung. Lab Invest 82(3):293–301
Ng YS, Rohan R, Sunday ME, Demello DE, D’Amore PA (2001) Differential expression of VEGF isoforms in mouse during development and in the adult. Dev Dyn 220:112–121
Cross MJ, Claesson-Welsh L (2001) FGF and VEGF function in angiogenesis: signalling pathways, biological responses and therapeutic inhibition. Trends Pharmacol Sci 22:201–207
Dvorak HF, Brown LF, Detmar M, Dvorak AM (1995) Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 146:1029–1039
Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML, Schuh AC (1995) Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 6 376(6535):62–66
Desai TJ, Cardoso WV (2001) Growth factors in lung development and disease: friends or foe? Respir Res 2002 3:2
Liang Q, Mohan RR, Chen L, Wilson SE (1998) Signaling by HGF and KGF in corneal epithelial cells: Ras/MAP kinase and Jak-STAT pathways. Invest Ophthalmol Vis Sci 39:1329–1338
Portnoy J, Curran-Everett D, Mason RJ (2004) Keratinocyte growth factor stimulates alveolar type II cell proliferation through the extracellular signal-regulated kinase and phosphatidylinositol 3-OH kinase pathways. Am J Respir Cell Mol Biol 30:901–907
Nakamura T, Nawa K, Ichihara A (1984) Partial purification and characterization of hepatocyte growth factor from serum of hepatectomized rats. Biochem Biophys Res Commun 122:1450–1459
Mason RJ (2002) Hepatocyte growth factor. The key to alveolar septation? Am J Respir Cell Mol Biol 26:517–520
Panos RJ, Rubin JS, Csaky KG, Aaronson SA, Mason RJ (1993) Keratinocyte growth factor and hepatocyte growth factor/scatter factor are heparin-binding growth factors for alveolar type II cells in fibroblast-conditioned medium. J Clin Investig 92:969–977
Ohmichi H, Matsumoto K, Nakamura T (1996) In vivo mitogenic action of HGF on lung epithelial cells: pulmotrophic role in lung regeneration. Am J Physiol 270:L1031–L1039
Furuyama A, Mochitate K (2004) Hepatocyte growth factor inhibits the formation of the basement membrane of alveolar epithelial cells in vitro. Am J Physiol Lung Cell Mol Physiol 286:L939–L946
Sakamaki Y, Matsumoto K, Mizuno S, Miyoshi S, Matsuda H, Nakamura T (2001) Hepatocyte growth factor stimulates proliferation of respiratory epithelial cells during postpneumonectomy compensatory lung growth in mice. Am J Respir Cell Mol Biol 26:525–533
Plantier L, Marchand-Adam S, Marchal-Somme J, Leseche G, Foumier M, Dehoux M, Aubier M, Crestani B (2005) Defect of hepatocyte growth factor production by fibroblasts in human pulmonary emphysema. Am J Physiol Lung Cell Mol Physiol 288:L641–L647
Bonay M, Boutten A, Lecon-Malas V, Marchal J, Soler P, Foumier M, Leseche G, Dehoux M, Crestani B (2005) Hepatocyte and keratinocyte growth factors and their receptors in human lung emphysema. BMC Pulm Med 5:13
Griffiths MJ, Bonnet D, Janes SM (2005) Stem cells of the alveolar epithelium. Lancet 366:249–260
Ishizawa K, Kubo H, Yamada M, Kobayashi S, Suzuki T, Mizuno S, Nakamura T, Sasaki H (2004) Hepatocyte growth factor induces angiogenesis in injured lungs through mobilizing endothelial progenitor cells. Biochem Biophys Res Commun 324:276–280
Hegab AE, Kubo H, Yamaya M, Asada M, He M, Fujino N, Mizuno S, Nakamura T (2008) Intranasal HGF administration ameliorates the physiologic and morphologic changes in lung emphysema. Mol Ther 16(8):1417–1426
Yamashita T, Yoshioka M, Itoh N (2000) Identification of a novel fibroblast growth factor, FGF-23, preferentially expressed in the ventrolateral thalamic nucleus of the brain. Biochem Biophys Res Commun 277:494–498
Klagsbrun M (1989) The fibroblast growth factor family: structural and biological properties. Prog Growth Factor Res 1:207–235
Thomas KA (1987) Fibroblast growth factors. FASEB J 1:434–440
Basilico C, Moscatelli D (1992) The FGF family of growth factors and oncogenes. Adv Cancer Res 59:115–165
Martin GR (1998) The roles of FGFs in the early development of vertebrate limbs. Genes Dev 12:1571–1586
Peters KG, Werner S, Chen G, Williams LT (1992) Two FGF receptor genes are differentially expressed in epithelial and mesenchymal tissues during limb formation and organogenesis in the mouse. Development 114:233–243
Orr-Urtreger A, Bedford MT, Burakova T, Arman E, Zimmer Y, Yayon A, Givol D, Lonai P (1993) Developmental localization of the splicing alternatives of fibroblast growth factor receptor-2 (FGFR2). Dev Biol 158:475–486
Mason IJ (1994) The ins and outs of fibroblast growth factors. Cell 78:547–552
McKeehan WL, Wang F, Kan M (1998) The heparan sulfate–fibroblast growth factor family: diversity of structure and function. Prog Nucleic Acids Res Mol Biol 59:135–176
Johnson DE, Lu J, Chen H, Werner S, Williams LT (1991) The human fibroblast growth factor receptor genes: a common structural arrangement underlies the mechanisms for generating receptor forms that differ in their third immunoglobulin domain. Mol Cell Biol 11:4627–4634
Finch PW, Rubin JS, Miki T, Ron D, Aaronson SA (1989) Human KGF is FGF-related with properties of a paracrine effector of epithelial cell growth. Science 245:752–755
Wen J, Hsu E, Kenney WC, Philo JS, Morris CF, Arakawa T (1996) Characterization of keratinocyte growth factor binding to heparin and dextran sulfate. Arch Biochem Biophys 332:41–46
Staiano-Coico L, Krueger JG, Rubin JS, D’Limi S, Vallat VP, Valentino L, Fahey T 3rd, Hawes A, Kingston G, Madden MR, Mathwich M, Gottlieb A, Aaronson SA (1993) Human keratinocyte growth factor effects in a porcine model of epidermal wound healing. J Exp Med 178:865–878
Sotozono C, Inatomi T, Nakamura M, Kinoshita S (1995) Keratinocyte growth factor accelerates corneal epithelial wound healing in vivo. Invest Ophthalmol Vis Sci 36:1524–1529
Zeeh JM, Procaccino F, Hoffmann P, Aukerman SL, McRoberts JA, Soltani S, Pierce GF, Lakshmanan J, Lacey D, Eysselein VE (1996) Keratinocyte growth factor ameliorates mucosal injury in an experimental model of colitis in rats. Gastroenterology 110:1077–1083
Rubin JS, Osada H, Finch PW, Taylor WG, Rudikoff S, Aaronson SA (1989) Purification and characterization of a newly identified growth factor specific for epithelial cells. Proc Natl Acad Sci USA 86:802–806
Winkles JA, Alberts GF, Chedid M, Taylor WG, Demartino S, Rubin JS (1997) Differential expression of the keratinocyte growth factor (KGF) and KGF receptor genes in human vascular smooth muscle cells and arteries. J Cell Physiol 173:380–386
Smola H, Thiekötter, Fusenig NE (1993) Mutual induction of growth factor gene expression by epidermal–dermal cell interaction. J Cell Biol 122:417–429
Boismenu R, Havran WL (1994) Modulation of epithelial cell growth by intraepithelial γδT cells. Science 266:1253–1255
Igarashi M, Finch PW, Aaronson SA (1998) Characterization of recombinant human fibroblast growth factor (FGF)-10 reveals functional similarities with keratinocyte growth factor (FGF-7). J Biol Chem 273:13230–13235
Aaronson SA, Bottaro DP, Miki T, Ron D, Finch PW, Fleming TP, Ahn J, Taylor WG, Rubin JS (1991) Keratinocyte growth factor: a fibroblast growth factor family member with unusual target cell specificity. Ann NY Acad Sci 638:62–77
Miki T, Fleming TP, Bottaro DP, Rubin JS, Ron D, Aaronson SA (1991) Expression cDNA cloning of the KGF receptor by creation of a transforming autocrine loop. Science 251:72–75
Ulich TR, Yi ES, Longmuir K, Yin S, Biltz R, Morris CF, Housley RM, Pierce GF (1994) Keratinocyte growth factor is a growth factor for type II pneumocytes in vivo. J Clin Investig 93:1298–1306
Fehrenbach H, Kasper M, Tschernig T, Pan T, Schuh D, Shannon JM, Muller M, Mason RJ (1999) Keratinocyte growth factor-induced hyperplasia of rat alveolar type II cells in vivo is resolved by differentiation into type I cells and apoptosis. Eur Respir J 14:534–544
Michelson PH, Tigue M, Panos RJ, Sporn PH (1999) Keratinocyte growth factor stimulates bronchial epithelial cell proliferation in vitro and in vivo. Am J Physiol Lung Cell Mol Physiol 277:L737–L742
Panos RJ, Bak PM, Simone WS, Rubin JS, Smith LJ (1995) Intratracheal instillation of KGF decreases hyperoxia-induced mortality in rats. J Clin Investig 96:2026–2033
Deterding RR, Havill AM, Yano T, Middleton SC, Jacoby CR, Shannon JM, Simonet WS, Mason RJ (1997) Prevention of bleomycin-induced lung injury in rats by keratinocyte growth factor. Proc Assoc Am Phys 109:254–268
Sugahara K, Iyama K, Kuroda MJ, Sano K (1998) Double intratracheal instillation of keratinocyte growth factor prevents bleomycin-induced lung fibrosis in rats. J Pathol 186:90–98
Viget NB, Guery BPH, Ader F, Neviere R, Alfandari S, Creuzy C, Roussel-Delvallez M, Foucher C, Mason CM, Beaucaire G, Pittet JF (2000) Keratinocyte growth factor protects against Pseudomonas aeruginosa-induced lung injury. Am J Physiol Lung Cell Mol Physiol 279:L1199–L1209
Nemzek JA, Ebong SJ, Kim J, Bolgos GL, Remick DG (2002) Keratinocyte growth factor pretreatment is associated with decreased MIP-2 concentrations and reduced neutrophil recruitment in acid aspiration lung injury. Shock 18:501–506
Yano T, Deterding RR, Simonet WS, Shannon JM, Mason RJ (1996) Keratinocyte growth factor reduces lung damage due to acid instillation in rats. Am J Respir Cell Mol Biol 15:433–442
Ulrich K, Stern M, Goddard ME, Williams J, Zhu J, Dewar A, Painter HA, Jeffery PK, Gill DR, Hyde SC, Geddes DM, Takata M, Alton EW (2005) Keratinocyte growth factor therapy in murine oleic acid-induced acute lung injury. Am J Physiol Lung Cell Mol Physiol 288:L1179–L1192
Yi ES, Williams ST, Lee H, Malicki DM, Chin EM, Yin S, Tarpley J, Ulich TR (1996) Keratinocyte growth factor ameliorates radiation- and bleomycin-induced lung injury and mortality. Am J Pathol 149:1963–1970
Plantier L, Marchand-Adam S, Antico VG, Boyer L, De CC, Marchal J, Bachoual R, Mailleux A, Boczkowski J, Crestani B (2007) Keratinocyte growth factor protects against elastase-induced pulmonary emphysema in mice. Am J Physiol Lung Cell Mol Physiol 293:L1230–L1239
Yaldirim AO, Muyal V, John G, Müller B, Seifart C, Kasper M, Fehrenbach H (2010) Palifermin induces alveolar maintenance programs in emphysematous mice. Am J Respir Crit Care Med 181(7):705–717
Kuang PP, Zhang XH, Rich CB, Foster JA, Subramanian M, Goldstein RH (2007) Activation of elastin transcription by transforming growth factor beta in human lung fibroblasts. Am J Physiol Lung Cell Mol Physiol 292:L944–L952
Shifren A, Mecham RP (2006) The stumbling block in lung repair of emphysema: elastic fiber assembly. Proc Am Thorac Soc 3:428–433
Wendel DP, Taylor DG, Albertine KH, Keating MT, Li DY (2000) Impaired distal airway development in mice lacking elastin. Am J Respir Cell Mol Biol 23:320–326
Morris DG, Huang X, Kaminski N, Wang Y, Shapiro SD, Dolganov G, Glick A, Sheppard D (2003) Loss of integrin alpha(v)beta6-mediated TGF-beta activation causes Mmp12-dependent emphysema. Nature 422:169–173
Chen H, Sun J, Buckley S, Chen C, Warburton D, Wang XF, Shi W (2005) Abnormal mouse lung alveolarization caused by Smad3 deficiency is developmental antecedent centrilobular emphysema. Am J Physiol Lung Cell Mol Physiol 288:L683–L691
Gerber HP, Hillan KJ, Ryan AM, Kowalski J, Keller GA, Rangell L, Wright BD, Radtke F, Aguet M, Ferrara N (1999) VEGF is required for growth and survival in neonatal mice. Development 126:1149–1159
Ferrara N (2004) Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 25:581–611
Zeltner TB, Caaduff JH, Gehr P, Pfenninger J, Burri PH (1987) The postnatal development and growth of the human lung. I. Morphometry. Respir Physiol 67:247–267
Monacci WT, Merrill MJ, Oldfield EH (1993) Expression of vascular permeability factor/vascular endothelial growth factor in normal rat tissues. Am J Physiol 264:C995–C1002
Mura M, dos Santos CC, Stewart D, Liu M (2004) Vascular endothelial growth factor and related molecules in acute lung injury. J Appl Physiol 97:1605–1617
Tuder RM, Flook BE, Voelkel NF (1995) Increased gene expression for VEGF and the VEGF receptors KDR/Flk and Flt in lungs exposed to acute or to chronic hypoxia. Modulation of gene expression by nitric oxide. J Clin Investig 95:1798–1807
Cross MJ, Claesson-Welsh L (2001) FGF and VEGF function in angiogenesis: signalling pathways, biological responses and therapeutic inhibition. Trends Pharmacol Sci 22:201–207
Matsumoto T, Claesson-Welsh L (2003) VEGF receptor signal transduction. Trends Biochem Sci 2003:488–494
Fong GH, Rossant J, Gertsenstein M (1995) Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376(6535):66–70
Brown KR, England KM, Goss KL (2001) VEGF induces airway epithelial cell proliferation in human fetal lung in vitro. Am J Physiol Lung Cell Mol Physiol 281(4):L1001–L1010
Kasahara Y, Tuder RM, Cool CD, Lynch DA, Flores SC, Voelkel NF (2001) Endothelial cell death and decreased expression of vascular endothelial growth factor receptor 2 in emphysema. Am J Respir Crit Care Med 163:737–744
Marwick JA, Stevenson CS, Giddings J, MacNee W, Butler K, Rahman I, Kirkham PA (2006) Cigarette smoke disrupts VEGF165-VEGFR-2 receptor signaling complex in rat lungs and patients with COPD: morphological impact of VEGFR-2 inhibition. Am J Physiol Lung Cell Mol Physiol 290:L897–L908
Kasahara Y, Tuder RM, Taraseviciene-Stewart L, Le Cras TD, Abman S, Hirth PK, Waltenberger J, Voelkel NF (2000) Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J Clin Investig 106:1311–1319
Fadok VA, Bratton DL, Rose DM, Pearson A, Ezekewitz RAB, Henson PM (2000) A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature 405:85–90
Vandivier RW, Fadok VA, Ogden CA, Hoffmann PR, Brain JD, Accurso FJ, Fisher JH, Greene KE, Henson PM (2002) Impaired clearance of apoptotic cells from cystic fibrosis airways. Chest 121:89S
Hodge S, Hodge G, Scicchitano R, Reynolds PN, Holmes M (2003) Alveolar macrophages from subjects with chronic obstructive pulmonary disease are deficient in their ability to phagocytose apoptotic airway epithelial cells. Immunol Cell Biol 81:289–296
Wyllie AH, Kerr JF, Currie AR (1980) Cell death: the significance of apoptosis. Int Rev Cytol 68:251–306
Odaka C, Mizuochi T, Yang J, Ding A (2003) Murine macrophages produce secretory leukocyte protease inhibitor during clearance of apoptotic cells: implications for resolution of the inflammatory response. J Immunol 171:1507–1514
Morimoto K, Amano H, Sonoda F, Baba M, Senba M, Yoshimine H, Yamamoto H, Ii T, Oishi K, Nagatake T (2001) Alveolar macrophages that phagocytose apoptotic neutrophils produce hepatocyte growth factor during bacterial pneumonia in mice. Am J Respir Cell Mol Biol 24:608–615
Golpon HA, Fadok VA, Taraseviciene-Stewart L, Scerbavicius R, Sauer C, Welte T, Henson PM, Voelkel NF (2004) Life after corpse engulfment: phagocytosis of apoptotic cells leads to VEGF secretion and cell growth. FASEB J 18:1716–1718
Vandivier RW, Tuder RM, Morimoto K, Voelkel NF, Henson PM (2006) Vascular endothelial growth factor regulates clearance of apoptotic cells: implications for emphysema. Proc Am Thorac Soc 3:552
Kearns MT, Dalal S, Horstmann SA, Richens TR, Tanaka T, Doe JM, Boe DM, Voelkel NF, Taraseviciene-Stewart L, Janssen WJ, Lee CG, Elias JA, Bratton D, Tuder RM, Henson PM, Vandivier RW (2012) Vascular endothelial growth factor enhances macrophage clearance of apoptotic cells. Am J Physiol Lung Cell Mol Physiol 302(7):L711–L718
McGrath-Morrow SA, Cho C, Cho C, Zhen L, Hicklin DJ, Tuder RM (2005) Vascular endothelial growth factor receptor 2 blockade disrupts postnatal lung development. Am J Respir Cell Mol Biol 32:420–427
Westermark B, Wasteson A (1976) A platelet factor stimulating human normal glial cells. Exp Cell Res 98:170–174
Bauer EA, Cooper TW, Huang JS, Altman J, Deuel TF (1985) Stimulation of in vitro human skin collagenase expression by platelet-derived growth factor. Proc Natl Acad Sci USA 82:4132–4136
Majack RA, Cook SC, Bornstein P (1985) Platelet-derived growth factor and heparin-like glycosaminoglycans regulate thrombospondin synthesis and deposition in the matrix by smooth muscle cells. J Cell Biol 101:1059–1070
Barrett TB, Gajdusek CM, Schwartz SM, McDougall JK, Benditt EP (1984) Expression of the sis gene by endothelial cells in culture and in vivo. Proc Natl Acad Sci USA 81:6772–6774
Goustin AS, Betsholtz C, Pfeifer-Ohlsson S, Persson H, Rydnert J, Bywater M, Holmgren G, Heldin CH, Westermark B, Ohlsson R (1985) Co-expression of the sis and myc proto-oncogenes in developing human placenta suggests autocrine control of trophoblast growth. Cell 41:301–312
Martinet Y, Bitterman PB, Mornex JF, Grotendorst GR, Martin GR, Crystal RG (1986) Activated human monocytes express the c-sis proto-oncogene and release a mediator showing PDGF-like activity. Nature 319:158–160
Reigstad LJ, Varhaug JE, Lillehaug JR (2005) Structural and functional specificities of PDGF-C and PDGF-D, the novel members of the platelet-derived growth factors family. FEBS J 272:5723–5741
Yarden Y, Escobedo JA, Kuang WJ, Yang-Feng TL, Daniel TO, Trembel PM, Chen EY, Ando ME, Harkins RN, Francke U, Fried VA, Ullrich A, Williams LT (1986) Structure of the receptor for platelet-derived growth factor helps define a family of closely related growth factor receptors. Nature 323:226–232
Hart CE, Forstrom JW, Kelley JD, Seifert RA, Smith RA, Ross R, Murray MJ, Bowen-Pope DF (1988) Two classes of PDGF receptor recognize different isoforms of PDGF. Science 240:1529–1531
Ataliotis P, Symes K, Chou MM, Ho L, Mercola M (1995) PDGF signalling is required for gastrulation in Xenopus laevis. Development 121:3099–3110
Lindahl P, Johansson B, Levéen P, Betsholtz C (1997) Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277:242–245
Levéen P, Pekny M, Gebre-Medhin S, Swolin B, Larsson E, Betsholtz C (1994) Mice deficient for PDGF B show renal, cardiovascular and hematological abnormalities. Genes Dev 8:1875–1887
Boström H, Willetts K, Pekny M, Levéen P, Lindahl P, Hedstrand H, Pekna M, Hellström M, Gebre-Medhin S, Schalling M, Nilsson M, Kurland S, Törnell J, Heath JK, Betsholtz C (1996) PDGF-A signaling is a critical event in lung alveolar myofibroblast development and alveogenesis. Cell 85:863–873
Noguchi A, Reddy R, Kursar JD, Parks WC, Mecham RP (1989) Smooth muscle isoactin and elastin in fetal bovine lung. Exp Lung Res 4:537–552
Kapanchi Y, Assimacopoulos A, Irle C, Zwahlen A, Gabbigrants G (1974) Contractile interstitial cells in pulmonary alveolar septa: a possible regulator of ventilation/perfusion ratio? J Cell Biol 60:375–392
Kapanchi Y, Gabbiani G (1997) Contractile cells in pulmonary alveolar tissue. In: Crystal RG, West JB, Weibel ER, Barnes PJ (eds) The lung. Scientific foundations, 2nd edn. Lippincott-Raven Publishers, Philadelphia, pp 697–707
Lindahl P, Karlsson L, Hellström M, Gebre-Medhin S, Willetts K, Heath JK, Betsholtz C (1997) Alveogenesis failure in PDGF-A-deficient mice is coupled to lack of distal spreading of alveolar smooth muscle cell progenitors during lung development. Development 124:3943–3953
Laschke MW, Elitzsch A, Vollmer B, Vajkoczy P, Menger MD (2006) Combined inhibition of vascular endothelial growth factor (VEGF), fibroblast growth factor and platelet-derived growth factor, but not inhibition of VEGF alone, effectively suppress angiogenesis and vessel maturation in endometriotic lesions. Hum Reprod 21:262–268
Hellström M, Gerhardt H, Kalen M, Li X, Eriksson U, Wolburg H, Betsholtz C (2001) Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J Cell Biol 153:543–553
Magnusson PU, Looman C, Ahgren A, Wu Y, Claesson-Welsh L, Heuchel RL (2007) Platelet-derived growth factor receptor-beta constitutive activity promotes angiogenesis in vivo and in vitro. Arterioscler Thromb Vasc Biol 27:2142–2149
von Tell D, Armulik A, Betsholtz C (2006) Pericyte and vascular stability. Exp Cell Res 312:623–629
Derynck R (1986) Transforming growth factor-α: structure and biologic activities. J Cell Biochem 32:293–304
King RJ, Jones MB, Minoo P (1989) Regulation of lung cell proliferation by polypeptides growth factors. Am J Physiol 257:L23–L38
Carpenter G (1987) Receptors for epidermal growth factor and other polypeptide mitogens. Annu Rev Biochem 56:881–914
Stoscheck CM, King LE (1986) Functional and structural characteristics of EGF and its receptor and their relationship to transforming proteins. J Cell Biochem 31:135–152
Raaberg L, Nexo E, Buckley S, Luo W, Snead ML, Warburton D (1992) Epidermal growth factor transcription, translation, and signal transduction by rat type II pneumocytes in culture. Am J Respir Cell Mol Biol 6:44–49
Jetten AM (1991) Growth and differentiation factors in tracheobronchial epithelium. Am J Physiol 4(260):L361–L373
Schuger L, Varani J, Mitra R, Gilbride K (1993) Retinoic acid stimulates mouse lung development by a mechanism involving epithelial-mesenchymal interaction and regulation of epidermal growth factor receptors. Dev Biol 159:462–473
Warburton D, Seth R, Shum L, Horcher PG, Hall FL, Werb Z, Slavkin HC (1992) Epigenetic role of epidermal growth factor expression and signalling in embryonic mouse lung morphogenesis. Dev Biol 149:123–133
Ganser GL, Stricklin GP, Matrisian LM (1991) EGF and TGF-α influence in vitro lung development by the induction of matrix-degrading metalloproteinases. Int J Dev Biol 35:453–461
Ryan RM, Mineo-Kuhn MM, Kramer CM, Finkelstein JN (1994) Growth factors alter neonatal type II alveolar epithelial cell proliferation. Am J Physiol Lung Cell Mol Physiol 266:L17–L22
Ruocco S, Lallemand A, Tournier JM, Gaillard D (1996) Expression and localization of epidermal growth factor, transforming growth factor-alpha, and localization of their common receptor in fetal human lung development. Pediatr Res 39:448–455
Plopper CG, St George JA, Read LC, Nishio SJ, Weir AJ, Edwards L, Tarantal AF, Pinkerton KE, Merritt A, Whitsett JA, George-Nascimento C, Styne D (1992) Acceleration of alveolar type II cell differentiation in fetal rhesus monkey lung by administration of EGF. Am J Physiol 262:L313–L321
Gross I, Dynia DW, Rooney SA, Smart DA, Warshaw JB, Sissom JF, Hoath SB (1986) Influence of epidermal growth factor on fetal rat lung development in vitro. Pediatr Res 20:473–477
Zahm JM, Chevillard M, Puchelle E (1991) Wound repair of human surface respiratory epithelium. Am J Respir Cell Mol Biol 5:242–248
Clark RAF, Mason RJ, Folkvord JM, McDonald JA (1986) Fibronectin mediates adherence of rat alveolar type II epithelial cells via the fibroblastic cell-attachment domain. J Clin Investig 77:1831–1840
Crouch EC (1990) Pathobiology of pulmonary fibrosis. Am J Physiol 259:L159–L184
Torikata C, Villiger B, Kuhn C III, McDonald JA (1985) Ultrastructural distribution of fibronectin in normal and fibrotic human lung. Lab Invest 52:399–408
Dos Santos CC (2008) Advances in mechanisms of repair and remodelling in acute lung injury. Intensive Care Med 34:619–630
Uhal BD, Flowers KM, Rannels DE (1991) Type II pneumocyte proliferation in vitro: problems and future directions. Am J Physiol Suppl 261:L110–L117
Lesur O, Arsalane K, Lane D (1996) Lung alveolar epithelial cell migration in vitro: modulators and regulation processes. Am J Physiol Lung Cell Mol Physiol 270:L311–L319
Trinh NT, Prive A, Maille E, Noel J, Brochiero E (2008) EGF and K+ channel activity control normal and cystic fibrosis bronchial epithelia repair. Am J Physiol Lung Cell Mol Physiol 295:L866–L880
Garcia O, Carraro G, Navarro S, Bertoncello I, McQualter I, Driscoll B, Jesudason E, Warburton D (2012) Cell-based therapies for lung disease. Br Med Bull 101:147–161
Hong KU, Reynolds SD, Watkins S, Fuchs E, Stripp BR (2004) In vivo differentiation potential of tracheal basal cells: evidence for multipotent and unipotent subpopulations. Am J Physiol Lung Cell Mol Physiol 286:L643–L649
Giangreco A, Shen H, Reynolds SD, Stripp BR (2004) Molecular phenotype of airway side population cells. Am J Physiol Lung Cell Mol Physiol 286:L624–L630
Hong KU, Reynolds SD, Giangreco A, Hurley CM, Stripp BR (2001) Clara cell secretory protein-expressing cells of the airway neuroepithelial body microenvironment include a label-retaining subset and are critical for epithelial renewal after progenitor cell depletion. Am J Respir Cell Mol Biol 24:671–681
Giangreco A, Reynolds SD, Stripp BR (2002) Terminal bronchioles harbor a unique airway stem cell population that localizes to the bronchoalveolar duct junction. Am J Pathol 161:173–182
Driscoll B, Buckley S, Bui KC, Anderson KD, Warburton D (2000) Telomerase in alveolar epithelial development and repair. Am J Physiol Lung Cell Mol Physiol 279:L1191–L1198
Krause DS, Theise ND, Collector MI, Henegariu O, Hwang S, Gardner R, Neutzel S, Sharkis SJ (2001) Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 105:369–377
Theise ND, Henegariu O, Grove J, Jagirdar J, Kao PN, Crawford JM, Badve S, Saxena R, Krause DS (2002) Radiation pneumonitis in mice: a severe injury model for pneumocyte engraftment from bone marrow. Exp Hematol 30:1333–1338
Kotton DN, Ma BY, Cardoso WV, Sanderson EA, Summer RS, Williams MC, Fine A (2001) Bone marrow-derived cells as progenitors of lung alveolar epithelium. Development 128:5181–5188
Kotton D, Fine A (2003) Derivation of lung epithelium from bone marrow cells. Cytotherapy 5:169–173
Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, Reyes M, Lenvik T, Lund T, Blackstad M, Du J, Aldrich S, Lisberg A, Low WC, Largaespada DA, Verfaillie CM (2002) Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418:41–49
Fadini GP, Schiavon M, Cantini M, Baesso I, Facco M, Miorin M, Tassinato M, de Kreutzenberg SV, Avogaro A, Agostini C (2006) Circulating progenitor cells are reduced in patients with severe lung disease. Stem Cells 24:1806–1813
Palange P, Testa U, Huertas A, Calabro L, Antonucci R, Petrucci E, Pelosi E, Pasquini L, Satta A, Morici G, Vignola MA, Bonsignore MR (2006) Circulating haemopoietic and endothelial progenitor cells are decreased in COPD. Eur Respir J 27:529–541
Suratt BT, Cool CD, Serls AE, Chen L, Varella-Garcia M, Shpall EJ, Brown KK, Worthen GS (2003) Human pulmonary chimerism after hematopoietic stem cell transplantation. Am J Respir Crit Care Med 168:318–322
Ortiz LA, Gambelli F, McBride C, Gaupp D, Baddoo M, Kaminski N, Phinney DG (2003) Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci USA 100:8407–8411
Rojas M, Xu J, Woods CR, Mora AL, Spears W, Roman J, Brigham KL (2005) Bone marrow-derived mesenchymal stem cells in repair of the injured lung. Am J Respir Cell Mol Biol 33:145–152
Ortiz LA, Dutreil M, Fattman C, Pandey AC, Torres G, Go K, Phinney DG (2007) Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc Natl Acad Sci USA 104:11002–11007
Yuhgetsu H, Ohno Y, Funaguchi N, Asai T, Sawada M, Takemura G (2006) Beneficial effects of autologous bone marrow mononuclear cell transplantation against elastase-induced emphysema in rabbits. Exp Lung Res 32:413–426
Gimble J, Guilak F (2003) Adipose-derived adult stem cells: isolation, characterization, and differentiation potential. Cytotherapy 5:362–369
Pittenger MF, Martin BJ (2004) Mesenchymal stem cells and their potential as cardiac therapeutics. Circ Res 95:9–20
Shigemura N, Okumura M, Mizuno S, Imanishi Y, Nakamura T, Sawa Y (2006) Autologous transplantation of adipose tissue-derived stromal cells ameliorates pulmonary emphysema. Am J Transplant 6:2592–2600
Anderlini P, Przepiorka D, Champlin R, Korbling M (1996) Biological and clinical effects of granulocyte colony-stimulating factor in normal individuals. Blood 88:2819–2825
Basu S, Dunn A, Ward A (2002) G-CSF: function and modes of action (review). Int J Mol Med 10:3–10
Carulli G (1997) Effects of recombinant human granulocyte colony-stimulating factor administration on neutrophil phenotype and functions. Haematologica 82:606–616
Hierholzer C, Kelly E, Tsukada K, Loeffert E, Watkins S, Billiar TR, Tweardy DJ (1997) Hemorrhagic shock induces granulocyte colony-stimulating factor (G-CSF) expression in bronchial epithelium. Am J Physiol 273:L1058–L1064
Lieschke GJ, Burgess AW (1992) Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor. N Engl J Med 327:99–106
Bensinger WI, Price TH, Dale DC, Appelbaum FR, Clift R, Lilleby K, Williams B, Storb R, Thomas ED, Buckner CD (1993) The effects of daily recombinant human granulocyte colony-stimulating factor administration on normal granulocyte donors undergoing leukapheresis. Blood 81:1883–1888
Bungart B, Loeffler M, Goris H, Dontje B, Diehl U, Nijhof W (1990) Differential effects of human granulocyte colony-stimulating factor (rh G-CSF) on stem cells in marrow, spleen and peripheral blood in mice. Br J Haematol 76:174–179
Schmitz N, Dreger P, Suttorp M, Rohwedder EB, Haferlach T, Löffler H, Hunter A, Russell NH (1995) Primary transplantation of allogeneic peripheral blood progenitor cells mobilized by filgrastim (granulocyte colony-stimulating factor). Blood 85:1666–1672
Aliotta JM (2006) Bone marrow production of lung cells: the impact of G-CSF, cardiotoxin, graded doses of irradiation, and subpopulation phenotype. Exp Hematol 34:230–241
Ishizawa K, Kubo H, Yamada M, Kobayashi S, Numasaki M, Ueda S, Suzuki T, Sasaki H (2004) Bone marrow-derived cells contribute to lung regeneration after elastase-induced pulmonary emphysema. FEBS Lett 556:249–252
Yoshida M, Sakuma J, Hayashi S, Kinya A, Saito I, Harada S, Sakatani M, Yamamoto S, Matsumoto N, Kaneda Y, Kishimoto T (1995) A histologically distinctive interstitial pneumonia induced by overexpression of the interleukin 6, transforming growth factor β1, or platelet-derived growth factor B gene. Proc Natl Acad Sci USA 92:9570–9574
Azoulay E, Herigault S, Levame M, Brochard L, Schlemmer B, Harf A, Delclaux C (2003) Effect of granulocyte colony-stimulating factor on bleomycin-induced acute lung injury and pulmonary fibrosis. Crit Care Med 31(5):1442–1448
Adach K, Suzuki M, Sugimoto T, Suzuki S, Niki R, Oyama A, Uetsuka K, Nakamaya H, Doi K (2002) Granulocyte colony-stimulating factor exacerbates the acute lung injury and pulmonary fibrosis induced by intratracheal administration of bleomycin in rats. Exp Toxicol Pathol 53(6):501–510
Gertz MA, Lacy MQ, Bjornsson J, Litzow MR (2000) Fatal pulmonary toxicity related to the administration of granulocyte colony-stimulating factor in amyloidosis: a report and review of growth factor-induced pulmonary toxicity. J Hematother Stem Cell Res 9(5):635–643
Bousquet J, Chanez P, Lacoste JY, White R, Vic P, Godard P, Michel FB (1992) Asthma: a disease remodeling the airways. Allergy 47:3–11
Roche WR, Beasley R, Williams JH, Holgate ST (1989) Subepithelial fibrosis in the bronchi of asthmatics. Lancet 1:520–524
Brewster CE, Howarth PH, Djukanovic R, Wilson J, Holgate ST, Roche WR (1990) Myofibroblasts and subepithelial fibrosis in bronchial asthma. Am J Respir Cell Mol Biol 3:507–511
Vignola AM, Chanez P, Chiappara G, Merendino A, Pace E, Rizzo A, la Rocca AM, Bellia V, Bonsignore G, Bousquet J (1997) Transforming growth factor-β expression in mucosal biopsies in asthma and chronic bronchitis. Am J Respir Crit Care Med 156:591–599
Redington AE, Madden J, Frew AJ, Djukanovic R, Roche WR, Holgate ST, Howarth PH (1997) Transforming growth factor β 1 in asthma: measurement in bronchoalveolar lavage fluid. Am J Respir Crit Care Med 156:642–647
Hoshino M, Nakamura Y, Soon J (1998) Expression of growth factors and remodeling of the airway wall in bronchial asthma. Thorax 53:21–27
Schmidt M, Sun G, Stacey MA, Mori L, Mattoli S (2003) Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma. J Immunol 171(1):380–389
Kenyon NJ, Ward RW, McGrew G, Last JA (2003) TGF-β 1 causes airway fibrosis and increased collagen I and III mRNA in mice. Thorax 58(9):772–777
Pilewski JM, Bumbalo TS III, Davis AG, Siegfried JM (2001) Hepatocyte growth factor promotes tumor growth in a novel in vivo model of human lung cancer. Am J Respir Cell Mol Biol 24(5):556–562
Shih AH, Dai C, Hu X, Rosenblum MK, Koutcher JA, Holland EC (2004) Dose-dependent effects of platelet-derived growth factor-B on glial tumorigenesis. Cancer Res 64(14):4783–4789
Curtis RE, Rowlings PA, Deeg HJ, Shriner DA, Socie G, Travis LB, Horowitz MM, Witherspoon RP, Hoover RN, Sobocinski KA, Fraumeni JF Jr, Boice JD Jr (1997) Solid cancers after bone marrow transplantation. N Engl J Med 336:897–904
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Muyal, J.P., Muyal, V., Kotnala, S. et al. Therapeutic Potential of Growth Factors in Pulmonary Emphysematous Condition. Lung 191, 147–163 (2013). https://doi.org/10.1007/s00408-012-9438-0
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DOI: https://doi.org/10.1007/s00408-012-9438-0