Bronchopulmonary dysplasia (BPD) is the chronic lung disease of prematurity that affects very preterm infants. Although advances in perinatal care have changed the course of lung injury and enabled the survival of infants born as early as 23-24 weeks of gestation, BPD still remains a common complication of extreme prematurity, and there is no specific treatment for it. Furthermore, children, adolescents, and adults who were born very preterm and developed BPD have an increased risk of persistent lung dysfunction, including early-onset emphysema. Therefore, it is possible that early-life pulmonary insults, such as extreme prematurity and BPD, may increase the risk of COPD later in life, especially if exposed to secondary challenges such as respiratory infections and/or smoking. Recent advances in our understanding of stem/progenitor cells and their potential to repair damaged organs offer the possibility of cell-based treatments for neonatal and adult lung injuries. This paper summarizes the long-term pulmonary outcomes of preterm birth and BPD and discusses the recent advances of cell-based therapies for lung diseases, with a particular focus on BPD and COPD. 1. Introduction Intrauterine and early postnatal environments have been shown to play an influential role in the development and maturation of the lung [1]. Suboptimal conditions that interfere with normal development may result in altered lung structure and function and increase the risk for disease later in life. Alarmingly, the onset of adult lung disease following inadequate development and maturation is becoming apparent at an early age. Recently, Wong and colleagues [2] showed that survivors of moderate-severe bronchopulmonary dysplasia (BPD) presented with emphysema in early adulthood (17–33 years of age). Understanding how the fetus and developing lung responds to intrauterine alterations and adapts to the postnatal environment can teach us about basic biology and the implications for adult lung diseases [3, 4]. 2. Early Life Origins of BPD Development of the lung throughout gestation is a vital process required for adequate fetal to neonatal transition at birth. As the fetal lung proceeds through its developmental stages in utero, it becomes progressively prepared for exposure to the external environment. Successful transition to ex utero life at birth is dependent upon the ability of the lungs to effectively function as an organ of gas exchange. Indeed, organs of the developing fetus and newborn infant are extremely plastic and are particularly vulnerable to intrauterine and early
References
[1]
R. Harding and G. Maritz, “Maternal and fetal origins of lung disease in adulthood,” Seminars in Fetal & Neonatal Medicine, vol. 17, pp. 67–72, 2012.
[2]
P. M. Wong, A. N. Lees, J. Louw et al., “Emphysema in young adult survivors of moderate-to-severe bronchopulmonary dysplasia,” European Respiratory Journal, vol. 32, no. 2, pp. 321–328, 2008.
[3]
J. R. Bourbon, O. Boucherat, J. Boczkowski, B. Crestani, and C. Delacourt, “Bronchopulmonary dysplasia and emphysema: in search of common therapeutic targets,” Trends in Molecular Medicine, vol. 15, no. 4, pp. 169–179, 2009.
[4]
D. Warburton, D. Tefft, A. Mailleux et al., “Do lung remodeling, repair, and regeneration recapitulate respiratory ontogeny?” American Journal of Respiratory and Critical Care Medicine, vol. 164, no. 10, pp. S59–S62, 2001.
[5]
L. A. Joss-Moore, K. H. Albertine, and R. H. Lane, “Epigenetics and the developmental origins of lung disease,” Molecular Genetics and Metabolism, vol. 104, pp. 61–66, 2011.
[6]
J. P. Kinsella, A. Greenough, and S. H. Abman, “Bronchopulmonary dysplasia,” Lancet, vol. 367, no. 9520, pp. 1421–1431, 2006.
[7]
S. M. Schulzke and J. J. Pillow, “The management of evolving bronchopulmonary dysplasia,” Paediatric Respiratory Reviews, vol. 11, no. 3, pp. 143–148, 2010.
[8]
D. J. Henderson-Smart, J. L. Hutchinson, D. A. Donoghue, N. J. Evans, J. M. Simpson, and I. Wright, “Prenatal predictors of chronic lung disease in very preterm infants,” Archives of Disease in Childhood: Fetal and Neonatal Edition, vol. 91, no. 1, pp. F40–F45, 2006.
[9]
E. Ralser, W. Mueller, C. Haberland, et al., “Rehospitalization in the first 2 years of life in children born preterm,” Acta Paediatrica, vol. 101, no. 1, pp. e1–e5, 2012.
[10]
L. Friedrich, P. M. C. Pitrez, R. T. Stein, M. Goldani, R. Tepper, and M. H. Jones, “Growth rate of lung function in healthy preterm infants,” American Journal of Respiratory and Critical Care Medicine, vol. 176, no. 12, pp. 1269–1273, 2007.
[11]
O. Hjalmarson and K. Sandberg, “Abnormal lung function in healthy preterm infants,” American Journal of Respiratory and Critical Care Medicine, vol. 165, no. 1, pp. 83–87, 2002.
[12]
L. Friedrich, R. T. Stein, P. M. C. Pitrez, A. L. Corso, and M. H. Jones, “Reduced lung function in healthy preterm infants in the first months of life,” American Journal of Respiratory and Critical Care Medicine, vol. 173, no. 4, pp. 442–447, 2006.
[13]
S. J. Gross, D. M. Iannuzzi, D. A. Kveselis, and R. D. Anbar, “Effect of preterm birth on pulmonary function at school age: A prospective controlled study,” Journal of Pediatrics, vol. 133, no. 2, pp. 188–192, 1998.
[14]
B. Robin, Y. J. Kim, J. Huth et al., “Pulmonary Function in Bronchopulmonary Dysplasia,” Pediatric Pulmonology, vol. 37, no. 3, pp. 236–242, 2004.
[15]
R. S. Tepper, W. J. Morgan, K. Cota, and L. M. Taussig, “Expiratory flow limitation in infants with bronchopulmonary dysplasia,” Journal of Pediatrics, vol. 109, no. 6, pp. 1040–1046, 1986.
[16]
J. E. Balinotti, V. C. Chakr, C. Tiller et al., “Growth of lung parenchyma in infants and toddlers with chronic lung disease of infancy,” American Journal of Respiratory and Critical Care Medicine, vol. 181, no. 10, pp. 1093–1097, 2010.
[17]
I. Narang, “Review series: what goes around, comes around: childhood influences on later lung health? Long-term follow-up of infants with lung disease of prematurity,” Chronic Respiratory Disease, vol. 7, pp. 259–269, 2010.
[18]
J. Fawke, S. Lum, J. Kirkby et al., “Lung function and respiratory symptoms at 11 years in children born extremely preterm: The EPICure study,” American Journal of Respiratory and Critical Care Medicine, vol. 182, no. 2, pp. 237–245, 2010.
[19]
L. W. Doyle, “Respiratory function at age 8-9 years in extremely low birthweight/very preterm children born in Victoria in 1991-1992,” Pediatric Pulmonology, vol. 41, no. 6, pp. 570–576, 2006.
[20]
E. B. Brostr？m, P. Thunqvist, G. Adenfelt, E. Borling, and M. Katz-Salamon, “Obstructive lung disease in children with mild to severe BPD,” Respiratory Medicine, vol. 104, no. 3, pp. 362–370, 2010.
[21]
L. J. Smith, P. P. Van Asperen, K. O. McKay, H. Selvadurai, and D. A. Fitzgerald, “Reduced exercise capacity in children born very preterm,” Pediatrics, vol. 122, no. 2, pp. e287–e293, 2008.
[22]
L. Welsh, J. Kirkby, S. Lum et al., “The EPICure study: maximal exercise and physical activity in school children born extremely preterm,” Thorax, vol. 65, no. 2, pp. 165–171, 2010.
[23]
P. Santuz, E. Baraldi, P. Zaramella, M. Filippone, and F. Zacchello, “Factors limiting exercise performance in long-term survivors of bronchopulmonary dysplasia,” American Journal of Respiratory and Critical Care Medicine, vol. 152, no. 4, pp. 1284–1289, 1995.
[24]
C. E. Bolton, J. Stocks, E. Hennessy, et al., “The EPICure Study: Association between hemodynamics and lung function at 11 years after extremely preterm birth,” Journal of Pediatrics, vol. 161, no. 4, pp. 595–601, 2012.
[25]
H. Clemm, O. Roksund, E. Thorsen, G. E. Eide, T. Markestad, and T. Halvorsen, “Aerobic capacity and exercise performance in young people born extremely preterm,” Pediatrics, vol. 129, pp. e97–e105, 2012.
[26]
D. F. Hacking, A. M. Gibson, C. Robertson, and L. W. Doyle, “Respiratory function at age 8-9 after extremely low birthweight or preterm birth in Victoria in 1997,” Pediatric Pulmonology. In press.
[27]
E. Kaplan, E. B. Yishay, D. Prais, et al., “Encouraging pulmonary outcome for surviving, neurologically intact extremely premature infants in the post surfactant era,” Chest, vol. 142, no. 3, pp. 725–733, 2012.
[28]
P. Korhonen, J. Laitinen, E. Hy？dynmaa, and O. Tammela, “Respiratory outcome in school-aged, very-low-birth-weight children in the surfactant era,” Acta Paediatrica, vol. 93, no. 3, pp. 316–321, 2004.
[29]
S. J. Kotecha, W. J. Watkins, S. Paranjothy, F. D. Dunstan, A. J. Henderson, and S. Kotecha, “Effect of late preterm birth on longitudinal lung spirometry in school age children and adolescents,” Thorax, vol. 67, pp. 54–61, 2012.
[30]
K. Kulasekaran, P. H. Gray, and B. Masters, “Chronic lung disease of prematurity and respiratory outcome at eight years of age,” Journal of Paediatrics and Child Health, vol. 43, no. 1-2, pp. 44–48, 2007.
[31]
X. M. Mai, P. O. G？ddlin, L. Nilsson et al., “Asthma, lung function and allergy in 12-year-old children with very low birth weight: a prospective study,” Pediatric Allergy and Immunology, vol. 14, no. 3, pp. 184–192, 2003.
[32]
T. Halvorsen, B. T. Skadberg, G. E. Eide, O. D. R？ksund, K. H. Carlsen, and P. Bakke, “Pulmonary outcome in adolescents of extreme preterm birth: a regional cohort study,” Acta Paediatrica, International Journal of Paediatrics, vol. 93, no. 10, pp. 1294–1300, 2004.
[33]
L. W. Doyle, B. Faber, C. Callanan, N. Freezer, G. W. Ford, and N. M. Davis, “Bronchopulmonary dysplasia in very low birth weight subjects and lung function in late adolescence,” Pediatrics, vol. 118, no. 1, pp. 108–113, 2006.
[34]
I. Narang, M. Rosenthal, D. Cremonesini, M. Silverman, and A. Bush, “Longitudinal evaluation of airway function 21 years after preterm birth,” American Journal of Respiratory and Critical Care Medicine, vol. 178, no. 1, pp. 74–80, 2008.
[35]
E. J. L. E. Vrijlandt, J. Gerritsen, H. M. Boezen, R. G. Grevink, and E. J. Duiverman, “Lung function and exercise capacity in young adults born prematurely,” American Journal of Respiratory and Critical Care Medicine, vol. 173, no. 8, pp. 890–896, 2006.
[36]
M. Filippone, G. Bonetto, M. Corradi, A. C. Frigo, and E. Baraldi, “Evidence of unexpected oxidative stress in airways of adolescents born very preterm,” European Respiratory Journal, vol. 40, no. 5, pp. 1253–1259, 2012.
[37]
S. M. Aukland, K. Rosendahl, C. M. Owens, K. R. Fosse, G. E. Eide, and Halvorsen, “Neonatal bronchopulmonary dysplasia predicts abnormal pulmonary HRCT scans in long-term survivors of extreme preterm birth,” Thorax, vol. 64, no. 5, pp. 405–410, 2009.
[38]
G. Sharma and J. Goodwin, “Effect of aging on respiratory system physiology and immunology.,” Clinical interventions in aging, vol. 1, no. 3, pp. 253–260, 2006.
[39]
L. Wang, F. H. Y. Green, S. M. Smiley-Jewell, and K. E. Pinkerton, “Susceptibility of the aging lung to environmental injury,” Seminars in Respiratory and Critical Care Medicine, vol. 31, no. 5, pp. 539–553, 2010.
[40]
K. E. Pinkerton and F. H. Y. Green, “Normal Aging of the Lung,” in The Lung: Development, Aging and the Environment, R. Harding, K. E. Pinkerton, and C. G. Plopper, Eds., pp. 213–233, Elsevier, London, UK, 2004.
[41]
K. C. Meyer, “Aging,” Proceedings of the American Thoracic Society, vol. 2, pp. 433–439, 2005.
[42]
K. C. Meyer, W. Ershler, N. S. Rosenthal, X. G. Lu, and K. Peterson, “Immune dysregulation in the aging human lung,” American Journal of Respiratory and Critical Care Medicine, vol. 153, no. 3, pp. 1072–1079, 1996.
[43]
M. Filippone and E. Baraldi, “On early life risk factors for COPD,” American Journal of Respiratory and Critical Care Medicine, vol. 183, no. 3, pp. 415–416, 2011.
[44]
A. H. Jobe, “The new bronchopulmonary dysplasia,” Current Opinion in Pediatrics, vol. 23, no. 2, pp. 167–172, 2011.
[45]
C. Agostini, “Stem cell therapy for chronic lung diseases: hope and reality,” Respiratory Medicine, vol. 104, no. 1, pp. S86–S91, 2010.
[46]
C. J. Blaisdell, D. B. Gail, and E. G. Nabel, “National heart, lung, and blood institute perspective: lung progenitor and stem cells—gaps in knowledge and future opportunities,” Stem Cells, vol. 27, no. 9, pp. 2263–2270, 2009.
[47]
V. Sueblinvong and D. J. Weiss, “Stem cells and cell therapy approaches in lung biology and diseases,” Translational Research, vol. 156, no. 3, pp. 188–205, 2010.
[48]
T. Van Haaften, R. Byrne, S. Bonnet et al., “Airway delivery of mesenchymal stem cells prevents arrested alveolar growth in neonatal lung injury in rats,” American Journal of Respiratory and Critical Care Medicine, vol. 180, no. 11, pp. 1131–1142, 2009.
[49]
C. D. Baker, S. L. Ryan, D. A. Ingram, G. J. Seedorf, S. H. Abman, and V. Balasubramaniam, “Endothelial colony-forming cells from preterm infants are increased and more susceptible to hyperoxia,” American Journal of Respiratory and Critical Care Medicine, vol. 180, no. 5, pp. 454–461, 2009.
[50]
A. Borghesi, M. Massa, R. Campanelli et al., “Circulating endothelial progenitor cells in preterm infants with bronchopulmonary dysplasia,” American Journal of Respiratory and Critical Care Medicine, vol. 180, no. 6, pp. 540–546, 2009.
[51]
X. Liu and C. Xie, “Human endothelial progenitor cells isolated from COPD patients are dysfunctional,” Molecular and Cellular Biochemistry, vol. 363, pp. 53–63, 2012.
[52]
F. Timmermans, J. Plum, M. C. Y？der, D. A. Ingram, B. Vandekerckhove, and J. Case, “Endothelial progenitor cells: identity defined?” Journal of Cellular and Molecular Medicine, vol. 13, no. 1, pp. 87–102, 2009.
[53]
E. K. Kim, J. H. Lee, H. C. Jeong, et al., “Impaired colony-forming capacity of circulating endothelial progenitor cells in patients with emphysema,” The Tohoku Journal of Experimental Medicine, vol. 227, pp. 321–331, 2012.
[54]
M. Aslam, R. Baveja, O. D. Liang et al., “Bone marrow stromal cells attenuate lung injury in a murine model of neonatal chronic lung disease,” American Journal of Respiratory and Critical Care Medicine, vol. 180, no. 11, pp. 1122–1130, 2009.
[55]
K. A. Tropea, E. Leder, M. Aslam, et al., “Bronchioalveolar stem cells increase after mesenchymal stromal cell treatment in a mouse model of bronchopulmonary dysplasia,” American Journal of Physiology, vol. 302, pp. L829–L837, 2012.
[56]
X. Zhang, H. Wang, Y. Shi, et al., “The role of bone marrow-derived mesenchymal stem cells in the prevention of hyperoxia-induced lung injury in newborn mice,” Cell Biology International, vol. 36, pp. 589–594, 2012.
[57]
G. Hansmann, A. Fernandez-Gonzalez, M. Aslam, et al., “Mesenchymal stem cell-mediated reversal of bronchopulmonary dysplasia and associated pulmonary hypertension,” Pulmonary Circulation, vol. 2, pp. 170–181, 2012.
[58]
M. Pierro, L. Ionescu, T. Montemurro, et al., “Short-term, long-term and paracrine effect of human umbilical cord-derived stem cells in lung injury prevention and repair in experimental bronchopulmonary dysplasia,” Thorax. In press.
[59]
Y. S. Chang, S. J. Choi, D. K. Sung, et al., “Intratracheal transplantation of human umbilical cord blood derived mesenchymal stem cells dose-dependently attenuates hyperoxia-induced lung injury in neonatal rats,” Cell Transplantation, vol. 20, pp. 1843–1854, 2011.
[60]
Y. S. Chang, W. Oh, S. J. Choi et al., “Human umbilical cord blood-derived mesenchymal stem cells attenuate hyperoxia-induced lung injury in neonatal rats,” Cell Transplantation, vol. 18, no. 8, pp. 869–886, 2009.
[61]
J. W. Huh, S. Y. Kim, J. H. Lee, et al., “Bone marrow cells repair cigarette smoke-induced emphysema in rats,” American Journal of Physiology, vol. 301, pp. L255–L266, 2011.
[62]
G. Zhen, H. Liu, N. Gu, H. Zhang, Y. Xu, and Z. Zhang, “Mesenchymal stem cells transplantation protects against rat pulmonary emphysema,” Frontiers in Bioscience, vol. 13, no. 9, pp. 3415–3422, 2008.
[63]
N. Shigemura, M. Okumura, S. Mizuno et al., “Lung tissue engineering technique with adipose stromal cells improves surgical outcome for pulmonary emphysema,” American Journal of Respiratory and Critical Care Medicine, vol. 174, no. 11, pp. 1199–1205, 2006.
[64]
N. Shigemura, M. Okumura, S. Mizuno, Y. Imanishi, T. Nakamura, and Y. Sawa, “Autologous transplantation of adipose tissue-derived stromal cells ameliorates pulmonary emphysema,” American Journal of Transplantation, vol. 6, no. 11, pp. 2592–2600, 2006.
[65]
A. M. Katsha, S. Ohkouchi, H. Xin et al., “Paracrine factors of multipotent stromal cells ameliorate lung injury in an elastase-induced emphysema model,” Molecular Therapy, vol. 19, no. 1, pp. 196–203, 2011.
[66]
M. Kumamoto, T. Nishiwaki, N. Matsuo, H. Kimura, and K. Matsushima, “Minimally cultured bone marrow mesenchymal stem cells ameliorate fibrotic lung injury,” European Respiratory Journal, vol. 34, no. 3, pp. 740–748, 2009.
[67]
Y. Moodley, D. Atienza, U. Manuelpillai et al., “Human umbilical cord mesenchymal stem cells reduce fibrosis of bleomycin-induced lung injury,” American Journal of Pathology, vol. 175, no. 1, pp. 303–313, 2009.
[68]
L. A. Ortiz, M. DuTreil, C. Fattman et al., “Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 26, pp. 11002–11007, 2007.
[69]
L. A. Ortiz, F. Gambelli, C. McBride et al., “Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 14, pp. 8407–8411, 2003.
[70]
M. Rojas, J. Xu, C. R. Woods et al., “Bone marrow-derived mesenchymal stem cells in repair of the injured lung,” American Journal of Respiratory Cell and Molecular Biology, vol. 33, no. 2, pp. 145–152, 2005.
[71]
J. W. Lee, X. Fang, A. Krasnodembskaya, J. P. Howard, and M. A. Matthay, “Concise review: mesenchymal stem cells for acute lung injury: role of paracrine soluble factors,” Stem Cells, vol. 29, no. 6, pp. 913–919, 2011.
[72]
V. Balasubramaniam, S. L. Ryan, G. J. Seedorf et al., “Bone marrow-derived angiogenic cells restore lung alveolar and vascular structure after neonatal hyperoxia in infant mice,” American Journal of Physiology, vol. 298, no. 3, pp. L315–L323, 2010.
[73]
P. Vosdoganes, R. J. Hodges, R. Lim et al., “Human amnion epithelial cells as a treatment for inflammation-induced fetal lung injury in sheep,” American Journal of Obstetrics and Gynecology, vol. 205, no. 2, pp. 156.e26–156.e33, 2011.
[74]
Y. Moodley, S. Ilancheran, C. Samuel et al., “Human amnion epithelial cell transplantation abrogates lung fibrosis and augments repair,” American Journal of Respiratory and Critical Care Medicine, vol. 182, no. 5, pp. 643–651, 2010.
[75]
S. Murphy, R. Lim, H. Dickinson, et al., “Human amnion epithelial cells prevent bleomycin-induced lung injury and preserve lung function,” Cell Transplantation, vol. 20, pp. 909–923, 2011.
[76]
A. E. Hegab, H. Kubo, N. Fujino et al., “Isolation and characterization of murine multipotent lung stem cells,” Stem Cells and Development, vol. 19, no. 4, pp. 523–535, 2010.
[77]
D. Wang, J. E. Morales, D. G. Calame, J. L. Alcorn, and R. A. Wetsel, “Transplantation of human embryonic stem cell-derived alveolar epithelial type II cells abrogates acute lung injury in mice,” Molecular Therapy, vol. 18, no. 3, pp. 625–634, 2010.
[78]
S. Aguilar, C. J. Scotton, K. McNulty et al., “Bone marrow stem cells expressing keratinocyte growth factor via an inducible lentivirus protects against bleomycin-induced pulmonary fibrosis,” PLoS ONE, vol. 4, no. 11, article e8013, 2009.
