- Email: [email protected]
Impaired Lung Development and Neonatal Lung Diseases: A Never-Ending (Vascular) Story
THE JOURNAL OF PEDIATRICS • www.jpeds.com
EDITORIALS
Impaired Lung Development and Neonatal Lung Diseases: A Never-Ending (Vascular) Story
G
DS by alveolar simplification and a persistent double capilreat progress has been made in our understanding of lary network, as well as pulmonary arterial hypertensive renormal lung development. Studies done using fruit modeling. Three-dimensional reconstruction techniques also flies and mice have unraveled the histologic develidentified the presence of prominent IBA.20 opmental stages of the lung and the cellular See related article, p ••• The first observation regarding alveolar and molecular mechanisms that regulate the simplification in this patient population is ingrowth of the conducting airways.1-5 However, less is known about the development of the alveoli in the distal teresting and consistent with the role of lung angiogenesis lung and the underlying pulmonary vasculature. This may in during lung development. Indeed, human chromosome 21 part be due to the lack of alveoli and pulmonary circulation encodes several anti-angiogenic growth factors and the authors in fruit flies. Nonetheless, pioneering work has described the recently showed increased fetal lung expression of antistructural changes during normal lung vascular development6-8 angiogenic factors in DS.21 It can be speculated that chromoand the interruption of lung vascular growth that occurs in some 21-specific antiangiogenic factors contribute to abnormal some of the most severe neonatal lung diseases, including bronlung vascular growth and that the reduced total arterial surface chopulmonary dysplasia,9,10 congenital diaphragmatic hernia,11 area increases the risk of vascular injury through hemodyand alveolar capillary dysplasia.12 These anomalies, including namic stress in these patients. alveolar simplification with fewer and larger alveoli, are acThe second observation regarding intrapulmonary shunts companied consistently by abnormalities in the lung vascuis intriguing, but consistent with recent findings of the preslature. These observations suggest that pulmonary blood vessels ence of IBA in other severe neonatal diseases complicated by are not just bystanders in lung development, passively followPH.16-19 The presence of intrapulmonary shunts was described more than 50 years ago in the normal human lung.22,23 ing the growth of the airways. On the contrary, increasing eviWith exercise, almost all healthy humans demonstrate blood dence suggests that lung blood vessels actively promote lung flow through intrapulmonary arteriovenous anastomoses.24 The growth. Temporospatial expression patterns of angiogenic significance of these shunts in disease, including PH compligrowth factors and their pharmacologic and genetic moducating severe neonatal respiratory failure or in patients with lation during the critical period of alveolar growth and miDS, remains unknown. IBA may represent a compensatory crovascular maturation provide strong evidence that mechanisms to overcome the reduction in vascular surface area angiogenesis is necessary for normal lung development and or, similar to the patent ductus arteriosus, a protective mecharepair, and that an imbalance in angiogenic growth factors nism serving as a “pop-off” valve or overflow system to reduce during a critical period of lung growth13 contributes to neonatal lung diseases, pulmonary hypertension (PH), and their the severity of PH and protect the right ventricle. potential long-term consequences.14,15 Unfortunately, this knowlInterestingly, hyperoxia prevents exercise-induced intrapuledge has not yet resulted in novel, effective therapies. monary arteriovenous shunt in healthy humans,25 suggesting these vessels may be oxygen-sensitive and constrict in reRecent observations have highlighted the existence of yet sponse to oxygen similar to the ductus arteriosus,26 whereas another lung vascular feature in severe neonatal lung dis16-19 identified intrapulmonary bronchointrapulmonary arteries dilate in response to oxygen and coneases. Galambos et al pulmonary anastomoses (IBA) in infants with PH, complicating strict in response to hypoxia. It is, therefore, conceivable that the course of diverse causes of developmental lung diseases, persistent hypoxemia in these patients may keep the IBA patent. including bronchopulmonary dysplasia, congenital diaphragConversely, episodes of hypoxemia attributed to apnea of matic hernia, alveolar capillary dysplasia, and meconium asprematurity or sleep apneas in children with DS may in fact piration syndrome. The authors suggested these vessels acted be the result of IBA. The answer to these questions may have as arteriovenous shunts that contribute to hypoxemia. In this opposite therapeutic implications. volume of The Journal, the authors extend their observation IBA have only been described in autopsy samples. Thus, one to infants with Down syndrome (DS), a neglected group of can only speculate whether IBA contribute to the clinical course patients known to have a higher incidence of PH and more of patients who do not die. Novel imaging techniques may allow severe PH than children without DS and similar cardiopulthe visualization of IBA and overcome these limitations.27 20 monary diseases. They found indicators of lung immaturity and impaired lung growth characterized in children with
DS IBA PH
Down syndrome Intrapulmonary bronchopulmonary anastomoses Pulmonary hypertension
Supported by the Canadian Institute of Health Research (CIHR; CIHR-FDN143316). The author declares no conflicts of interest. 0022-3476/$ - see front matter. © 2016 Elsevier Inc. All rights reserved. http://dx.doi.org10.1016/j.jpeds.2016.10.030
1 EDI 5.4.0 DTD ■ YMPD8740_proof ■ October 25, 2016
THE JOURNAL OF PEDIATRICS • www.jpeds.com Similarly, in humans, further physiologic exploration of these shunts in vivo24,25 or in vitro28 may shed further light on their pathophysiologic significance. Likewise, large animal models with high pulmonary blood flow offer the opportunity to identify the presence of IBA, study their pathophysiology, and test potential therapeutic targets.29 In summary, Bush et al20 add another chapter to a neverending vascular story in normal and impaired lung development by demonstrating convincingly the presence of IBA in several neonatal lung diseases complicated by PH. Further efforts are now required to explore in more detail the implications of these observations. ■ Bernard Thébaud, MD, PhD Department of Pediatrics Children’s Hospital of Eastern Ontario and Children’s Hospital of Ontario Research Institute (CHEORI) Sinclair Centre for Regenerative Medicine Ottawa Hospital Research Institute (OHRI) Department of Cellular and Molecular Biology University of Ottawa Ottawa, Ontario, Canada Reprint requests: Bernard Thébaud, MD, PhD, Sinclair Centre for Regenerative Medicine, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada. E-mail: [email protected]
References 1. Burri PH, Dbaly J, Weibel ER. The postnatal growth of the rat lung. I. Morphometry. Anat Rec 1974;178:711-30. 2. Metzger RJ, Klein OD, Martin GR, Krasnow MA. The branching programme of mouse lung development. Nature 2008;453:745-50. 3. Metzger RJ, Krasnow MA. Genetic control of branching morphogenesis. Science 1999;284:1635-9. 4. Morrisey EE, Hogan BL. Preparing for the first breath: genetic and cellular mechanisms in lung development. Dev Cell 2010;18:823. 5. Whitsett J. A lungful of transcription factors. Nat Genet 1998;20:7-8. 6. deMello DE, Sawyer D, Galvin N, Reid LM. Early fetal development of lung vasculature. Am J Respir Cell Mol Biol 1997;16:568-81. 7. Hall SM, Hislop AA, Haworth SG. Origin, differentiation, and maturation of human pulmonary veins. Am J Respir Cell Mol Biol 2002;26:33340. 8. Peng T, Morrisey EE. Development of the pulmonary vasculature: current understanding and concepts for the future. Pulm Circ 2013;3: 176-8. 9. Coalson JJ. Pathology of new bronchopulmonary dysplasia. Semin Neonatol 2003;8:73-81.
Volume ■■ 10. De Paepe ME, Mao Q, Powell J, Rubin SE, DeKoninck P, Appel N, et al. Growth of pulmonary microvasculature in ventilated preterm infants. Am J Respir Crit Care Med 2006;173:204-11. 11. Levin DL. Morphologic analysis of the pulmonary vascular bed in congenital left- sided diaphragmatic hernia. J Pediatr 1978;92:805-9. 12. Bishop NB, Stankiewicz P, Steinhorn RH. Alveolar capillary dysplasia. Am J Respir Crit Care Med 2011;184:172-9. 13. Thebaud B, Abman SH. Bronchopulmonary dysplasia: where have all the vessels gone? Roles of angiogenic growth factors in chronic lung disease. Am J Respir Crit Care Med 2007;175:978-85. 14. Baraldi E, Filippone M. Chronic lung disease after premature birth. N Engl J Med 2007;357:1946-55. 15. Jeandot R, Lambert B, Brendel AJ, Guyot M, Demarquez JL. Lung ventilation and perfusion scintigraphy in the follow up of repaired congenital diaphragmatic hernia. Eur J Nucl Med 1989;15:591-6. 16. Acker SN, Mandell EW, Sims-Lucas S, Gien J, Abman SH, Galambos C. Histologic identification of prominent intrapulmonary anastomotic vessels in severe congenital diaphragmatic hernia. J Pediatr 2015;166:178-83. 17. Ali N, Abman SH, Galambos C. Histologic evidence of intrapulmonary bronchopulmonary anastomotic pathways in neonates with meconium aspiration syndrome. J Pediatr 2015;167:1445-7. 18. Galambos C, Sims-Lucas S, Abman SH. Histologic evidence of intrapulmonary anastomoses by three-dimensional reconstruction in severe bronchopulmonary dysplasia. Ann Am Thorac Soc 2013;10:474-81. 19. Galambos C, Sims-Lucas S, Abman SH. Three-dimensional reconstruction identifies misaligned pulmonary veins as intrapulmonary shunt vessels in alveolar capillary dysplasia. J Pediatr 2014;164:192-5. 20. Bush D, Abman SH, Galambos C. Prominent intrapulmonary bronchopulmonary anastomoses and abnormal lung development in infants and children with Down syndrome. J Pediatr 2016;doi:10.1016/ j.jpeds.2016.08.063. 21. Galambos C, Minic AD, Bush D, Nguyen D, Dodson B, Seedorf G, et al. Increased lung expression of anti-angiogenic factors in Down syndrome: potential role in abnormal lung vascular growth and the risk for pulmonary hypertension. PLoS ONE 2016;11:e0159005. 22. Tobin CE. Arteriovenous shunts in the peripheral pulmonary circulation in the human lung. Thorax 1966;21:197-204. 23. Tobin CE, Zariquiey MO. Arteriovenous shunts in the human lung. Proc Soc Exp Biol Med 1950;75:827-9. 24. Lovering AT, Haverkamp HC, Romer LM, Hokanson JS, Eldridge MW. Transpulmonary passage of 99mTc macroaggregated albumin in healthy humans at rest and during maximal exercise. J Appl Physiol 2009;106:198692. 25. Lovering AT, Stickland MK, Amann M, Murphy JC, O’Brien MJ, Hokanson JS, et al. Hyperoxia prevents exercise-induced intrapulmonary arteriovenous shunt in healthy humans. J Physiol 2008;586:4559-65. 26. Weir EK, Lopez-Barneo J, Buckler KJ, Archer SL. Acute oxygen-sensing mechanisms. N Engl J Med 2005;353:2042-55. 27. Freed BH, Collins JD, Francois CJ, Barker AJ, Cuttica MJ, Chesler NC, et al. MR and CT imaging for the evaluation of pulmonary hypertension. JACC Cardiovasc Imaging 2016;9:715-32. 28. Michelakis E, Rebeyka I, Bateson J, Olley P, Puttagunta L, Archer S. Voltagegated potassium channels in human ductus arteriosus. Lancet 2000;356:1347. 29. Oishi PE, Sharma S, Datar SA, Kumar S, Aggarwal S, Lu Q, et al. Rosiglitazone preserves pulmonary vascular function in lambs with increased pulmonary blood flow. Pediatr Res 2013;73:54-61.
2 EDI 5.4.0 DTD ■ YMPD8740_proof ■ October 25, 2016
EDITORIALS
Impaired Lung Development and Neonatal Lung Diseases: A Never-Ending (Vascular) Story
G
DS by alveolar simplification and a persistent double capilreat progress has been made in our understanding of lary network, as well as pulmonary arterial hypertensive renormal lung development. Studies done using fruit modeling. Three-dimensional reconstruction techniques also flies and mice have unraveled the histologic develidentified the presence of prominent IBA.20 opmental stages of the lung and the cellular See related article, p ••• The first observation regarding alveolar and molecular mechanisms that regulate the simplification in this patient population is ingrowth of the conducting airways.1-5 However, less is known about the development of the alveoli in the distal teresting and consistent with the role of lung angiogenesis lung and the underlying pulmonary vasculature. This may in during lung development. Indeed, human chromosome 21 part be due to the lack of alveoli and pulmonary circulation encodes several anti-angiogenic growth factors and the authors in fruit flies. Nonetheless, pioneering work has described the recently showed increased fetal lung expression of antistructural changes during normal lung vascular development6-8 angiogenic factors in DS.21 It can be speculated that chromoand the interruption of lung vascular growth that occurs in some 21-specific antiangiogenic factors contribute to abnormal some of the most severe neonatal lung diseases, including bronlung vascular growth and that the reduced total arterial surface chopulmonary dysplasia,9,10 congenital diaphragmatic hernia,11 area increases the risk of vascular injury through hemodyand alveolar capillary dysplasia.12 These anomalies, including namic stress in these patients. alveolar simplification with fewer and larger alveoli, are acThe second observation regarding intrapulmonary shunts companied consistently by abnormalities in the lung vascuis intriguing, but consistent with recent findings of the preslature. These observations suggest that pulmonary blood vessels ence of IBA in other severe neonatal diseases complicated by are not just bystanders in lung development, passively followPH.16-19 The presence of intrapulmonary shunts was described more than 50 years ago in the normal human lung.22,23 ing the growth of the airways. On the contrary, increasing eviWith exercise, almost all healthy humans demonstrate blood dence suggests that lung blood vessels actively promote lung flow through intrapulmonary arteriovenous anastomoses.24 The growth. Temporospatial expression patterns of angiogenic significance of these shunts in disease, including PH compligrowth factors and their pharmacologic and genetic moducating severe neonatal respiratory failure or in patients with lation during the critical period of alveolar growth and miDS, remains unknown. IBA may represent a compensatory crovascular maturation provide strong evidence that mechanisms to overcome the reduction in vascular surface area angiogenesis is necessary for normal lung development and or, similar to the patent ductus arteriosus, a protective mecharepair, and that an imbalance in angiogenic growth factors nism serving as a “pop-off” valve or overflow system to reduce during a critical period of lung growth13 contributes to neonatal lung diseases, pulmonary hypertension (PH), and their the severity of PH and protect the right ventricle. potential long-term consequences.14,15 Unfortunately, this knowlInterestingly, hyperoxia prevents exercise-induced intrapuledge has not yet resulted in novel, effective therapies. monary arteriovenous shunt in healthy humans,25 suggesting these vessels may be oxygen-sensitive and constrict in reRecent observations have highlighted the existence of yet sponse to oxygen similar to the ductus arteriosus,26 whereas another lung vascular feature in severe neonatal lung dis16-19 identified intrapulmonary bronchointrapulmonary arteries dilate in response to oxygen and coneases. Galambos et al pulmonary anastomoses (IBA) in infants with PH, complicating strict in response to hypoxia. It is, therefore, conceivable that the course of diverse causes of developmental lung diseases, persistent hypoxemia in these patients may keep the IBA patent. including bronchopulmonary dysplasia, congenital diaphragConversely, episodes of hypoxemia attributed to apnea of matic hernia, alveolar capillary dysplasia, and meconium asprematurity or sleep apneas in children with DS may in fact piration syndrome. The authors suggested these vessels acted be the result of IBA. The answer to these questions may have as arteriovenous shunts that contribute to hypoxemia. In this opposite therapeutic implications. volume of The Journal, the authors extend their observation IBA have only been described in autopsy samples. Thus, one to infants with Down syndrome (DS), a neglected group of can only speculate whether IBA contribute to the clinical course patients known to have a higher incidence of PH and more of patients who do not die. Novel imaging techniques may allow severe PH than children without DS and similar cardiopulthe visualization of IBA and overcome these limitations.27 20 monary diseases. They found indicators of lung immaturity and impaired lung growth characterized in children with
DS IBA PH
Down syndrome Intrapulmonary bronchopulmonary anastomoses Pulmonary hypertension
Supported by the Canadian Institute of Health Research (CIHR; CIHR-FDN143316). The author declares no conflicts of interest. 0022-3476/$ - see front matter. © 2016 Elsevier Inc. All rights reserved. http://dx.doi.org10.1016/j.jpeds.2016.10.030
1 EDI 5.4.0 DTD ■ YMPD8740_proof ■ October 25, 2016
THE JOURNAL OF PEDIATRICS • www.jpeds.com Similarly, in humans, further physiologic exploration of these shunts in vivo24,25 or in vitro28 may shed further light on their pathophysiologic significance. Likewise, large animal models with high pulmonary blood flow offer the opportunity to identify the presence of IBA, study their pathophysiology, and test potential therapeutic targets.29 In summary, Bush et al20 add another chapter to a neverending vascular story in normal and impaired lung development by demonstrating convincingly the presence of IBA in several neonatal lung diseases complicated by PH. Further efforts are now required to explore in more detail the implications of these observations. ■ Bernard Thébaud, MD, PhD Department of Pediatrics Children’s Hospital of Eastern Ontario and Children’s Hospital of Ontario Research Institute (CHEORI) Sinclair Centre for Regenerative Medicine Ottawa Hospital Research Institute (OHRI) Department of Cellular and Molecular Biology University of Ottawa Ottawa, Ontario, Canada Reprint requests: Bernard Thébaud, MD, PhD, Sinclair Centre for Regenerative Medicine, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada. E-mail: [email protected]
References 1. Burri PH, Dbaly J, Weibel ER. The postnatal growth of the rat lung. I. Morphometry. Anat Rec 1974;178:711-30. 2. Metzger RJ, Klein OD, Martin GR, Krasnow MA. The branching programme of mouse lung development. Nature 2008;453:745-50. 3. Metzger RJ, Krasnow MA. Genetic control of branching morphogenesis. Science 1999;284:1635-9. 4. Morrisey EE, Hogan BL. Preparing for the first breath: genetic and cellular mechanisms in lung development. Dev Cell 2010;18:823. 5. Whitsett J. A lungful of transcription factors. Nat Genet 1998;20:7-8. 6. deMello DE, Sawyer D, Galvin N, Reid LM. Early fetal development of lung vasculature. Am J Respir Cell Mol Biol 1997;16:568-81. 7. Hall SM, Hislop AA, Haworth SG. Origin, differentiation, and maturation of human pulmonary veins. Am J Respir Cell Mol Biol 2002;26:33340. 8. Peng T, Morrisey EE. Development of the pulmonary vasculature: current understanding and concepts for the future. Pulm Circ 2013;3: 176-8. 9. Coalson JJ. Pathology of new bronchopulmonary dysplasia. Semin Neonatol 2003;8:73-81.
Volume ■■ 10. De Paepe ME, Mao Q, Powell J, Rubin SE, DeKoninck P, Appel N, et al. Growth of pulmonary microvasculature in ventilated preterm infants. Am J Respir Crit Care Med 2006;173:204-11. 11. Levin DL. Morphologic analysis of the pulmonary vascular bed in congenital left- sided diaphragmatic hernia. J Pediatr 1978;92:805-9. 12. Bishop NB, Stankiewicz P, Steinhorn RH. Alveolar capillary dysplasia. Am J Respir Crit Care Med 2011;184:172-9. 13. Thebaud B, Abman SH. Bronchopulmonary dysplasia: where have all the vessels gone? Roles of angiogenic growth factors in chronic lung disease. Am J Respir Crit Care Med 2007;175:978-85. 14. Baraldi E, Filippone M. Chronic lung disease after premature birth. N Engl J Med 2007;357:1946-55. 15. Jeandot R, Lambert B, Brendel AJ, Guyot M, Demarquez JL. Lung ventilation and perfusion scintigraphy in the follow up of repaired congenital diaphragmatic hernia. Eur J Nucl Med 1989;15:591-6. 16. Acker SN, Mandell EW, Sims-Lucas S, Gien J, Abman SH, Galambos C. Histologic identification of prominent intrapulmonary anastomotic vessels in severe congenital diaphragmatic hernia. J Pediatr 2015;166:178-83. 17. Ali N, Abman SH, Galambos C. Histologic evidence of intrapulmonary bronchopulmonary anastomotic pathways in neonates with meconium aspiration syndrome. J Pediatr 2015;167:1445-7. 18. Galambos C, Sims-Lucas S, Abman SH. Histologic evidence of intrapulmonary anastomoses by three-dimensional reconstruction in severe bronchopulmonary dysplasia. Ann Am Thorac Soc 2013;10:474-81. 19. Galambos C, Sims-Lucas S, Abman SH. Three-dimensional reconstruction identifies misaligned pulmonary veins as intrapulmonary shunt vessels in alveolar capillary dysplasia. J Pediatr 2014;164:192-5. 20. Bush D, Abman SH, Galambos C. Prominent intrapulmonary bronchopulmonary anastomoses and abnormal lung development in infants and children with Down syndrome. J Pediatr 2016;doi:10.1016/ j.jpeds.2016.08.063. 21. Galambos C, Minic AD, Bush D, Nguyen D, Dodson B, Seedorf G, et al. Increased lung expression of anti-angiogenic factors in Down syndrome: potential role in abnormal lung vascular growth and the risk for pulmonary hypertension. PLoS ONE 2016;11:e0159005. 22. Tobin CE. Arteriovenous shunts in the peripheral pulmonary circulation in the human lung. Thorax 1966;21:197-204. 23. Tobin CE, Zariquiey MO. Arteriovenous shunts in the human lung. Proc Soc Exp Biol Med 1950;75:827-9. 24. Lovering AT, Haverkamp HC, Romer LM, Hokanson JS, Eldridge MW. Transpulmonary passage of 99mTc macroaggregated albumin in healthy humans at rest and during maximal exercise. J Appl Physiol 2009;106:198692. 25. Lovering AT, Stickland MK, Amann M, Murphy JC, O’Brien MJ, Hokanson JS, et al. Hyperoxia prevents exercise-induced intrapulmonary arteriovenous shunt in healthy humans. J Physiol 2008;586:4559-65. 26. Weir EK, Lopez-Barneo J, Buckler KJ, Archer SL. Acute oxygen-sensing mechanisms. N Engl J Med 2005;353:2042-55. 27. Freed BH, Collins JD, Francois CJ, Barker AJ, Cuttica MJ, Chesler NC, et al. MR and CT imaging for the evaluation of pulmonary hypertension. JACC Cardiovasc Imaging 2016;9:715-32. 28. Michelakis E, Rebeyka I, Bateson J, Olley P, Puttagunta L, Archer S. Voltagegated potassium channels in human ductus arteriosus. Lancet 2000;356:1347. 29. Oishi PE, Sharma S, Datar SA, Kumar S, Aggarwal S, Lu Q, et al. Rosiglitazone preserves pulmonary vascular function in lambs with increased pulmonary blood flow. Pediatr Res 2013;73:54-61.
2 EDI 5.4.0 DTD ■ YMPD8740_proof ■ October 25, 2016