Embriyoloji ve Etiyopatogenez
Özet
Akciğer gelişimi, bronşiyal dallanma, alveoler maturasyon ve pulmoner vaskülogenez süreçlerinin eşzamanlı ilerleyişine bağlıdır; bu alanlardan birindeki bozukluk diğerini doğrudan etkiler. Konjenital diyafram hernisine (KDH) eşlik eden pulmoner hipoplazi, akciğer dokusunun hacimsel ve fonksiyonel yetersizliğiyle karakterize olup bronşiyal segment sayısında azalma, alveoler farklılaşmada gecikme ve pulmoner damar duvarlarında hipertrofi ile belirgindir. Mekanik kompresyon teorisi, herniye abdominal organların torasik alanı daraltarak akciğer büyümesini sınırladığını öne sürse de güncel kanıtlar intrinsik gelişimsel bozuklukların da temel rol oynadığını göstermektedir. Hipoplazi yalnızca herni tarafında değil, kontralateral akciğerde de izlenerek sistemik bir gelişim kusuruna işaret etmektedir. Nitrofen modellerinde azalmış akciğer DNA/protein içeriği ve belirgin vazoreaktivite kaybı bu patolojiyi desteklemektedir. Prenatal steroid ve surfaktan uygulamaları yararsız bulunmuştur. Güncel araştırmalar retinoik asit metabolizmasının düzenlenmesi, fetal trakeal oklüzyon ve rejeneratif hücre temelli tedavilere odaklanmakta olup özellikle retinoik asit yolağını hedefleyen müdahaleler güvenlik ve etkinlik açısından umut vaat etmektedir.
Referanslar
Kluth D, Keijzer R, Hertl M, et al. Embryology of congenital diaphragmatic hernia. Semin Pediatr Surg. 1996;5:224–233.
Iritani I. Experimental study on embryogenesis of congenital diaphragmatic hernia. Anat Embryol (Berl). 1984;169:133–139.
Babiuk RP, Zhang W, Clugston R, et al. Embryological origins and development of the rat diaphragm. J Comp Neurol. 2003;455:477–487.
Greer JJ. Current concepts on the pathogenesis and etiology of congenital diaphragmatic hernia. Respir Physiol Neurobiol. 2013;189:232–240.
Greer JJ, Allan DW, Babiuk RP, et al. Recent advances in understanding the pathogenesis of nitrofen-induced congenital diaphragmatic hernia. Pediatr Pulmonol. 2000;29:394–399.
Merrell AJ, Ellis BJ, Fox ZD, et al. Muscle connective tissue controls development of the diaphragm and is a source of congenital diaphragmatic hernias. Nat Genet. 2015;47:496–504.
Noble BR, Babiuk RP, Clugston RD, et al. Mechanisms of action of the congenital diaphragmatic hernia-inducing teratogen nitrofen. Am J Physiol Lung Cell Mol Physiol. 2007;293:L1079–L1087.
Kluth D, Kangah R, Reich P, et al. Nitrofen-induced diaphragmatic hernias in rats: an animal model. J Pediatr Surg. 1990;25:850–854.
Mey J, Babiuk RP, Clugston R, et al. Retinal dehydrogenase-2 is inhibited by compounds that induce congenital diaphragmatic hernias in rodents. Am J Pathol. 2003;162:673–679.
Wilson JG, Roth CB, Warkany J. An analysis of the syndrome of malformations induced by maternal vitamin A deficiency. Am J Anat. 1953;92:189–217.
Mendelsohn C, Lohnes D, Decimo D, et al. Function of the retinoic acid receptors during development (II): Multiple abnormalities at various stages of organogenesis in RAR double mutants. Development. 1994;120:2749–2771.
Major D, Cadenas M, Fournier L, et al. Retinol status of newborn infants with congenital diaphragmatic hernia. Pediatr Surg Int. 1998;13:547–549.
Keijzer R, Liu J, Deimling J, et al. Dual-hit hypothesis explains pulmonary hypoplasia in the nitrofen model of congenital diaphragmatic hernia. Am J Pathol. 2000;156:1299–1306.
Wilson JG, Roth CB, Warkany J. An analysis of the syndrome of malformations induced by maternal vitamin A deficiency. Am J Anat. 1953;92:189–217.
Mendelsohn C, Lohnes D, Decimo D, et al. Function of the retinoic acid receptors during development (II): Multiple abnormalities at various stages of organogenesis in RAR double mutants. Development. 1994;120:2749–2771.
Major D, Cadenas M, Fournier L, et al. Retinol status of newborn infants with congenital diaphragmatic hernia. Pediatr Surg Int. 1998;13:547–549.
Chinoy MR. Lung growth and development. Front Biosci. 2003;8:d392–d415.
Schittny JC. Development of the lung. Cell Tissue Res. 2017;367:427–444.
Miniati D. Pulmonary vascular remodeling. Semin Pediatr Surg. 2007;16:80–87.
Kool H, Mous D, Tibboel D, et al. Pulmonary vascular development goes awry in congenital lung abnormalities. Birth Defects Res C Embryo Today. 2014;102:343–358.
Lally KP, Bagolan P, Hosie S, et al. Corticosteroids for fetuses with congenital diaphragmatic hernia: can we show benefit? J Pediatr Surg. 2006;41:668–674.
Colby CE, Lally KP, Hintz SR, et al. Surfactant replacement therapy on ECMO does not improve outcome in neonates with congenital diaphragmatic hernia. J Pediatr Surg. 2004;39:1632–1637.
Van Meurs K, Congenital Diaphragmatic Hernia Study Group. Is surfactant therapy beneficial in the treatment of term newborn infants with congenital diaphragmatic hernia? J Pediatr. 2004;145:312–316.
Eastwood MP, Russo FM, Toelen J, et al. Medical interventions to reverse pulmonary hypoplasia in animal models of congenital diaphragmatic hernia: a systematic review. Pediatr Pulmonol. 2015;50:820–838.
De Coppi P, Deprest J. Regenerative medicine solutions in congenital diaphragmatic hernia. Semin Pediatr Surg. 2017;26:171–177.
Clugston RD, Zhang W, Alvarez S, et al. Understanding abnormal retinoid signaling as a causative mechanism in congenital diaphragmatic hernia. Am J Respir Cell Mol Biol. 2010;42:276–285.
Baptista MJ, Melo-Rocha G, Pedrosa C, et al. Antenatal vitamin A administration attenuates lung hypoplasia in congenital diaphragmatic hernia. J Pediatr Surg. 2005;40:658–665.
Thebaud B, Tibboel D, Rambaud C, et al. Vitamin A decreases the incidence and severity of nitrofen-induced congenital diaphragmatic hernia in rats. Am J Physiol. 1999;277:L423–L429.
Clugston RD, et al. Retinoid signaling in lung development and congenital diaphragmatic hernia. Am J Physiol Lung Cell Mol Physiol. 2006;290:L893–L902.
Montedonico S, Nakazawa N, Puri P. Retinoic acid pathway and congenital diaphragmatic hernia: experimental and clinical evidence. Pediatr Surg Int. 2008;24:733–736.
Kohl T, Hering R, Heep A, et al. Tracheal occlusion in congenital diaphragmatic hernia: experimental results, current clinical experience, and future prospects. Semin Pediatr Surg. 2009;18:48–56.
Flageole H, Evrard VA, Piedboeuf B, et al. Tracheal obstruction in fetal lambs with congenital diaphragmatic hernia reverses the structural pulmonary hypoplasia. J Pediatr Surg. 1998;33:299–303.
Fauza DO, Jennings RW. Fetal surgery for congenital diaphragmatic hernia. Semin Pediatr Surg. 2019;28:150819.
Russo FM, Eastwood MP, Deprest JA. Fetoscopic endoluminal tracheal occlusion for severe congenital diaphragmatic hernia. Semin Fetal Neonatal Med. 2021;26:101257.
Sbragia L, Nassr AC, Gonçalves FL, et al. Mesenchymal stem cell therapy in congenital diaphragmatic hernia-induced pulmonary hypoplasia: experimental studies. Front Pediatr. 2019;7:347.
Ding J, Xu Y, Chen L, et al. Stem cell-based therapy for pulmonary hypoplasia in congenital diaphragmatic hernia: recent advances and future perspectives. Stem Cells Int. 2020;2020:6726798.
Deprest JA, Nicolaides KH, Gratacos E. Fetoscopic tracheal occlusion (FETO) for severe congenital diaphragmatic hernia: evolution of a technique and outcomes. Prenat Diagn. 2021;41:1457–1472.
Harting MT. Congenital diaphragmatic hernia-associated pulmonary hypertension. Semin Pediatr Surg. 2017;26:147–153.
Roubliova X, Verbeken E, Wu J, et al. Pulmonary vascular morphology in a fetal rabbit model for congenital diaphragmatic hernia. J Pediatr Surg. 2004;39:1066–1072.
Jakkula M, Le Cras TD, Gebb S, et al. Inhibition of angiogenesis decreases alveolarization in the developing rat lung. Am J Physiol Lung Cell Mol Physiol. 2000;279:L600–L607.
Grover TR, Parker TA, Balasubramaniam V, et al. Pulmonary hypertension impairs alveolarization and reduces lung growth in the ovine fetus. Am J Physiol Lung Cell Mol Physiol. 2005;288:L648–L654.
Derderian SC, Jayme CM, Cheng LS, et al. Mass effect alone may not explain pulmonary vascular pathology in severe congenital diaphragmatic hernia. Fetal Diagn Ther. 2016;39:117–124.
Dillon PW, Cilley RE, Mauger D, et al. The relationship of pulmonary artery pressure and survival in congenital diaphragmatic hernia. J Pediatr Surg. 2004;39:307–312.
Lusk LA, Wai KC, Moon-Grady AJ, et al. Persistence of pulmonary hypertension by echocardiography predicts short-term outcomes in congenital diaphragmatic hernia. J Pediatr. 2015;166:251–256.
Kinsella JP, Ivy DD, Abman SH. Pulmonary vasodilator therapy in persistent pulmonary hypertension of the newborn. Pediatr Clin North Am. 1995;42:881–902.
Lally KP, Lally PA, Lasky RE, et al. Defect size determines survival in infants with congenital diaphragmatic hernia. Pediatrics. 2007;120:e651–e657.
