Enteric Nervous System and Esophageal-Gastrointestinal Motility in Experimental Congenital Diaphragmatic Hernia

Abstract

Gastroesophageal reflux and intestinal distension have been described in survivors of congenital diaphragmatic hernia (CDH). Deficient enteric innervation demonstrated in experimental models is a likely explanation for these symptoms. This study aimed at further characterizing these anomalies and examining esophageal and intestinal motility in this condition. Pregnant rats received either nitrofen or vehicle on E9.5. Sections of E15, E18, and E21 esophagus and small bowel were stained for protein gene product 9.5, nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase (NADPHd), and acetylcholinesterase (AChE). The proportion of neural tissue/muscle surface was measured and the NADPHd- and AChE-positive motor endplates (MEPs) were counted. E18 and E21 stomachs were stained for AChE, the ganglia were counted and measured. The peristalsis of the esophagus and small bowel was video recorded. The relative neural/muscle surface and the number of NADPHd- and AChE-positive MEPs were decreased on E15 and E18 in the esophagus and small bowel of embryos with CDH, but they tended to improve on E21. The number and the mean surface of stomach ganglia were smaller in E18 and E21 fetuses with CDH. Peristaltic movements were decreased in the esophagus and small bowel of animals with CDH. Deficient enteric innervation impaired gastrointestinal motility in experimental CDH. This could explain some long-term morbidity in the human condition.

Keywords

diaphragmatic hernia - enteric nervous system - peristalsis

• References

• 1 Chiu PP, Ijsselstijn H. Morbidity and long-term follow-up in CDH patients. Eur J Pediatr Surg 2012; 22 (5) 384-392
• 2 Chiu P, Hedrick HL. Postnatal management and long-term outcome for survivors with congenital diaphragmatic hernia. Prenat Diagn 2008; 28 (7) 592-603
• 3 Peetsold MG, Kneepkens CM, Heij HA, IJsselstijn H, Tibboel D, Gemke RJ. Congenital diaphragmatic hernia: long-term risk of gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr 2010; 51 (4) 448-453
• 4 Vanamo K, Rintala RJ, Lindahl H, Louhimo I. Long-term gastrointestinal morbidity in patients with congenital diaphragmatic defects. J Pediatr Surg 1996; 31 (4) 551-554
• 5 Koot VC, Bergmeijer JH, Bos AP, Molenaar JC. Incidence and management of gastroesophageal reflux after repair of congenital diaphragmatic hernia. J Pediatr Surg 1993; 28 (1) 48-52
• 6 Koivusalo AI, Pakarinen MP, Lindahl HG, Rintala RJ. The cumulative incidence of significant gastroesophageal reflux in patients with congenital diaphragmatic hernia-a systematic clinical, pH-metric, and endoscopic follow-up study. J Pediatr Surg 2008; 43 (2) 279-282
• 7 Arena F, Romeo C, Baldari S , et al. Gastrointestinal sequelae in survivors of congenital diaphragmatic hernia. Pediatr Int 2008; 50 (1) 76-80
• 8 Pederiva F, Rodriguez JI, Ruiz-Bravo E, Martinez L, Tovar JA. Abnormal intrinsic esophageal innervation in congenital diaphragmatic hernia: a likely cause of motor dysfunction. J Pediatr Surg 2009; 44 (3) 496-499
• 9 Martinez L, Pederiva F, Martinez-Calonge W, Aras-Lopez R, Tovar JA. The myenteric plexus of the esophagus is abnormal in an experimental congenital diaphragmatic hernia model. Eur J Pediatr Surg 2009; 19 (3) 163-167
• 10 Martínez L, Aras-López R, Lancha S , et al. Abnormal development of the enteric nervous system in rat embryos and fetuses with congenital diaphragmatic hernia. Pediatr Surg Int 2011; 27 (2) 165-173
• 11 Pederiva F, Aras Lopez R, Martinez L, Tovar JA. Abnormal development of tracheal innervation in rats with experimental diaphragmatic hernia. Pediatr Surg Int 2008; 24 (12) 1341-1346
• 12 Rishniw M, Fisher PJ, Doran RM, Bliss SP, Kotlikoff MI. Striated myogenesis and peristalsis in the fetal murine esophagus occur without cell migration or interstitial cells of Cajal. Cells Tissues Organs 2009; 189 (6) 410-419
• 13 Fasching G, Huber A, Uray E, Sorantin E, Lindbichler F, Mayr J. Gastroesophageal reflux and diaphragmatic motility after repair of congenital diaphragmatic hernia. Eur J Pediatr Surg 2000; 10 (6) 360-364
• 14 Sigalet DL, Nguyen LT, Adolph V, Laberge JM, Hong AR, Guttman FM. Gastroesophageal reflux associated with large diaphragmatic hernias. J Pediatr Surg 1994; 29 (9) 1262-1265
• 15 Kieffer J, Sapin E, Berg A, Beaudoin S, Bargy F, Helardot PG. Gastroesophageal reflux after repair of congenital diaphragmatic hernia. J Pediatr Surg 1995; 30 (9) 1330-1333
• 16 Stolar CJ, Levy JP, Dillon PW, Reyes C, Belamarich P, Berdon WE. Anatomic and functional abnormalities of the esophagus in infants surviving congenital diaphragmatic hernia. Am J Surg 1990; 159 (2) 204-207
• 17 Wörl J, Neuhuber WL. Enteric co-innervation of motor endplates in the esophagus: state of the art ten years after. Histochem Cell Biol 2005; 123 (2) 117-130
• 18 Kallmünzer B, Sörensen B, Neuhuber WL, Wörl J. Enteric co-innervation of striated muscle fibres in human oesophagus. Neurogastroenterol Motil 2008; 20 (6) 597-610
• 19 Neuhuber WL, Wörl J, Berthoud HR, Conte B. NADPH-diaphorase-positive nerve fibers associated with motor endplates in the rat esophagus: new evidence for co-innervation of striated muscle by enteric neurons. Cell Tissue Res 1994; 276 (1) 23-30
• 20 Grozdanovic Z, Brüning G, Baumgarten HG. Nitric oxide—a novel autonomic neurotransmitter. Acta Anat (Basel) 1994; 150 (1) 16-24
• 21 Grozdanovic Z, Baumgarten HG, Brüning G. Histochemistry of NADPH-diaphorase, a marker for neuronal nitric oxide synthase, in the peripheral autonomic nervous system of the mouse. Neuroscience 1992; 48 (1) 225-235
• 22 Koivusalo A, Pakarinen M, Vanamo K, Lindahl H, Rintala RJ. Health-related quality of life in adults after repair of congenital diaphragmatic defects—a questionnaire study. J Pediatr Surg 2005; 40 (9) 1376-1381
• 23 Peetsold MG, Heij HA, Kneepkens CM, Nagelkerke AF, Huisman J, Gemke RJ. The long-term follow-up of patients with a congenital diaphragmatic hernia: a broad spectrum of morbidity. Pediatr Surg Int 2009; 25 (1) 1-17
• 24 Nobuhara KK, Lund DP, Mitchell J, Kharasch V, Wilson JM. Long-term outlook for survivors of congenital diaphragmatic hernia. Clin Perinatol 1996; 23 (4) 873-887
• 25 van Eijck FC, Wijnen RM, van Goor H. The incidence and morbidity of adhesions after treatment of neonates with gastroschisis and omphalocele: a 30-year review. J Pediatr Surg 2008; 43 (3) 479-483
• 26 Kapur RP, Yost C, Palmiter RD. A transgenic model for studying development of the enteric nervous system in normal and aganglionic mice. Development 1992; 116 (1) 167-175
• 27 Young HM, Hearn CJ, Ciampoli D, Southwell BR, Brunet JF, Newgreen DF. A single rostrocaudal colonization of the rodent intestine by enteric neuron precursors is revealed by the expression of Phox2b, Ret, and p75 and by explants grown under the kidney capsule or in organ culture. Dev Biol 1998; 202 (1) 67-84