Reduced Neuronal Innervation in the Distal End of the Proximal Esophageal Atretic Segment in Cases of Esophageal Atresia with Distal Tracheoesophageal Fistula

Abstract

We concluded that the distribution of ganglion cells and some nerve fibers in the distal end of the atretic esophageal segment is deficient. Inadequate and abnormal neuronal innervation of the esophagus could be related to the esophageal dysmotility seen in EA. Because GDNF is a survival factor for central and peripheral neurons, defective expression of GDNF could have an important role in the defective and/or abnormal neuronal innervation of atretic esophageal segment.

Intrinsic esophageal innervation in esophageal atresia without fistula

“…However, the innervation patterns were in part different from those of regular EA/TEF. The scarcity of the neural fraction and the hypoganglionism described at the upper [29] and lower [28] segments of babies and in the fistula of rats [35] with EA/TEF was not confirmed in our investigation of isolated EA. The fibrillar network was apparently denser than in controls at both segments of the atretic esophagus (although only significantly at the proximal one).…”

“…On the other hand, the markedly larger intramural ganglia without variation of the number of neurons described at the upper pouch of human EA/TEF [28] (but not in the rat model [35]), was also observed on both esophageal segments of our cases of isolated EA. We observed increased expression of S-100 in the neural elements of both the upper pouch and the lower segment of the atretic esophagus had that might represent a compensatory hypertrophy of the glial components of the neural network as previously suggested [29]. This hyperexpression was also found in the distal fistula in the rat model of EA/TEF [33].…”

“…Our use of image analysis software attempted at reducing subjectivity in all measurements. These drawbacks also apply to the studies carried out in human EA/TEF by other authors, that of Nakazato et al [28] was the only one in which both ends of the atretic esophagus were examined whereas that of Boleken et al [29] only addressed the tip of the upper pouch and that of Li et al [30] only examined a short distal fistula segment that can hardly represent the overall histology of the malformed esophagus. Studies in rats involved only the distal esophagus due to the minimal size of the upper pouch [33][34][35].…”

“…Recently, other authors addressed this issue in different ways. Boleken et al investigated immunohistochemically (neurofilament, synaptophysin, S-100 and glial cell-line derived neurotrophic factor-GNDF) the tip of the upper pouch in nine cases of EA/TEF and nine age matched-controls and found marked hypoganglionosis with immature neurons and decreased GNDF, SY and NF immunoreactivity with increased S-100 reactive fibers in the myenteric plexus [29]. Li et al studied only the upper part of the fistula in 24 patients with EA/TEF and the corresponding level of the esophagus in 10 controls by immunohistochemistry (neuron-specific enolase, NSE; substance P, SP; vasoactive intestinal peptide, VIP and nitric oxide synthase, NOS) and electron-microscopy.…”

Abnormal development of tracheal innervation in rats with experimental diaphragmatic hernia

“…Its increased expression has been interpreted as a compensatory mechanism for defective neural tissue [20] and S100B mRNA levels have been used as a marker for brain injury [21,22]. We found significantly increased population of glial cells in nitrofen-exposed embryos on E15 and in CDH fetuses on E18.…”