Glial-derived growth factor signaling pathway in infantile hypertrophic pyloric stenosis

Background/Purpose: Glial-derived growth factor (GDNF), which is the ligand of RET is reported to be essential for the development of enteric nervous system. A GDNF knockout mouse model has shown that the gastric region is a critical passing site between GDNF-RET-independent neuroblasts (colonizing the esophagus) and GDNF-RET-dependent neuroblasts (colonizing the small and large bowel). The earliest GDNF site of production is the mesenchyme and t he outer smooth muscle cell (SMC) layer of the developing bowel. In the mat ure gastrointestinal tract the presence of GDNF is restricted to enteric gl ial cells. The aim of this study was to investigate the expression of GDNF and RET in infantile hypertrophic pyloric stenosis (IHPS), Methods: Full-thickness muscle biopsy specimens were obtained from 8 IHPS p atients at pyloromyotomy and from 8 age-matched controls without gastrointe stinal disease. Indirect immunohistochemistry was performed using avidin-bi otin-peroxidase complex method with anti-GDNF and anti-RET antibodies. Quan titative analysis was performed using sandwich-type enzyme-linked immunosor bent assay (ELISA) for GDNF. Results: GDNF- and RET-positive nerve fibers were absent or markedly reduce d in IHPS compared with controls. GDNF was expressed strongly by smooth mus cle cells of both muscular layers in IHPS, whereas no GDNF expression was d etected in pyloric muscle of controls, The quantity of total GDNF in IHPS w as significantly higher than in controls (P < .01). Conclusions: The lack or markedly decreased number of GDNF-positive nerve f ibers in IHPS supports the hypothesis of a selective immaturity of the ente ric glia in the muscular layers in IHPS. The strong expression of GDNF in s mooth muscle cells in IHPS and the increased levels of GDNF in IHPS suggest a compensatory mechanism by which the smooth muscle cells continue to prod uce GDNF until maturation of the enteric glial cells occurs. Copyright (C) 2000 by W.B, Saunders Company.