HIGH EXPRESSION OF NEUTRAL ENDOPEPTIDASE IN IDIOPATHIC DIFFUSE HYPERPLASIA OF PULMONARY NEUROENDOCRINE CELLS

Idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells (IDHP NC) is a clinicopathological entity characterized by a diffuse hyperpl asia of neuroendocrine cells involving distal bronchi and bronchioles. The pathogenesis of this syndrome remains unknown. The hyperplastic n euroendocrine (NE) cells contain multiple neuropeptides, including the bombesinlike peptides (BLP), which are likely important in the pathog enesis of the disorder by stimulating proliferation of fibroblasts in a paracrine fashion and the NE cells themselves in an autocrine manner . Neutral endopeptidase (NEP) is a cell-surface enzyme that hydrolyzes BLP and other bioactive peptides. Low or undetectable NEP is present in many primary lung cancers and cell lines. Low NEP expression could increase neuropeptide-induced autocrine effects by increasing local le vels of neuropeptides. We hypothesized that IDHPNC was associated with low or absent NEP expression. NEP expression was assayed in patients with IDHPNC (n = 3) and was compared with expression in patients with idiopathic pulmonary fibrosis (n = 5), hypersensitivity pneumonitis (n = 5), and normal lung (n = 4) using immunohistochemistry, ELISA, acti vity assay, and Western blot analysis. By these assays, NEP expression was highest in lungs affected by IDHPNC. NEP mRNA, as assessed in IDH PNC lung tissue by RT-PCR, was the expected size and free of mutation between bp 238-2437. Therefore, IDHPNC is unlikely to be the result of a defect in NEP expression. The apparent increase in NEP expression i n lung tissue from patients with IDHPNC may reflect a compensatory inc rease that partly counteracts abundant neuropeptides, including BLP, p resent in this disorder.