HYPEROXIA-INDUCED AIRWAY REMODELING AND PULMONARY NEUROENDOCRINE CELLHYPERPLASIA IN THE WEANLING RAT

Infants dying with bronchopulmonary dysplasia (BPD) demonstrate increa sed numbers of pulmonary neuroendocrine cells (PNEC). These infants al so possess altered airway epithelial and smooth muscle dimensions remi niscent of oxygen-exposed animals. Because the pathogenesis of BPD inv olves oxygen toxicity, we hypothesized that chronic hyperoxia would in duce both airway remodeling and PNEC hyperplasia. To test this theory, we compared the small airway morphology of 21-d-old rats subsequently exposed to 2 wk of >95% O-2, (Ox; n = 12) with that of normoxic contr ols (Con; n = 12). In paraffin-embedded sections, airways <1500 mu m c ut in cross-section were analyzed using light microscopy and image ana lysis software. The degree of epithelial and smooth muscle hyperplasia was assessed with proliferating cell nuclear antigen (PCNA). PNEC con tent was assessed via immunohistochemical staining for calcitonin gene -related peptide (CGRP) and the number of solitary PNEC (PNECsol) and PNEC clusters (neuroepithelial bodies, NEB) counted per section. We fo und that oxygen exposure increased epithelial and smooth muscle wall t hickness (epithelium: Con, 12.3 +/- 1.4 versus Ox, 14.8 +/- 1.4 mu m, p < 0.05; smooth muscle: Con, 7.0 +/- 1.0 versus Ox, 10.0 +/- 1.0 mu m , p < 0.05). The changes in wall dimensions were accompanied by a 20% increase in fractional PCNA labeling of the epithelium but not the smo oth muscle. Both PNECsol and NEB number increased in the Ox group (PNE Csol Con, 3.6 +/- 2.6 versus Ox, 6.3 +/- 3.1/100 mm epithelium, p < 0. 05; NEB Con, 7.1 +/- 4.0 versus 11.9 +/- 3.6/100 mm epithelium, p < 0. 05), These findings document an association between hyperoxia, airway remodeling, and PNEC hyperplasia and imply that PNEC products may cont ribute to the pathogenesis of oxygen-related pulmonary diseases such a s BPD.