Hyperoxia-induced airway remodeling and pulmonary neuroendocrine cell hyperplasia in the weanling rat

J. S. Shenberger, R. L. Shew, D. E. Johnson

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


Infants dying with bronchopulmonary dysplasia (BPD) demonstrate increased numbers of pulmonary neuroendocrine cells (PNEC). These infants also possess altered airway epithelial and smooth muscle dimensions reminiscent of oxygen-exposed animals. Because the pathogenesis of BPD involves oxygen toxicity, we hypothesized that chronic hyperoxia would induce 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% O2 (Ox; n = 12) with that of normoxic controls (Con; n = 12). In paraffin-embedded sections, airways <1500 μm cut in cross-section were analyzed using light microscopy and image analysis software. The degree of epithelial and smooth muscle hyperplasia was assessed with proliferating cell nuclear antigen (PCNA). PNEC content was assessed via immunohistochemical staining for calcitonin gene-related peptide (CGRP) and the number of solitary PNEC (PNEC(sol)) and PNEC clusters (neuroepithelial bodies, NEB) counted per section. We found that oxygen exposure increased epithelial and smooth muscle wall thickness (epithelium: Con, 12.3 ± 1.4 versus Ox, 14.8 ± 1.4 μm, p < 0.05; smooth muscle; Con, 7.0 ± 1.0 versus Ox, 10.0 ± 1.0 μm, p < 0.05). The changes in wall dimensions were accompanied by a 20% increase in fractional PCNA labeling of the epithelium but not the smooth muscle. Both PNEC(sol) and NEB number increased in the Ox group (PNEC(sol) 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 modeling, and PNEC hyperplasia and imply that PNEC products may contribute to the pathogenesis of oxygen- related pulmonary diseases such as BPD.

Original languageEnglish (US)
Pages (from-to)539-544
Number of pages6
JournalPediatric Research
Issue number4
StatePublished - 1997

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