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Modeling Encephalopathy of Prematurity Using Prenatal Hypoxia-ischemia with Intra-amniotic Lipopolysaccharide in Rats
Published on: November 20, 2015
Hyperoxia-induced airway remodeling and pulmonary neuroendocrine cell hyperplasia in the weanling rat
J S Shenberger1, R L Shew, D E Johnson
1Department of Pediatrics, USAF Medical Center, Lackland AFB, Texas 78236-5300, USA.
Insights
Chronic hyperoxia, or excess oxygen exposure, causes airway remodeling and increases pulmonary neuroendocrine cells (PNEC) in developing lungs. This suggests PNEC may play a role in oxygen-related lung diseases like bronchopulmonary dysplasia.
Area of Science:
- Pulmonary Medicine
- Neonatology
- Cell Biology
Background:
- Infants with bronchopulmonary dysplasia (BPD) exhibit increased pulmonary neuroendocrine cells (PNEC) and airway structural changes.
- These airway alterations in BPD resemble those seen in animal models exposed to oxygen.
- Oxygen toxicity is a key factor in BPD pathogenesis.
Purpose of the Study:
- To investigate whether chronic hyperoxia induces airway remodeling and PNEC hyperplasia in a developing rat model.
- To establish a link between oxygen exposure, airway structural changes, and PNEC proliferation.
Main Methods:
- Rats were exposed to hyperoxia (>95% O2) or normoxia for two weeks.
- Small airway morphology, including epithelial and smooth muscle thickness, was analyzed.
- Cell proliferation was assessed using PCNA staining.
- PNEC populations (solitary PNEC and neuroepithelial bodies) were quantified using CGRP immunohistochemistry.
Main Results:
- Hyperoxia significantly increased epithelial and smooth muscle wall thickness in small airways.
- A 20% increase in epithelial cell proliferation (PCNA labeling) was observed in hyperoxia-exposed rats.
- Both solitary PNEC and neuroepithelial bodies were significantly increased following oxygen exposure.
Conclusions:
- Chronic hyperoxia induces airway remodeling and PNEC hyperplasia in developing rat lungs.
- These findings suggest a potential role for PNEC and their products in the development of oxygen-induced lung diseases, including BPD.
- The study highlights the detrimental effects of hyperoxia on developing pulmonary structures.
Abstract:
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 microns 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 (PNECsol) 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 microns, p < 0.05; smooth muscle: Con, 7.0 +/- 1.0 versus Ox, 10.0 +/- 1.0 microns, 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 PNECsol and NEB number increased in the Ox group (PNECsol 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 contribute to the pathogenesis of oxygen-related pulmonary diseases such as BPD.
