A hyperoxic lung injury model in premature rabbits: the influence of different gestational ages and oxygen concentrations.

Roberta Munhoz Manzano,Luciana Branco Haddad,Aline Rabelo Fernandes,Ana M A Reyes,Celso Moura Rebello,Renata Suman Mascaretti,Valéria Carrer

doi:10.1371/journal.pone.0095844

Abstract

BackgroundMany animal models have been developed to study bronchopulmonary dysplasia (BPD). The preterm rabbit is a low-cost, easy-to-handle model, but it has a high mortality rate in response to the high oxygen concentrations used to induce lung injury. The aim of this study was to compare the mortality rates of two models of hyperoxia-induced lung injury in preterm rabbits.MethodsPregnant New Zealand white rabbits were subjected to caesarean section on gestational day 28 or 29 (full term = 31 days). The premature rabbits in the 28-day gestation group were exposed to room air or FiO2 ≥95%, and the rabbits in the 29-day gestation group were exposed to room air or FiO2 = 80% for 11 days. The mean linear intercept (Lm), internal surface area (ISA), number of alveoli, septal thickness and proportion of elastic and collagen fibers were quantified.ResultsThe survival rates in the 29-day groups were improved compared with the 28-day groups. Hyperoxia impaired the normal development of the lung, as demonstrated by an increase in the Lm, the septal thickness and the proportion of elastic fibers. Hyperoxia also decreased the ISA, the number of alveoli and the proportion of collagen fibers in the 28-day oxygen-exposed group compared with the control 28-day group. A reduced number of alveoli was found in the 29-day oxygen exposed animals compared with the control 29-day group.ConclusionsThe 29-day preterm rabbits had a reduced mortality rate compared with the 28-day preterm rabbits and maintained a reduction in the alveoli number, which is comparable to BPD in humans.

Highlights

Bronchopulmonary dysplasia (BPD) is a multifactorial disorder with a pathogenesis that includes prematurity, the requirement for mechanical ventilation, inadequate antioxidant defenses and activation of the inflammatory response through several mechanisms
The premature rat model subjected to hyperoxia is advantageous due to its ease of manipulation and lower cost compared with larger-animal models [20], their main disadvantage is the small body size, which is a restriction for the study of lung mechanics and the alveolar and total lung surfactant pool in premature newborns [11]
The oxygen concentrations used in most studies exceed the levels of supplementation currently applied to the preterm infant and lack the oxygen fluctuations that are clinically observed in preterm infants, which could potentially induce differences in molecular signaling not reproduced in the experimental setting [21]

Summary

Introduction

Bronchopulmonary dysplasia (BPD) is a multifactorial disorder with a pathogenesis that includes prematurity, the requirement for mechanical ventilation, inadequate antioxidant defenses and activation of the inflammatory response through several mechanisms. The most important mechanism for activating the inflammatory response is oxygen exposure [1], but other mechanisms can result in decreased alveolarization [2,3,4,5,6,7] Due to this complex pathogenesis, many experimental models have been developed by exposing the immature lung to injuries induced by hyperoxia, mechanical stretch, inflammation and genetic modification [8,9,10]. These BPD models, included rats, lambs and baboons were essential tools for obtaining a better understanding of this disease [11,12,13,14,15,16,17]. The aim of this study was to compare the mortality rates of two models of hyperoxia-induced lung injury in preterm rabbits

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