Animal models of bronchopulmonary dysplasia. The term rat models

Abstract

O'Reilly M, Thébaud B. Animal models of bronchopulmonary dysplasia. The term rat models. Am J Physiol Lung Cell Mol Physiol 307: L948 -L958, 2014. First published October 10, 2014; doi:10.1152/ajplung.00160.2014.-Bronchopulmonary dysplasia (BPD) is the chronic lung disease of prematurity that affects very preterm infants. Although advances in perinatal care have enabled the survival of infants born as early as 23-24 wk of gestation, the challenge of promoting lung growth while protecting the ever more immature lung from injury is now bigger. Consequently, BPD remains one of the most common complications of extreme prematurity and still lacks specific treatments. Progress in our understanding of BPD and the potential of developing therapeutic strategies have arisen from large (baboons, sheep, and pigs) and small (rabbits, rats, and mice) animal models. This review focuses specifically on the use of the rat to model BPD and summarizes how the model is used in various research studies and the advantages and limitations of this particular model, and it highlights recent therapeutic advances in BPD by using this rat model. hyperoxia; lung development; premature birth BRONCHOPULMONARY DYSPLASIA (BPD) is the most common chronic lung disease of very preterm infants. BPD interrupts lung development and has serious long-term respiratory complications that reach beyond childhood and into adult life (8,25,26,41,53). The multifactorial etiology of BPD has prompted research to investigate the many factors contributing to the pathogenesis of BPD (reviewed in Ref. 38), with the ultimate aim of developing effective therapies to prevent longterm pulmonary sequelae. To investigate the effectiveness of various therapeutic strategies on the development, structure, and function of the lungs, it is important to have animal models that reliably reproduce some of the features observed in very preterm infants developing BPD. To achieve this, known contributing factors of BPD, such as perinatal inflammation, growth restriction, hyperoxia, and mechanical ventilation, have been used in both large and small animals to mimic the BPD-like lung injury. In particular, exposure of neonatal rats to hyperoxia is extensively utilized as a small animal model of experimental BPD. Characterization of the Rat Model of Experimental BPDExposing the immature rat lung to hyperoxic gas through neonatal life closely reproduces the histopathology observed in human infants with BPD. Studies have shown that exposure of the developing rat lung to hyperoxic gas can have detrimental effects, particularly on the structure of the gas-exchanging region (14,30,34,46,62,66). The main overall finding, which is common to each study, is that exposure of the immature lung to hyperoxic gas impairs alveolarization, resulting in fewer and enlarged alveolar air spaces. Pulmonary hypertension, disrupted vascular growth, vascular leakage, accumulation of plasma proteins, extravascular fibrin deposition, increased lung collagen content, increased inflammatory cell influx, and diso...

Collagen and elastin cross-linking is altered during aberrant late lung development associated with hyperoxia

“…The P values were determined by one-way ANOVA with Tukey's post hoc test. Additional stereo-morphometric parameters are provided in Table 5. baboons, and lambs, in which an arrest of alveolarization has been induced by exposure to elevated inspired oxygen concentrations, injurious mechanical ventilation, or combinations thereof (6,13,49,66). Given the pivotal roles attributed to the ECM in directing both normal and aberrant late lung development, it has been speculated that these perturbations to ECM architecture may underlie the blunted secondary septation in affected lungs.…”

“…There is also evidence of altered elastin turnover, as assessed by urinary excretion of the desmosine elastin cross-link, in infants with BPD (12). These data point to disturbances to ECM production and processing in BPD, which may be mimicked in animal models, employing either hyperoxia, caloric restriction, mechanical ventilation, or preterm delivery as an injurious stimulus in rats, mice, lambs, and baboons (6,13,49,66). The lung histopathology that results is reminiscent of that of BPD in humans, with evident air space enlargement, septal wall thickening, and a reduced number of alveoli, as well as perturbations to ECM structures.…”

The impact of vitamin D on fetal and neonatal lung maturation. A systematic review

“…Contrary to humans, the expression of surfactant in rats starts in the saccular phase on the 19th gestational day and is completed on the 21st-22nd day (at term) (86). The alveolar phase in rats does not begin until postpartum at postnatal days 4 -5 and slowly progresses throughout life (7,66,72) (Fig. 1).…”

Therapeutic potential of soluble guanylate cyclase modulators in neonatal chronic lung disease

“…Recent studies in animal models provided new clues for the pharmacological treatment of BPD using compounds affecting multiple regulatory pathways (31), involved in endothelin receptor type B inhibition (42), stimulation of the beneficial arm of the renin-angiotensin pathway with agonists of the MAS oncogene receptor and the angiotensin type 2 receptor (43,44), and stimulation of AMP-activated protein kinase with metformin (11). These recent interventions significantly reduced severe BPD pathology by attenuating septal thickness, vascular remodeling and pulmonary hypertension, lung inflammation, and right ventricular hypertrophy but did not improve alveolar simplification.…”