Caffeine Prevents Hyperoxia-Induced Functional and Structural Lung Damage in Preterm Rabbits

Abstract

Background: Caffeine is a commonly used drug for apnea of prematurity. It may, however, also have a beneficial effect on bronchopulmonary dysplasia (BPD), which is the most common complication of extreme preterm birth. Objectives: To study the inflammatory, structural and functional effects of caffeine in an animal model of BPD. Methods: Preterm New Zealand-Dendermonde rabbits (gestational day 28; term 31) were randomized to three groups: normoxia-placebo (N-P), hyperoxia-placebo (H-P) and hyperoxia-caffeine (H-C). Lung function was assessed on postnatal day 5, along with airway morphometry, vascular morphometry and a score observing airway inflammation. Results: Caffeine improved lung function by increasing lung volume [mean displaced volume N-P: 40.1 ± 6 ml/kg, H-P: 27.8 ± 8 ml/kg and H-C: 34.4 ± 7 ml/kg (p < 0.05); total lung capacity: N-P: 1.17 ± 0.1 ml, H-P: 0.67 ± 0.1 ml and H-C: 1.1 ± 0.1 ml (p < 0.05)], decreasing tissue damping [N-P: 2.7 ± 0.3 cm H₂O/ml, H-P: 4.6 ± 0.6 cm H₂O/ml and H-C: 3.2 ± 0.4 cm H₂O/ml (p < 0.05)], elastance [N-P: 9.3 ± 2.4 cm H₂O/ml, H-P: 19.2 ± 7.4 cm H₂O/ml and H-C: 10.7 ± 2 cm H₂O/ml (p < 0.05)] and compliance [N-P: 0.06 ± 0.01 cm H₂O/ml, H-P: 0.054 ± 0.01 cm H₂O/ml and H-C: 0.07 ± 0.013 cm H₂O/ml (p < 0.05)]. Caffeine also improved histology by decreasing alveolar size [linear intercepts; N-P: 83.6 ± 1.7, H-P: 82.9 ± 1.6 and H-C: 67.3 ± 1.4 (p < 0.05)], increasing radial alveolar count (N-P: 6.6 ± 0.5, H-P: 5.7 ± 0.6 and H-C: 7.05 ± 0.5) and decreasing the acute inflammation score [N-P: 0.3 ± 0.1, H-P: 0.5 ± 0.1 and H-C: 0.4 ± 0.1 (p < 0.05)]. Conclusion: In preterm rabbits, caffeine reduces the functional, architectural and inflammatory pulmonary changes induced by hyperoxia in the lung.

Antioxidative effects of caffeine in a hyperoxia-based rat model of bronchopulmonary dysplasia

“…Postnatal hyperoxia led to structural changes in the immature lung at exposure times over the first few days of life (P3 and P5), furthermore the damage persisted even after recovery under normoxic conditions until the transition from the saccular to the alveolar phase of lung development. Caffeine reduced this structural damage, as shown in a previous study of acute hyperoxia [47,48].…”

A new target for caffeine in the developing lung: endoplasmic reticulum stress?

“…The study of Teng and coworkers in rats was able to document a protective effect of caffeine (by an as-yet-undetermined mechanism) on hyperoxia-induced arrest of lung alveolarization. This protective effect of caffeine and other methylxanthine derivatives has been noted in a variety of rat BPD models (17,20,23,26,38,40). Taken together, these reports beg the question: Is there a fundamental difference in the responsiveness of rats versus mice to caffeine, which is relevant to lung alveolarization?…”

“…1. Among the reports from the "pro-caffeine lobby" are observations that caffeine administration to neonatal rats blunted the lung inflammation that was provoked by hyperoxia (38) and that caffeine administration to preterm rabbits limited the damaging effects of hyperoxia on lung alveolarization, ostensibly also by blunting hyperoxia-provoked inflammation (23). When intra-amniotic bacterial lipopolysaccharide (LPS) was used to mimic chorioamnionitis in pregnant rats, leading to arrested lung alveolarization in offspring, the administration of caffeine (20) or the related methylxanthine theophylline (17,26), appreciably attenuated the blunted alveolarization, most likely by limiting inflammation.…”

Caffeine modulates glucocorticoid-induced expression of CTGF in lung epithelial cells and fibroblasts

“…Of note, caffeine treatment has been associated with reduced incidences of BPD [41] and the prevention of hyperoxia-mediated pulmonary inflammation and lung injury [42, 43]. Although caffeine has been demonstrated anti-inflammatory [44] and antifibrotic effects [45, 46], its potential impact on airway remodeling has not been investigated in detail.…”