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

Abstract

Background: While additional oxygen supply is often required for the survival of very premature infants in intensive care, this also brings an increasing risk of progressive lung diseases and poor long-term lung outcomes. Caffeine is administered to neonates in neonatal intensive care for the prevention and treatment of apneas and has been shown to reduce BPD incidence and the need for mechanical ventilation, although it is still unclear whether this is due to a direct pulmonary action via antagonism of adenosine receptors and/or an indirect action. This experimental study aims to investigate the action of caffeine on the oxidative stress response in pulmonary tissue in a hyperoxia-based model of bronchopulmonary dysplasia in newborn rats. Methods: Newborn Wistar rats were exposed to 21% or 80% oxygen for 3 (P3) or 5 (P5) postnatal days with or without recovery on room air until postnatal day 15 (P15) and treated with vehicle or caffeine (10 mg/kg) every 48 h beginning on the day of birth. The lung tissue of the rat pups was examined for oxidative stress response at P3 and P5 immediately after oxygen exposure or after recovery in ambient air (P15) by immunohistological staining and analysis of lung homogenates by ELISA and qPCR. Results: Lungs of newborn rats, corresponding to the saccular stage of lung development and to the human lung developmental stage of preterms, showed increased rates of total glutathione and hydrogen peroxide, oxidative damage to DNA and lipids, and induction of second-phase mediators of antioxidative stress response (superoxide dismutase, heme oxygenase-1, and the Nrf2/Keap1 system) in response to hyperoxia. Caffeine reduced oxidative DNA damage and had a protective interference with the oxidative stress response. Conclusion: In addition to the pharmacological antagonism of adenosine receptors, caffeine appears to be a potent antioxidant and modulates the hyperoxia-induced pulmonary oxidative stress response and thus protective properties in the BPD-associated animal model. Free-radical-induced damage caused by oxidative stress seems to be a biological mechanism progress of newborn diseases. New aspects of antioxidative therapeutic strategies to passivate oxidative stress-related injury should be in focus of further investigations.

Prevention of Oxygen-Induced Inflammatory Lung Injury by Caffeine in Neonatal Rats

“…The inflammatory response in hyperoxia-induced lung injury models of rodents is comparable to that of children affected by BPD [45,61,65]. As a result of oxidative damage caused by hyperoxia [39], here, we observed a drastic infiltration of immune cells as well as an overexpression of proinflammatory cytokines and chemokines in the lung tissue directly after hyperoxic exposure (P3 and P5) and following normoxic recovery (P15). These pathological alterations were largely reversed by caffeine delivery.…”

“…We demonstrate previously that caffeine diminishes oxidative stress and lung injury induced by hyperoxia [39], but little was known about effects on the secondary inflammatory response. Besides others [56,57], this study confirmed that exposure to high oxygen led to a massive increase in cell death as an important pathological feature.…”

“…No pups died during hyperoxia. Caffeine plasma concentrations and weight profiles were determined and presented in the previous work [39].…”

“…Oxygen toxicity is mediated by the production and accumulation of excessive reactive oxygen species (ROS), causes oxidative stress [38], and depleted antioxidant levels [39]. Supraphysiologic oxygen can cause oxygen toxicity and inflammation, ultimately leading to hyperoxic lung injury and impairment of lung development caused of an influx of inflammatory cells, increased pulmonary permeability, simplification of lung structure, and cell death [9,40].…”

Oxidative Stress in Preterm Infants: Overview of Current Evidence and Future Prospects

“…This resulted in reduced oxidative damage to DNA, and antagonism of adenosine receptors, a protective action against the response to oxidative stress, and complete interruption of oxidative damage induced by pulmonary hyperoxia. All of the abovementioned features have been found to be linked with a protective role in the development of BPD [26]. Pre-clinical data coming from newborn cavies (rats) has raised the hypothesis of a potential caffeine-related loss of weight.…”