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Abstract
BackgroundBronchopulmonary dysplasia (BPD) is a common chronic lung disease in premature infants and hyperoxia exposure is a major cause. In hyperoxic lung injury animal model, alveolar simplification and pro-inflammatory cells infiltration are the main pathophysiologic changes. Caffeine is a drug used to treat apnea in premature infants. Early use of caffeine can decrease the rate and the severity of BPD while the mechanisms are still unclear. The purpose of this study was to evaluate the effects of caffeine on inflammation and lung development in neonatal mice with hyperoxic lung injury and to explore the possible mechanism.MethodsFollowing 14 d of 75% oxygen exposure in newborn mouse, the BPD model was established. Caffeine at a dose of 1 g/L was added in drinking water to nursing mouse. We measured the concentration of caffeine in serum and oxidative stress in lung by commercially available kits. Adenosine 2A receptor (A2AR) expression and lung inflammation were measured by Immunohistochemistry and western blotting. Apoptosis and surfactant protein-C (SFTPC) levels were measured by immunofluorescence. The inflammasome and NF-κB pathway proteins were assessed by western blotting.ResultsWe found that the caffeine concentration in plasma at present dose significantly decreased the expression of A2AR protein in mice lung. Caffeine treatment significantly reduced oxidative stress, improved weight gain, promoted alveolar development, attenuated inflammatory infiltration and lung injury in hyperoxia-induced lung injury mice. Moreover, caffeine decreased the cell apoptosis in lung tissues, especially the Type II alveolar epithelial cell. The expression of NLRP3 inflammasome protein and NF-κB pathway were significantly inhibited by caffeine treatment.ConclusionCaffeine treatment can protect hyperoxia-induced mice lung from oxidative injury by inhibiting NLRP3 inflammasome and NF-κB pathway.
Highlights
Bronchopulmonary dysplasia (BPD) is a common chronic lung disease in premature infants and hyperoxia exposure is a major cause
There was a significant difference in the groups administered caffeine and the groups administered pure water, and there was no difference in the caffeine concentration of the Normoxia + Caffeine (267.19 ± 75.40 ng/mL) and Hyperoxia + Caffeine (292.75 ± 34.02 ng/ mL) group
Adenosine 2A receptor (A2AR) expression was decreased in the Hyperoxia + Caffeine group compared with the Hyperoxia group, and there was no significant difference in the A2AR levels of the Normoxia group and the Hyperoxia + Caffeine group
Summary
Bronchopulmonary dysplasia (BPD) is a common chronic lung disease in premature infants and hyperoxia exposure is a major cause. Excess reactive oxygen species (ROS) can activate specific inflammatory cells, increase the inflammatory cytokines and proteins level in the lung, resulted in lung injury and cell death, alveolar epithelial cells. Many studies have shown that an increase of pro-inflammatory factors, such as IL-6, IL-1β, and TNF-α, may activate cyto-immune responses, damage lung epithelial and endothelial cells and result in the development of BPD [7,8,9]. Among these proinflammatory factors, cyclooxygenase (COX) enzymes are considered as important rate-limiting enzymes involved in inflammatory tissue injury. Myeloperoxidase (MPO) is an important factor which is closely related to neutrophils activation [12]
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