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

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.

Neuroprotection by Caffeine in Hyperoxia-Induced Neonatal Brain Injury.

Sequelae of prematurity triggered by oxidative stress and free radical-mediated tissue damage have coined the term "oxygen radical disease of prematurity". Caffeine, a potent free radical scavenger and adenosine receptor antagonist, reduces rates of brain damage in preterm infants. In the present study, we investigated the effects of caffeine on oxidative stress markers, anti-oxidative response, inflammation, redox-sensitive transcription factors, apoptosis, and extracellular matrix following the induction of hyperoxia in neonatal rats. The brain of a rat pups at postnatal Day 6 (P6) corresponds to that of a human fetal brain at 28-32 weeks gestation and the neonatal rat is an ideal model in which to investigate effects of oxidative stress and neuroprotection of caffeine on the developing brain. Six-day-old Wistar rats were pre-treated with caffeine and exposed to 80% oxygen for 24 and 48 h. Caffeine reduced oxidative stress marker (heme oxygenase-1, lipid peroxidation, hydrogen peroxide, and glutamate-cysteine ligase catalytic subunit (GCLC)), promoted anti-oxidative response (superoxide dismutase, peroxiredoxin 1, and sulfiredoxin 1), down-regulated pro-inflammatory cytokines, modulated redox-sensitive transcription factor expression (Nrf2/Keap1, and NFκB), reduced pro-apoptotic effectors (poly (ADP-ribose) polymerase-1 (PARP-1), apoptosis inducing factor (AIF), and caspase-3), and diminished extracellular matrix degeneration (matrix metalloproteinases (MMP) 2, and inhibitor of metalloproteinase (TIMP) 1/2). Our study affirms that caffeine is a pleiotropic neuroprotective drug in the developing brain due to its anti-oxidant, anti-inflammatory, and anti-apoptotic properties.

Prevention of hyperoxia-mediated pulmonary inflammation in neonatal rats by caffeine.

In preterm human infants, briefly elevated concentrations of oxygen are associated with a prolonged increase in blood chemokine concentrations and the development of bronchopulmonary dysplasia (BPD). Caffeine given to preterm infants for the prevention or treatment of apnoea has been shown to reduce the rate of BPD. We tested the hypotheses that infant rats exposed to a combination of caffeine and hyperoxia would be less susceptible to lung injury than those exposed to hyperoxia alone and that caffeine decreases the pulmonary tissue expression of chemokines and leukocyte influx following hyperoxia. Using 6-day-old rat pups, we demonstrated that 24 h of 80% oxygen exposure caused pulmonary recruitment of neutrophils and macrophages. High levels of oxygen upregulated the expression of: the CXC chemokines, cytokine-induced neutrophil chemoattractant-1 and macrophage inflammatory protein-2; the CC-chemokine monocyte chemoattractant protein-1; the pro-inflammatory cytokines tumour necrosis factor-α and interleukin-6, as measured by realtime PCR after the administration of caffeine (10 mg · kg(-1) body weight); and attenuated chemokine and cytokine upregulation, as well as the influx of CD11b(+), ED-1(+) and myeloperoxidase(+) leukocytes. These experiments suggest that protective effects of caffeine in the neonatal lung are mediated, at least in part, by reduction of pulmonary inflammation.

The Conflicting Role of Caffeine Supplementation on Hyperoxia-Induced Injury on the Cerebellar Granular Cell Neurogenesis of Newborn Rats.

Preterm birth disrupts cerebellar development, which may be mediated by systemic oxidative stress that damages neuronal developmental stages. Impaired cerebellar neurogenesis affects several downstream targets important for cognition, emotion, and speech. In this study, we demonstrate that oxidative stress induced with high oxygen (80%) for three or five postnatal days (P3/P5) could significantly damage neurogenesis and proliferative capacity of granular cell precursor and Purkinje cells in rat pups. Reversal of cellular neuronal damage after recovery to room air (P15) was augmented by treatment with caffeine. However, downstream transcripts important for migration and differentiation of postmitotic granular cells were irreversibly reduced by hyperoxia, without rescue by caffeine. Protective effects of caffeine in the cerebellum were limited to neuronal survival but failed to restore important transcript signatures.

Christine Guthrie (1945-2022).

RNA trailblazer who illuminated splicing mechanics.

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

BACKGROUND: Preterm birth implies an array of respiratory diseases including apnea of prematurity and bronchopulmonary dysplasia (BPD). Caffeine has been introduced to treat apneas but also appears to reduce rates of BPD. Oxygen is essential when treating preterm infants with respiratory problems but high oxygen exposure aggravates BPD. This experimental study is aimed at investigating the action of caffeine on inflammatory response and cell death in pulmonary tissue in a hyperoxia-based model of BPD in the newborn rat. Material/Methods. Lung injury was induced by hyperoxic exposure with 80% oxygen for three (P3) or five (P5) postnatal days with or without recovery in ambient air until postnatal day 15 (P15). Newborn Wistar rats were treated with PBS or caffeine (10 mg/kg) every two days beginning at the day of birth. The effects of caffeine on hyperoxic-induced pulmonary inflammatory response were examined 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: Treatment with caffeine significantly attenuated changes in hyperoxia-induced cell death and apoptosis-associated factors. There was a significant decrease in proinflammatory mediators and redox-sensitive transcription factor NFκB in the hyperoxia-exposed lung tissue of the caffeine-treated group compared to the nontreated group. Moreover, treatment with caffeine under hyperoxia modulated the transcription of the adenosine receptor (Adora)1. Caffeine induced pulmonary chemokine and cytokine transcription followed by immune cell infiltration of alveolar macrophages as well as increased adenosine receptor (Adora1, 2a, and 2b) expression. CONCLUSIONS: The present study investigating the impact of caffeine on the inflammatory response, pulmonary cell degeneration and modulation of adenosine receptor expression, provides further evidence that caffeine acts as an antioxidative and anti-inflammatory drug for experimental oxygen-mediated lung injury. Experimental studies may broaden the understanding of therapeutic use of caffeine in modulating detrimental mechanisms involved in BPD development.

I come not to bury SAGE KE but to appraise It.

This article serves as a eulogy for the Science of Aging Knowledge Environment (SAGE KE). This online resource--Science's Web site on aging--is publishing its last issue today. The piece is a personal recollection of co-creating the site--and includes some thoughts on how the field of aging has changed over the last six years.

Science of aging knowledge environment: one-stop shopping for researchers in the field of aging.

The Science of Aging Knowledge Environment (SAGE KE) was launched in October 2001 to provide an online information source and community-building tool. The site offers a wide range of features, including original commentary articles, a database of genes and interventions related to aging, and a calendar of meetings and events. Users may initiate discussions and post comments on the articles; these features are intended to promote interaction between researchers in the field and to ensure the timeliness of information posted. This paper details SAGE KE's contents and offers suggestions about how to customize the site to save time and maximize information acquisition and exchange.

Vascular Endothelial Growth Factor (VEGF) and soluble VEGF receptor 1 (sFlt-1) levels in early and mature human milk from mothers of preterm versus term infants.

BACKGROUND: Vascular endothelial growth factor (VEGF) and its receptors regulate angiogenesis (formation of blood vessels). The soluble VEGF receptor 1 (sFlt-1) binds VEGF as a potent antagonist. OBJECTIVE: The objective of this study was to compare VEGF and sFlt-1 levels in milk from mothers of preterm (n = 50) versus term (n = 49) infants in a longitudinal study. METHODS: Milk samples were collected on days 3 and 28 of lactation. Vascular endothelial growth factor and sFlt-1 were quantified by sandwich-type enzyme-linked immunosorbent assay. RESULTS: Vascular endothelial growth factor and sFlt-1 were found in high concentrations in early milk (lactation day 3) from mothers of preterm and term infants and were lower in mature milk (lactation day 28). On day 3, median VEGF concentration was lower in preterm than in term milk (37.1 vs 53.9 ng/mL, P < .01). Otherwise, VEGF (day 28) and sFlt-1 (days 3 and 28) did not differ in preterm versus term milk. CONCLUSIONS: It was shown for the first time that sFlt-1 is present in human milk. Early human milk contains high concentrations of VEGF and sFlt-1, which decrease over the course of lactation.

Arrays of hope.

A large study by the MAQC consortium has established that different DNA microarray platforms can generate reproducible lists of differentially expressed genes. Now scientists are grappling with the challenges of moving the technology toward the clinic.

Changing expression of cyclooxygenases and prostaglandin receptor EP4 during development of the human ductus arteriosus.

Programmed proliferative degeneration of the human fetal ductus arteriosus (DA) in preparation for its definite postnatal closure has a large developmental variability and is controlled by several signaling pathways, most prominently by prostaglandin (PG) metabolism. Numerous studies in various mammalian species have shown interspecies and developmental differences in ductal protein expression of cyclooxygenase (COX) isoforms and PG E receptor subtypes (EP1-4). We examined COX1, COX2, and EP4 receptor protein expression immunohistochemically in 57 human fetal autopsy DA specimens of 11-38 wk of gestation. According to their histologic maturity, specimens were classified into four stages using a newly designed maturity score that showed that histologic maturity of the DA was not closely related to gestational age. COX1 expression was found in all DA regions and rose steadily during development. COX2 staining remained weak throughout gestation. EP4 receptor staining increased moderately during gestation and was limited to the intima and media. In conclusion, histologic maturity classification helps to address developmentally regulated processes in the fetal DA. Concerning prostaglandin metabolism our findings are in line with animal studies, which assigned COX1 the predominant role in the DA throughout gestation. EP4 receptor presumably plays a key role for active patency of the human DA in the third trimester.