title: Attenuation of endoplasmic reticulum stress by caffeine ameliorates hyperoxia-induced lung injury.
abstract: Rodent pups exposed to hyperoxia develop lung changes similar to bronchopulmonary dysplasia (BPD) in extremely premature infants. Oxidative stress from hyperoxia can injure developing lungs through endoplasmic reticulum (ER) stress. Early caffeine treatment decreases the rate of BPD, but the mechanisms remain unclear. We hypothesized that caffeine attenuates hyperoxia-induced lung injury through its chemical chaperone property. Sprague-Dawley rat pups were raised either in 90 (hyperoxia) or 21% (normoxia) oxygen frompostnatal day 1(P1) topostnatal day 10(P10) and then recovered in 21% oxygen until P21. Caffeine (20 mg/kg) or normal saline (control) was administered intraperitoneally daily starting from P2. Lungs were inflation-fixed for histology or snap-frozen for immunoblots. Blood caffeine levels were measured in treated pups at euthanasia and were found to be 18.4 ± 4.9 μg/ml. Hyperoxia impaired alveolar formation and increased ER stress markers and downstream effectors; caffeine treatment attenuated these changes at P10. Caffeine also attenuated the hyperoxia-induced activation of cyclooxygenase-2 and markers of apoptosis. In conclusion, hyperoxia-induced alveolar growth impairment is mediated, in part, by ER stress. Early caffeine treatment protects developing lungs from hyperoxia-induced injury by attenuating ER stress.
authors.affiliation: Division of Neonatology, Department of Pediatrics, Medical College of Wisconsin, Wauwatosa, Wisconsin rteng@mcw.edu.
authors.forename: Ru-Jeng
authors.identifier: 0000-0003-4321-2452
authors.initials: RJ
authors.lastname: Teng
authors.affiliation: Division of Neonatology, Department of Pediatrics, Medical College of Wisconsin, Wauwatosa, Wisconsin.
authors.forename: Xigang
authors.initials: X
authors.lastname: Jing
authors.affiliation: Division of Neonatology, Department of Pediatrics, Medical College of Wisconsin, Wauwatosa, Wisconsin.
authors.forename: Teresa
authors.initials: T
authors.lastname: Michalkiewicz
authors.affiliation: Division of Neonatology, Department of Pediatrics, Medical College of Wisconsin, Wauwatosa, Wisconsin.
authors.forename: Adeleye J
authors.initials: AJ
authors.lastname: Afolayan
authors.affiliation: Division of Neonatology, Department of Pediatrics, Medical College of Wisconsin, Wauwatosa, Wisconsin.
authors.forename: Tzong-Jin
authors.initials: TJ
authors.lastname: Wu
authors.affiliation: Division of Neonatology, Department of Pediatrics, Medical College of Wisconsin, Wauwatosa, Wisconsin.
authors.forename: Girija G
authors.initials: GG
authors.lastname: Konduri
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002110:Caffeine / Q000097:blood / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D006360:Heat-Shock Proteins / Q000378:metabolism; D018496:Hyperoxia / Q000150:complications* / Q000201:enzymology / Q000473:pathology*; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D055370:Lung Injury / Q000201:enzymology / Q000209:etiology* / Q000473:pathology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D018919:Neovascularization, Physiologic / Q000187:drug effects; D001678:Organelle Biogenesis; D018384:Oxidative Stress / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D011014:Pneumonia / Q000150:complications / Q000473:pathology; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000473:pathology; D017207:Rats, Sprague-Dawley; D056811:Unfolded Protein Response / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D002110:Caffeine; D051546:Cyclooxygenase 2; D006360:Heat-Shock Proteins; D009195:Peroxidase; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP
keywords: apoptosis; bronchopulmonary dysplasia; endoplasmic reticulum; hyperoxia; mitochondria