title: Metformin attenuates hyperoxia-induced lung injury in neonatal rats by reducing the inflammatory response.
abstract: Because therapeutic options are lacking for bronchopulmonary dysplasia (BPD), there is an urgent medical need to discover novel targets/drugs to treat this neonatal chronic lung disease. Metformin, a drug commonly used to lower blood glucose in type 2 diabetes patients, may be a novel therapeutic option for BPD by reducing pulmonary inflammation and fibrosis and improving vascularization. We investigated the therapeutic potential of daily treatment with 25 and 100 mg/kg metformin, injected subcutaneously in neonatal Wistar rats with severe experimental BPD, induced by continuous exposure to 100% oxygen for 10 days. Parameters investigated included survival, lung and heart histopathology, pulmonary fibrin and collagen deposition, vascular leakage, right ventricular hypertrophy, and differential mRNA expression in the lungs of key genes involved in BPD pathogenesis, including inflammation, coagulation, and alveolar development. After daily metformin treatment rat pups with experimental BPD had reduced mortality, alveolar septum thickness, lung inflammation, and fibrosis, demonstrated by a reduced influx of macrophages and neutrophils and hyperoxia-induced collagen III and fibrin deposition (25 mg/kg), as well as improved vascularization (100 mg/kg) compared with control treatment. However, metformin did not ameliorate alveolar enlargement, small arteriole wall thickening, vascular alveolar leakage, and right ventricular hypertrophy. In conclusion metformin prolongs survival and attenuates pulmonary injury by reducing pulmonary inflammation, coagulation, and fibrosis but does not affect alveolar development or prevent pulmonary arterial hypertension and right ventricular hypertrophy in neonatal rats with severe hyperoxia-induced experimental BPD.
authors.affiliation: Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, Leiden, The Netherlands;
authors.forename: Xueyu
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, Leiden, The Netherlands; Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles Medical Center, Torrance, California;
authors.forename: Frans J
authors.initials: FJ
authors.lastname: Walther
authors.affiliation: Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, Leiden, The Netherlands;
authors.forename: Rozemarijn M A
authors.initials: RM
authors.lastname: Sengers
authors.affiliation: Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, Leiden, The Netherlands;
authors.forename: El Houari
authors.initials: el H
authors.lastname: Laghmani
authors.affiliation: Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, Leiden, The Netherlands;
authors.forename: Asma
authors.initials: A
authors.lastname: Salam
authors.affiliation: Department of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands; and.
authors.forename: Gert
authors.initials: G
authors.lastname: Folkerts
authors.affiliation: Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Tonio
authors.initials: T
authors.lastname: Pera
authors.affiliation: Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, Leiden, The Netherlands; g.t.m.wagenaar@lumc.nl.
authors.forename: Gerry T M
authors.initials: GT
authors.lastname: Wagenaar
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001997:Bronchopulmonary Dysplasia / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D002199:Capillary Permeability / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004549:Elastin / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000517:prevention & control; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D017208:Rats, Wistar
chemical_list: D000893:Anti-Inflammatory Agents; D005337:Fibrin; D003094:Collagen; D004549:Elastin; D008687:Metformin
keywords: bronchopulmonary dysplasia; coagulation; fibrosis; lung inflammation