title: Deficient retinoid-driven angiogenesis may contribute to failure of adult human lung regeneration in emphysema.
abstract: Molecular pathways that regulate alveolar development and adult repair represent potential therapeutic targets for emphysema. Signalling via retinoic acid (RA), derived from vitamin A, is required for mammalian alveologenesis, and exogenous RA can induce alveolar regeneration in rodents. Little is known about RA signalling in the human lung and its potential role in lung disease.
  
  
  
  To examine regulation of human alveolar epithelial and endothelial repair by RA, and characterise RA signalling in human emphysema.
  
  
  
  The role of RA signalling in alveolar epithelial repair was investigated with a scratch assay using an alveolar cell line (A549) and primary human alveolar type 2 (AT2) cells from resected lung, and the role in angiogenesis using a tube formation assay with human lung microvascular endothelial cells (HLMVEC). Localisation of RA synthetic (RALDH-1) and degrading (cytochrome P450 subfamily 26 A1 (CYP26A1)) enzymes in human lung was determined by immunofluorescence. Regulation of RA pathway components was investigated in emphysematous and control human lung tissue by quantitative real-time PCR and Western analysis.
  
  
  
  RA stimulated HLMVEC angiogenesis in vitro; this was partially reproduced with a RAR-α agonist. RA induced mRNA expression of vascular endothelial growth factor A (VEGFA) and VEGFR2. RA did not modulate AT2 repair. CYP26A1 protein was identified in human lung microvasculature, whereas RALDH-1 partially co-localised with vimentin-positive fibroblasts. CYP26A1 mRNA and protein were increased in emphysema.
  
  
  
  RA regulates lung microvascular angiogenesis; the endothelium produces CYP26A1 which is increased in emphysema, possibly leading to reduced RA availability. These data highlight a role for RA in maintenance of the human pulmonary microvascular endothelium.
authors.affiliation: Inflammation, Repair and Development, National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: John-Poul
authors.initials: JP
authors.lastname: Ng-Blichfeldt
authors.affiliation: Inflammation, Repair and Development, National Heart and Lung Institute, Imperial College London, London, UK.|Royal Brompton and Harefield NHS Foundation Trust, London, UK.
authors.forename: Joana
authors.initials: J
authors.lastname: Alçada
authors.affiliation: Department of Histopathology, Royal Brompton and Harefield NHS Foundation Trust, London, UK.
authors.forename: M Angeles
authors.initials: MA
authors.lastname: Montero
authors.affiliation: Inflammation, Repair and Development, National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Charlotte H
authors.initials: CH
authors.lastname: Dean
authors.affiliation: Department of Gene Therapy, National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Uta
authors.initials: U
authors.lastname: Griesenbach
authors.affiliation: Inflammation, Repair and Development, National Heart and Lung Institute, Imperial College London, London, UK.|Royal Brompton and Harefield NHS Foundation Trust, London, UK.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Griffiths
authors.affiliation: Inflammation, Repair and Development, National Heart and Lung Institute, Imperial College London, London, UK.|Royal Brompton and Harefield NHS Foundation Trust, London, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Hind
mesh_terms: D000368:Aged; D056809:Alveolar Epithelial Cells / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D011650:Pulmonary Alveoli / Q000473:pathology; D011656:Pulmonary Emphysema / Q000473:pathology / Q000503:physiopathology*; D012333:RNA, Messenger / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014212:Tretinoin / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D014212:Tretinoin; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: COPD ÀÜ Mechanisms; Emphysema