title: Role of tetrahydrobiopterin in pulmonary vascular remodelling associated with pulmonary fibrosis.
abstract: BACKGROUND
  Pulmonary hypertension in idiopathic pulmonary fibrosis (IPF) is indicative of a poor prognosis. Recent evidence suggests that tetrahydrobiopterin (BH4), the cofactor of nitric oxide synthase (NOS), is involved in pulmonary hypertension and that pulmonary artery endothelial-to-mesenchymal transition (EnMT) may contribute to pulmonary fibrosis. However, the role of BH4 in pulmonary remodelling secondary to pulmonary fibrosis is unknown. This study examined the BH4 system in plasma and pulmonary arteries from patients with IPF as well as the antiremodelling and antifibrotic effects of the BH4 precursor sepiapterin in rat bleomycin-induced pulmonary fibrosis and in vitro EnMT models.
  
  
  METHODS
  BH4 and nitrotyrosine were measured by high-performance liquid chromatography and ELISA, respectively. Expression of sepiapterin reductase (SPR), GTP cyclohydrolase 1 (GCH-1), endothelial NOS (eNOS) and inducible NOS (iNOS) were measured by quantitative PCR and immunohistochemistry.
  
  
  RESULTS
  BH4 plasma levels were downregulated in patients with IPF compared with controls while nitrites, nitrates and nitrotyrosine were upregulated. GCH-1 and eNOS were absent in pulmonary arteries of patients with IPF; however, iNOS expression increased while SPR expression was unchanged. In rats, oral sepiapterin (10 mg/kg twice daily) attenuated bleomycin-induced pulmonary fibrosis, mortality, vascular remodelling and pulmonary hypertension by increasing rat plasma BH4, decreasing plasma nitrotyrosine and increasing vascular eNOS and GCH-1 expression. Both transforming growth factor β1 and endothelin-1 induced EnMT by decreasing BH4 and eNOS expression. In vitro administration of sepiapterin increased endothelial BH4 and inhibited EnMT in human pulmonary artery endothelial cells.
  
  
  CONCLUSIONS
  Targeting the BH4 synthesis 'salvage pathway' with sepiapterin may be a new therapeutic strategy to attenuate pulmonary hypertension in IPF.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Valencia, , Valencia, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Almudéver
authors.forename: Javier
authors.initials: J
authors.lastname: Milara
authors.forename: Alfredo
authors.initials: A
authors.lastname: De Diego
authors.forename: Ana
authors.initials: A
authors.lastname: Serrano-Mollar
authors.forename: Antoni
authors.initials: A
authors.lastname: Xaubet
authors.forename: Francisco
authors.initials: F
authors.lastname: Perez-Vizcaino
authors.forename: Angel
authors.initials: A
authors.lastname: Cogolludo
authors.forename: Julio
authors.initials: J
authors.lastname: Cortijo
mesh_terms: D000368:Aged; D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006136:GTP Cyclohydrolase / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology*; D011658:Pulmonary Fibrosis / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D001708:Biopterins; C002744:3-nitrotyrosine; D014443:Tyrosine; D000429:Alcohol Oxidoreductases; C022630:sepiapterin reductase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D006136:GTP Cyclohydrolase; C003402:sapropterin
keywords: Idiopathic pulmonary fibrosis; Interstitial Fibrosis; Oxidative Stress