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Role of tetrahydrobiopterin in pulmonary vascular remodelling associated with pulmonary fibrosis
  1. Patricia Almudéver1,
  2. Javier Milara2,3,4,5,
  3. Alfredo De Diego6,
  4. Ana Serrano-Mollar5,7,
  5. Antoni Xaubet5,8,
  6. Francisco Perez-Vizcaino5,9,
  7. Angel Cogolludo5,9,
  8. Julio Cortijo1,2,4,5
  1. 1Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain
  2. 2Clinical Research Unit (UIC), University General Hospital Consortium, Valencia, Spain
  3. 3Department of Biotechnology, Universidad Politécnica de Valencia, Valencia, Spain
  4. 4Research Foundation of General Hospital of Valencia, Valencia, Spain
  5. 5CIBERES, Health Institute Carlos III, Valencia, Spain
  6. 6Servicio de Neumología, Hospital Universitario y Politécnico La Fe, Valencia, Spain
  7. 7Dept de Patología Experimental, Instituto de Investigaciones Biomédicas de Barcelona, Consejo Superior de Investigaciones Científicas, Barcelona, Spain
  8. 8Servicio de Neumología, Hospital Clínico, Instituto de Investigaciones Biomédicas Agustí Pi Suñer (IDIBAPS), Barcelona, Spain
  9. 9Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain
  1. Correspondence to Dr Javier Milara, Unidad de Investigación, Consorcio, Hospital General Universitario, Avenida tres cruces s/n, Valencia E-46014, Spain; xmilara{at}hotmail.com

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.

  • Idiopathic pulmonary fibrosis
  • Oxidative Stress
  • Interstitial Fibrosis

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