title: Intrinsic defence capacity and therapeutic potential of natriuretic peptides in pulmonary hypertension associated with lung fibrosis.
abstract: OBJECTIVE
  Idiopathic pulmonary fibrosis (IPF) is a progressive fibro-proliferative disorder refractory to current therapy commonly complicated by the development of pulmonary hypertension (PH); the associated morbidity and mortality are substantial. Natriuretic peptides possess vasodilator and anti-fibrotic actions, and pharmacological augmentation of their bioactivity ameliorates renal and myocardial fibrosis. Here, we investigated whether natriuretic peptides possess an intrinsic cytoprotective function preventing the development of pulmonary fibrosis and associated PH, and whether therapeutics targeting natriuretic peptide signalling demonstrate efficacy in this life-threatening disorder.
  
  
  METHODS
  Pulmonary haemodynamics, right ventricular function and markers of lung fibrosis were determined in wild-type (WT) and natriuretic peptide receptor (NPR)-A knockout (KO) mice exposed to bleomycin (1 mg·kg(-1) ). Human myofibroblast differentiation was studied in vitro.
  
  
  RESULTS
  Exacerbated cardiac, vascular and fibrotic pathology was observed in NPR-A KO animals, compared with WT mice, exposed to bleomycin. Treatment with a drug combination that raised circulating natriuretic peptide levels (ecadotril) and potentiated natriuretic peptide-dependent signalling (sildenafil) reduced indices of disease progression, whether administered prophylactically or to animals with established lung disease. This positive pharmacodynamic effect was diminished in NPR-A KO mice. Atrial natriuretic peptide and sildenafil synergistically reduced TGFβ-induced human myofibroblast differentiation, a key driver of remodelling in IPF patients.
  
  
  CONCLUSIONS
  These data highlight an endogenous host-defence capacity of natriuretic peptides in lung fibrosis and PH. A combination of ecadotril and sildenafil reversed the pulmonary haemodynamic aberrations and remodelling that characterize the disease, advocating therapeutic manipulation of natriuretic peptide bioactivity in patients with IPF.
authors.affiliation: William Harvey Research Institute, Barts & The London School of Medicine, Queen Mary University of London, Charterhouse Square, London, UK.
authors.forename: R S
authors.initials: RS
authors.lastname: Baliga
authors.forename: C J
authors.initials: CJ
authors.lastname: Scotton
authors.forename: S L
authors.initials: SL
authors.lastname: Trinder
authors.forename: R C
authors.initials: RC
authors.lastname: Chambers
authors.forename: R J
authors.initials: RJ
authors.lastname: MacAllister
authors.forename: A J
authors.initials: AJ
authors.lastname: Hobbs
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor; D001761:Bleomycin; D002454:Cell Differentiation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058628:Myofibroblasts / Q000166:cytology / Q000187:drug effects; D020098:Natriuretic Peptide, C-Type / Q000172:deficiency / Q000378:metabolism; D045265:Natriuretic Peptides / Q000627:therapeutic use*; D011498:Protein Precursors / Q000172:deficiency / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D045265:Natriuretic Peptides; C431578:Nppa protein, mouse; D011498:Protein Precursors; D016212:Transforming Growth Factor beta; D001761:Bleomycin; D020098:Natriuretic Peptide, C-Type; D009320:Atrial Natriuretic Factor
keywords: bleomycin; cyclic GMP; guanylyl cyclase; natriuretic peptide; neutral endopeptidase; phosphodiesterase; pulmonary hypertension