Inhibition of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) reverses experimental pulmonary hypertension

Abdul G Hameed, Nadine D Arnold, Janet Chamberlain, Josephine A Pickworth, Claudia Paiva, Sarah Dawson, Simon Cross, Lu Long, Lan Zhao, Nicholas W Morrell, David C Crossman, Christopher M H Newman, David G Kiely, Sheila E Francis, Allan Lawrie

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57 Citations (Scopus)

Abstract

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by the progressive narrowing and occlusion of small pulmonary arteries. Current therapies fail to fully reverse this vascular remodeling. Identifying key pathways in disease pathogenesis is therefore required for the development of new-targeted therapeutics. We have previously reported tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) immunoreactivity within pulmonary vascular lesions from patients with idiopathic PAH and animal models. Because TRAIL can induce both endothelial cell apoptosis and smooth muscle cell proliferation in the systemic circulation, we hypothesized that TRAIL is an important mediator in the pathogenesis of PAH. We demonstrate for the first time that TRAIL is a potent stimulus for pulmonary vascular remodeling in human cells and rodent models. Furthermore, antibody blockade or genetic deletion of TRAIL prevents the development of PAH in three independent rodent models. Finally, anti-TRAIL antibody treatment of rodents with established PAH reverses pulmonary vascular remodeling by reducing proliferation and inducing apoptosis, improves hemodynamic indices, and significantly increases survival. These preclinical investigations are the first to demonstrate the importance of TRAIL in PAH pathogenesis and highlight its potential as a novel therapeutic target to direct future translational therapies.
Original languageEnglish
Pages (from-to)1919-35
Number of pages17
JournalJournal of Experimental Medicine
Volume209
Issue number11
DOIs
Publication statusPublished - 22 Oct 2012

Keywords

  • Adult
  • Animals
  • Anoxia
  • Antibodies
  • Apolipoproteins E
  • Apoptosis
  • Blotting, Western
  • Cell Proliferation
  • Cells, Cultured
  • Female
  • Gene Expression
  • Humans
  • Hypertension, Pulmonary
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Muscle, Smooth, Vascular
  • Myocytes, Smooth Muscle
  • Pulmonary Artery
  • Rats, Sprague-Dawley
  • Reverse Transcriptase Polymerase Chain Reaction
  • TNF-Related Apoptosis-Inducing Ligand
  • Young Adult

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