Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

ABSTRACT Rationale: Pulmonary arterial hypertension (PAH) is characterized by vascular cell proliferation and endothelial cell apoptosis. Toll-like receptor 3 (TLR3) is a receptor for double-stranded RNA and has been recently implicated in vascular protection. Objective: The goal was to study the expression and role of TLR3 in PAH and to determine whether a TLR3 agonist reduces Pulmonary Hypertension in preclinical models. Methods: Lung tissue and endothelial cells from PAH patients were investigated by polymerase chain reaction, immunofluorescence and apoptosis assays. TLR3-/- and TLR3+/+ mice were exposed to chronic hypoxia and SU5416. Chronic hypoxia or chronic hypoxia/SU5416 rats were treated with the TLR3 agonist polyinosinic:polycytidylic acid [Poly(I:C)]. Measurements and Main Results: TLR3 expression was reduced in PAH patient lung tissue and endothelial cells, and TLR3-/- mice exhibited more severe Pulmonary Hypertension following exposure to chronic hypoxia/SU5416. TLR3 knockdown promoted double-stranded RNA signaling via other intracellular RNA receptors in endothelial cells and this was associated with greater susceptibility to apoptosis, a known driver of pulmonary vascular remodeling. Poly(I:C) increased TLR3 expression via interleukin-10 in rat endothelial cells. In vivo, high dose Poly(I:C) reduced Pulmonary Hypertension in both rat models in proof-of-principle experiments. In addition, Poly(I:C) also reduced right ventricular failure in established Pulmonary Hypertension. Conclusions: Our work identifies a novel role for TLR3 in PAH based on the findings that reduced expression of TLR3 contributes to endothelial apoptosis and pulmonary vascular remodelling.

Original publication




Journal article


American Journal of Respiratory and Critical Care Medicine


American Thoracic Society

Publication Date