Toll-like Receptor 3 Is a Therapeutic Target for Pulmonary Hypertension.
Am J Respir Crit Care Med
; 199(2): 199-210, 2019 01 15.
Article
en En
| MEDLINE
| ID: mdl-30211629
ABSTRACT
RATIONALE Pulmonary arterial hypertension (PAH) is characterized by vascular cell proliferation and endothelial cell apoptosis. TLR3 (Toll-like receptor 3) is a receptor for double-stranded RNA and has been recently implicated in vascular protection. OBJECTIVES:
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 patients with PAH 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[IC]). MEASUREMENTS AND MAINRESULTS:
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. This was associated with greater susceptibility to apoptosis, a known driver of pulmonary vascular remodeling. Poly(IC) increased TLR3 expression via IL-10 in rat endothelial cells. In vivo, high-dose Poly(IC) reduced pulmonary hypertension in both rat models in proof-of-principle experiments. In addition, Poly(IC) 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 remodeling.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Receptor Toll-Like 3
/
Hipertensión Pulmonar
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Am J Respir Crit Care Med
Asunto de la revista:
TERAPIA INTENSIVA
Año:
2019
Tipo del documento:
Article