S87 Deficiency of toll-like receptor 3 (TLR3) exacerbates pulmonary hypertension in mice. (15th November 2016)

• Record Type: Journal Article
• Authors: Thompson, AAR; Arnold, ND; Braithwaite, AT; Casbolt, HL; Iremonger, J; Pickworth, JA; Monaco, C; Cole, JE; Sabroe, I; Lawrie, A
• Is Part Of: Thorax. Volume 71(2016)Supplement 3
• Page Start: A50
• Page End: A50
• Publication Date: 2016-11-15
• Subjects: Chest -- Diseases -- Periodicals; Thorax; Chest -- Diseases; Periodicals; Periodicals; 617.54
• DOI: 10.1136/thoraxjnl-2016-209333.93
• Languages: English
• ISSNs: 0040-6376

Abstract

Abstract : Introduction: The mechanisms regulating aberrant vascular remodelling in pulmonary arterial hypertension (PAH) are poorly understood and treatments targeted at halting or reversing this process are lacking. Toll-like receptor 3 (TLR3) is a viral sensor and more recently has been established as a sensor of endogenous damage signals, responding to mRNA released by damaged cells. TLR3 signalling induces pro- and anti-inflammatory cytokine production and regulates inflammation-associated apoptosis and tyrosine kinase signalling. In a model of systemic arterial injury, TLR3 signalling was shown to modulate neointimal remodelling in a protective manner. TLR3 is also expressed in pulmonary artery smooth muscle (PASMCs) and endothelial cells (PAECs). We therefore hypothesised that TLR3 would play roles in pulmonary vascular remodelling. Methods: TLR3-deficient (TLR3−/−) or wild-type C57BL/6 (WT) mice were exposed to hypoxia (10% Oxygen) and given Sugen 5416 (weekly 20 mg/kg subcutaneous injections) or maintained in normoxic conditions for 3 weeks. Haemodynamic (cardiac catheterisation and echocardiography) and histological assessments were performed after 3 weeks. Human PASMCs were serum-starved before stimulation with PDGF or poly(I:C) and proliferation was assessed after 72 hours. Results: TLR3−/− mice developed a markedly exaggerated phenotype of PAH in response to Sugen/Hypoxia with increased right ventricular systolic pressures (WT 51.6 mmHg ± 4.6 vs. TLR3−/− 73.0 mmHg ± 6.8; p < 0.05, mean ± SEM, n = 6), increased muscularisation of small pulmonary arteries and reduced right ventricular cardiac output (WT 424.2 RVUmin-1 ± 84.2 vs. TLR3−/− 283.3 RVUmin-1 ± 18.4, mean ± SEM, min n = 6) after 3 weeks. Poly(I:C) suppressed PDGF-induced PASMC proliferation in a dose-dependent manner. Conclusions: We have shown that mice deficient in TLR3 develop a markedly exaggerated haemodynamic pulmonary hypertension phenotype and human PASMC proliferation is suppressed by the TLR3 ligand, poly(I:C). Together these data imply that TLR3 signalling in disease mediates a protective phenotype in keeping with that observed in systemic vascular remodelling, and identify a protective pathway potentially amenable to therapeutic targeting.