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S87 Deficiency of toll-like receptor 3 (TLR3) exacerbates pulmonary hypertension in mice
  1. AAR Thompson1,
  2. ND Arnold1,
  3. AT Braithwaite1,
  4. HL Casbolt1,
  5. J Iremonger1,
  6. JA Pickworth1,
  7. C Monaco2,
  8. JE Cole2,
  9. I Sabroe1,
  10. A Lawrie1
  1. 1University of Sheffield, Sheffield, UK
  2. 2University of Oxford, Oxford, UK


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.

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