AbstractIntroduction and Objectives
Pulmonary Arterial Hypertension (PAH) is a life threatening disease characterised by the progressive narrowing and occlusion of small pulmonary arteries, driven by the dysregulated growth of vascular cells. Current therapies are unable to reverse PAH and so identifying key pathways in disease pathogenesis should permit the development of more targeted therapeutics. The cytokine, Tumour Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand (TRAIL) induces EC apoptosis and SMC proliferation in the systemic circulation, but hitherto has not been studied in PAH. We recently determined that TRAIL is a mitogen for human PA-SMCs in-vitro and was associated with pulmonary vascular lesions in humans and rodent models. We thus hypothesised that TRAIL is an important mediator in the pathogenesis of PAH and now describe the potential therapeutic benefits of targeting TRAIL in-vivo using two animal models.Methods
To test whether blocking TRAIL could prevent the development of PAH, an anti-TRAIL antibody was delivered via osmotic mini-pump coincident with the induction of PAH in the MCT rat model. We also tested whether genetic deletion of TRAIL (ApoE−/−/TRAIL−/− mice) would confer protection to diet-induced PAH. To test whether inhibiting TRAIL could reverse established disease we again treated both models with an anti-TRAIL antibody starting from day 21 in the rat and 8 weeks in the ApoE−/− mouse. Phenotyping included echocardiography, closed chest cardiac catheterisation followed by immuno-histological and biochemical analyses of the lung.Results
Antibody blockade (MCT) and genetic deletion (ApoE−/−) of TRAIL prevented the development of PAH in both models. Interestingly a PAH disease phenotype was restored in ApoE−/−/TRAIL−/− mice by the administration of recombinant TRAIL. In rodents with established PAH, an anti-TRAIL antibody, significantly increased survival and reduced pulmonary vascular remodelling in the fatal rat MCT model (p<0.05 cf control). In the murine model, an anti-TRAIL antibody treatment reversed both haemodynamics (RVSP 27 mm Hg vs 88 mm Hg, p<0.001) and pulmonary vascular remodelling.Conclusions
Our preclinical investigations are the first to determine the importance of TRAIL to disease pathogenesis and highlight its potential as a novel and rational target to direct future translational therapies for PAH.