John Wharton

Biography

Pulmonary hypertension is a relatively frequent occurrence as it is associated with common diseases such as chronic obstructive pulmonary disease, sickle cell disease, schistomiasis, sleep-disordered breathing, neonatal lung disease, chronic thromboembolic disease, heart disease and chronic exposure to high altitude. Pulmonary arterial hypertension (PAH) is one category of pulmonary hypertension that may occur as an isolated disease, known as idiopathic PAH (IPAH), or where there is evidence of inheritance, familial PAH or in association with conditions such as connective tissue disease, congenital heart disease, viral infection and exposure to drugs or toxins. The main research interest of the Group is in understanding the pathogenesis of PAH and developing new therapeutic strategies to treat this progressive disease. The increase in pulmonary artery pressure puts an excess load on the relatively thin-walled right ventricle, leading to right ventricular hypertrophy and right heart failure. The disease is generally characterized by increased pulmonary vascular resistance due to vasoconstriction and obliterative remodelling of the pulmonary circulation, involving occlusion of the lumen due to cellular proliferation in the wall of distal arteries and in situ thrombosis, as well as the loss of microvessels. Current therapies were developed on the basis of an imbalance in vasoactive factors, targeting down regulation of prostacyclin and nitric oxide (NO)-cGMP signalling and upregulation of endothelin production. Within the Cardiovascular Group, we have adopted an integrated approach to study the mechanisms of pulmonary vascular disease and identify therapeutic targets, taking studies with human vascular cell cultures through to whole animal models and proof-of-concept studies in patients. For example, recent studies have demonstrated a beneficial role for phosphodiesterase type 5 inhibition by sildenafil in pulmonary hypertension and thereby contributed to the development of a much-needed orally-active treatment for this condition. Novel therapies are being sought that target other aspects of the pathophysiology of PAH, such as the proliferative, anti-apoptotic, oxidative and inflammatory environment in the pulmonary artery wall. We have found that agents such as simvastatin and tetrahydrobiopterin have therapeutic potential in cultured cells and experiment models and these are now at the clinical stage of investigation. In addition to pharmacological agents, we are investigating the role of circulating bone marrow-derived progenitor and mononuclear cells in pulmonary vascular disease and their potential as a cell-based therapy for the treatment of IPAH. Indeed, we were the first to show that the treatment of IPAH patients with sildenafil increases the number of circulating progenitor cells and thereby may influence the course of the disease.

Research Interest

Pulmonary hypertension