Pulmonary Vascular
The main focus of the research in our laboratory the study of the molecular mechanisms underlying that pathogenesis of pulmonary arterial hypertension (PAH).
More information about PAH can be found on the Pulmonary Hypertension Association UK website. A primary interest within our laboratory can broadly be divided into two groups:
- identifying molecules that can increase the proliferation and migration of pulmonary artery vascular smooth muscle cells (PA-SMC), and
- the role inflammation and inflammatory signalling in PAH pathogenesis.
(i) Novel modifiers of PA-SMC proliferation and migration.
Recent interest has centred on investigating the role of several members of the tumour necrosis factor (TNF) superfamily. We have evidence demonstrating that levels of osteoprotegerin (OPG, TNFRSF11B) and Tumour necrosis factor-Related Apoptosis Inducing Ligand (TRAIL, TNFSF10) are increased within lesions in patients with idiopathic PAH (see figure below), and that these molecules induce the proliferation and migration of PA-SMC. These observations have led to the following ongoing studies.
- Expression and function of osteoprotegerin in pulmonary artery smooth muscle cells in vitro.
- Investigation into the role of osteoprotegerin in pulmonary arterial hypertension.
- Investigation into the role of TRAIL in pulmonary arterial hypertension.
- Investigation into the influence of regulatory T cells, stress proteins, and their interactions in pulmonary hypertension.
Current Research Projects
1. Expression and function of osteoprotegerin in pulmonary artery smooth muscle cells in vitro. British Heart Foundation 2006-2009.
We have previously demonstrated that the secretion of OPG increased from PA-SMC by a number of key pathways associated with PAH, namely bone morphogenetic protein receptor 2 (BMPR2), serotonin and inflammatory cytokines (e.g. IL-1), and that recombinant OPG is a potent mitogen and migratory stimulus for PA-SMC (Lawrie et al Am J Path 2008 - hyperlink). Current work is examining the expression profile of OPG in PA-SMC and whether there are synergistic responses within these pathways.
2. Investigation into the role of osteoprotegerin in pulmonary arterial hypertension. Medical Research Council 2008-1013.
It remains unclear whether OPG is causal and/or a potential new biomarker in PAH. We are currently determining the temporal relationship between the pattern of OPG expression and onset/progression of PAH. We are also focused on identifying associated binding partners and signalling cascades involved in OPG-induced PA-SMC proliferation and migration. The aim of these studies is to identify molecules that can be treated to block this pathway, and potentially identify a new targets for therapy.
3. Investigation into the role of TRAIL in pulmonary arterial hypertension. British Heart Foundation 2008-2011.
Through our interest in OPG we have also become interested in two other molecules that can interact with OPG, TRAIL and RANKL. Early data shown above revealed that TRAIl expression is increased within the pulmonary arteries of patients with PAH. We are subsequently investigating the function of TRAIL in PA-SMC and PA-EC in vitro and its expression pattern during PAH pathogenesis. Through a collaboration with the NIHR Cardiovascular Biomedical Research Unit (CVBRU) we are also measuring the levels of OPG, TRAIL and RANKL in patients attending the supra-regional Pulmonary Hypertension Centre in Sheffield.
4. Investigation into the influence of regulatory T cells, stress proteins, and their interactions in pulmonary hypertension. NIHR CVBRU 2008-2012.
Collaboration with Professor A. G. Pockley
The interaction between circulating inflammatory and vascular cells is a key aspect of vascular injury, and is poorly understood in PAH. Similarly, inflammation has long been regarded as playing an important role in PAH pathogenesis but the exact mechanisms are unclear. Counter intuitively, the observations that PAH can be associated with HIV infection, in which CD4 lymphocytes are depleted, and that athymic rats which lack T lymphocytes can develop PAH suggest that T cells temper rather than promote the development and progression of PAH. A recent study on a small number of patients has shown that the ratio of CD4+/CD8+ T cells and levels of CD4+CD25int-hi regulatory T cells (Tregs) are elevated in a PAH. The role of Treg and other T cell subsets and their role in PAH pathogenesis is poorly understood.
Recent evidence suggests that stress proteins such as Hsp60 and Hsp70, which can be expressed on the surface of stressed endothelial cells and released by them, can activate Treg cells. These proteins may influence the pathogenesis of PAH by protecting the stressed endothelium by interacting with innate immune cells or by influencing the presence and/or functional capacity of endogenous Treg cells. This study is investigating the elationships between PAH, stress protein expression and release, and Treg cell presence and function in patients with PAH.
Additional Research Interests
Through the National Institute for Health Research Cardiovascular Biomedical Research Unit (CVBRU), which is actively establishing a large `biobank´ from both acute coronary syndrome (ACS) and pulmonary hypertension (PH) patients, we have a number of additional research interests. These include:
- Studying the role of innate immunity in PAH (collaboration with Prof Ian Sabroe).
- Studying the role of endothelial precursors in PAH pathogenesis (collaboration with Dr S. E. Francis).
Additional research themes include developing gene therapy/delivery techniques, particularly utilising ultrasound technology through a long-standing collaboration with Dr C. M. Newman.