Systemic Sclerosis Associated Pulmonary Arterial Hypertension: Exploration in Transgenic Mice

Christopher P. Denton, MD, PhD, FRCP
Royal Free Hospital London and University College

Project Summary:

Pulmonary arterial hypertension (PAH) is an important complication of scleroderma (SSc) and has a very high mortality. Overall PAH is the single biggest cause of SSc-related death. Its occurrence in only a subset of SSc cases suggests that multiple factors are likely to be involved. Dr. Denton and his colleagues believe that SSc may involve a generalized defect in Transforming Growth Factor-beta (TGF-beta) bioactivity in fibroblastic cells and that, in certain background situations, PAH is more severe and may be more easily triggered. In order to explore this hypothesis, they will start with their novel mouse model of SSc in which the activity of TGF-beta is disrupted in fibroblasts. Approximately 25% of these mice develop symptoms of SSc, such as skin thickening and lung fibrosis. Deliberate injury to lung epithelium induces fibrosis in 100% of this mouse strain. These mice also develop structural changes in the pulmonary blood vessels, which leads Dr. Denton to believe they may have an associated susceptibility to pulmonary hypertension. Dr. Denton’s laboratory will investigate the development of pulmonary hypertension in this novel mouse model by asking whether stimuli such as hypoxia cause a more severe defect in this mouse strain than in controls. If this is the case, these mice may serve as a useful new model for SSc-associated pulmonary hypertension. Such novel models for SSc-PAH are likely to provide a valuable platform for investigating therapeutic effects and exploring the potential synergy between different PAH therapies in vivo.

Research Update:

Dr. Denton’s lab has established that within transgenic lungs there are thicker arteries; a likely precursor to disease. However, these animals do not show other features of PAH. So, as a stimulus, these animals will be subjected to increased hypoxia to assess the ability to remodel and to develop more canonical PAH features. An important next step will be to assess the impact of drug therapy (e.g., bosentan and other endothelial receptor antagonists) on the transgenic mice.

What this project means for people with scleroderma:

As lung disease is the number one killer in SSc, dissecting how the disease progresses, what cell types are involved and where they come from is a critical goal. There are unique features of pulmonary hypertension in scleroderma. This project will lead to better recognition of the key abnormalities that determine the development of PAH in scleroderma and help improve the use of new therapies as they become available.

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