Systemic Sclerosis-Associated Pulmonary Arterial Hypertension: From Bedside to Bench and Back Again

Abstract

Systemic sclerosis (SSc) is a heterogeneous disease characterized by autoimmunity, vasculopathy, and fibrosis which affects the skin and internal organs. One key aspect of SSc vasculopathy is pulmonary arterial hypertension (SSc-PAH) which represents a leading cause of morbidity and mortality in patients with SSc. The pathogenesis of pulmonary hypertension is complex, with multiple vascular cell types, inflammation, and intracellular signaling pathways contributing to vascular pathology and remodeling. In this review, we focus on shared molecular features of pulmonary hypertension and those which make SSc-PAH a unique entity. We highlight advances in the understanding of the clinical and translational science pertinent to this disease. We first review clinical presentations and phenotypes, pathology, and novel biomarkers, and then highlight relevant animal models, key cellular and molecular pathways in pathogenesis, and explore emerging treatment strategies in SSc-PAH.

Keywords: biomarkers; molecular pathogenesis; pulmonary arterial hypertension; pulmonary hypertension; scleroderma; systemic sclerosis; therapeutics.

Figure 1

Cellular mechanisms and histology of SSc-PAH. (A) Schematic representing a cross-section of pulmonary artery from a control. Created with BioRender.com. (B,C) Representative images of pulmonary artery histology (H&E staining, 20×) from two control individuals with no signs of PAH. Note the open lumen, thin media, and adventitia without perivascular inflammation. (D) Diagram of early SSc-PAH. Note the increased medial hypertrophy, luminal narrowing, endothelial apoptosis presence of vascular adhesion molecules, and adventitial inflammatory infiltrates including macrophages and lymphocytes. (E,F) Partially occluded pulmonary arterial vessels from patients with SSc-PAH. Note increased thickness of the media causing luminal narrowing and adventitial proliferation. (G) Schematic of advanced SSc-PAH. Note luminal occlusion due to adventitial thickening, medial hypertrophy, and the presence of in situ thrombosis, as well as the presence of macrophages, lymphocytes, and myofibroblasts now infiltrating into the adventitial and medial layers. (H,I) Histology demonstrating complete luminal occlusion in severe SSc-PAH. Note extensive thickening of the adventitial and medial layers causing luminal obliteration as well as significant adventitial inflammatory infiltrate.

Figure 2

Characterization of the TNF-Tg model of PH. (A) Pulmonary vessels (20×, H&E) in TNF-Tg mice demonstrate inflammation at around 3 months, with severe occlusion by 5.5 months. (B) μCT demonstrating significant pruning of the distal vasculature in TNF-Tg lungs. (C) Heart histology (5X, H&E) reveals significant right ventricular (RV) hypertrophy in TNF-Tg mice at 5.5 months of age. (D) Right heart catheterization demonstrates significantly elevated right ventricular pressures (RVSP) in TNF-Tg mice. *** p < 0.001, **** p < 0.0001.