Limited systemic sclerosis patients with pulmonary arterial hypertension show biomarkers of inflammation and vascular injury

Abstract

Background: Pulmonary arterial hypertension (PAH) is a common complication for individuals with limited systemic sclerosis (ISSc). The identification and characterization of biomarkers for ISSc-PAH should lead to less invasive screening, a better understanding of pathogenesis, and improved treatment. Methods and Findings: Forty-nine PBMC samples were obtained from 21 ISSc subjects without PAH (ISSc-noPAH), 15 ISSc subjects with PAH (ISSc-PAH), and 10 healthy controls; three subjects provided PBMCs one year later. Genome-wide gene expression was measured for each sample. The levels of 89 cytokines were measured in serum from a subset of subjects by Multi-Analyte Profiling (MAP) immunoassays. Gene expression clearly distinguished ISSc samples from healthy controls, and separated ISSc-PAH from ISSc-NoPAH patients. Real-time quantitative PCR confirmed increased expression of 9 genes (ICAM1, IFNGR1, IL1B, IL13Ra1, JAK2, AIF1, CCR1, ALAS2, TIMP2) in ISSc-PAH patients. Increased circulating cytokine levels of inflammatory mediators such as TNF-alpha, IL1-beta, ICAM-1, and IL-6, and markers of vascular injury such as VCAM-1, VEGF, and von Willebrand Factor were found in ISSc-PAH subjects. Conclusions and Significance: The gene expression and cytokine profiles of ISSc-PAH patients suggest the presence of activated monocytes, and show markers of vascular injury and inflammation. These genes and factors could serve as biomarkers of PAH involvement in ISSc. © 2010 Pendergrass et al.