C26-24 Circulating Endothelial Transcriptional Signature Associates With Pulmonary Hypertension and Mortality in Interstitial Lung Disease

Introduction

Endothelial dysfunction and pulmonary vascular remodeling contribute to pulmonary hypertension in interstitial lung disease (ILD-PH). We therefore hypothesized that peripheral blood transcriptomics could identify circulating endothelial signatures associated with pulmonary hypertension (PH) and adverse outcomes.

Methods

Peripheral blood bulk RNA sequencing was performed in 1,433 participants from the Pulmonary Fibrosis Foundation Patient Registry. Differential expression, cell deconvolution, and co-expression network analyses were used to identify endothelial transcriptional programs linked to PH and outcomes. Findings were validated in external cohorts and an experimental rat ILD-PH model.

Results

Among 1,433 ILD subjects, 109 had PH at baseline. Circulating endothelial cell (EC) fraction was higher in ILD-PH and independently associated with mortality or lung transplantation after adjustment for GAP index and idiopathic pulmonary fibrosis (IPF) status, with validation in two external IPF cohorts. Co-expression network analysis identified an endothelial transcriptional program strongly associated with EC fraction, PH, and mortality. A composite score derived from this program was prognostic for mortality across cohorts. Network analysis prioritized NCF2, a regulator of NADPH oxidase-mediated oxidative stress, as a central hub gene. Higher NCF2 expression was associated with PH and worse survival and was upregulated in lung and right ventricular tissue in a rat ILD-PH model.

Conclusion

Peripheral blood transcriptomics identified a circulating endothelial signature that reflects pulmonary vascular disease and is independently associated with PH and mortality in ILD. This endothelial gene program, highlighted by NCF2, represents a candidate biomarker and potential therapeutic target in ILD-PH.

This abstract is funded by: K23HL181383