Histological hallmarks and role of Slug/ PIP axis in pulmonary hypertension secondary to pulmonary fibrosis

Pulmonary hypertension secondary to pulmonary fibrosis ( PF ‐ PH ) is one of the most common causes of PH , and there is no approved therapy. The molecular signature of PF ‐ PH and underlying mechanism of why pulmonary hypertension ( PH ) develops in PF patients remains understudied and poorly understood. We observed significantly increased vascular wall thickness in both fibrotic and non‐fibrotic areas of PF ‐ PH patient lungs compared to PF patients. The increased vascular wall thickness in PF ‐ PH patients is concomitant with a significantly increased expression of the transcription factor Slug within the macrophages and its target prolactin‐induced protein ( PIP ), an extracellular matrix protein that induces pulmonary arterial smooth muscle cell proliferation. We developed a novel translational rat model of combined PF ‐ PH that is reproducible and shares similar histological features (fibrosis, pulmonary vascular remodeling) and molecular features (Slug and PIP upregulation) with human PF ‐ PH . We found Slug inhibition decreases PH severity in our animal model of PF ‐ PH . Our study highlights the role of Slug/ PIP axis in PF ‐ PH .