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

  • Author(s): Ruffenach, Gregoire;
  • Umar, Soban;
  • Vaillancourt, Mylene;
  • Hong, Jason;
  • Cao, Nancy;
  • Sarji, Shervin;
  • Moazeni, Shayan;
  • Cunningham, Christine M;
  • Ardehali, Abbas;
  • Reddy, Srinivasa T;
  • Saggar, Rajan;
  • Fishbein, Gregory;
  • Eghbali, Mansoureh
  • et al.
Abstract

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.

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