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

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.

• Authors: Gregoire Ruffenach, Soban Umar, Mylene Vaillancourt, Jason Hong, Nancy Cao, Shervin Sarji, Shayan Moazeni, Christine M Cunningham, Abbas Ardehali, Srinivasa T Reddy, Rajan Saggar, Gregory Fishbein, Mansoureh Eghbali
• Journal: EMBO molecular medicine (EMBO Mol Med) Vol. 11 Issue 9 Pg. e10061 (09 2019) ISSN: 1757-4684 [Electronic] England
• PMID: 31468711 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 The Authors. Published under the terms of the CC BY 4.0 license.

Chemical References

• Membrane Transport Proteins
• PIP protein, human
• SNAI1 protein, human
• Snail Family Transcription Factors

Topics

• Adult
• Aged
• Animals
• Female
• Humans
• Hypertension, Pulmonary (genetics, metabolism, pathology)
• Lung (metabolism, pathology)
• Macrophages (metabolism)
• Male
• Membrane Transport Proteins (genetics, metabolism)
• Middle Aged
• Myocytes, Smooth Muscle (metabolism)
• Pulmonary Artery (metabolism, pathology)
• Pulmonary Fibrosis (genetics, metabolism, pathology)
• Rats, Wistar
• Snail Family Transcription Factors (genetics, metabolism)
• Young Adult