Halting Slug Protein May Lessen Risk of PH in Fibrotic Lungs, Study Suggests

Halting a protein called Slug may help reduce the severity of increased blood pressure related to lung scarring — a condition called pulmonary hypertension (PH) secondary to pulmonary fibrosis, or PF-PH, a new animal study shows.

The study, “Histological hallmarks and role of Slug/PIP axis in pulmonary hypertension secondary to pulmonary fibrosis,” was published in the journal EMBO Molecular Medicine.

PH can be a major complication of pulmonary fibrosis (PF), a disease marked by scarring — called fibrosis — of the lung tissues, which makes breathing difficult. However, the molecular mechanisms that lead to the development of PH secondary to pulmonary fibrosis remain poorly understood.

To learn more, researchers examined scarred and non-scarred areas within lung tissue of PF and PF‐PH patients. They saw an increased thickness in blood vessel walls in both fibrotic and non‐fibrotic areas of PF‐PH patient lungs. However, in people with PF, wall thickening was mainly seen in fibrotic areas.

“We report a distinct pulmonary vascular remodeling pattern that differentiates PF‐PH and PF patients,” the researchers said. “In PF‐PH patients, we observed increased vascular wall thickening in both non‐fibrotic and fibrotic areas, whereas PF patients mainly exhibit vascular wall thickening in fibrotic areas.”

The increased thickening in blood vessel walls was found to be linked with higher levels — 2.5-fold — of a protein called Slug within the macrophages, or cells of the immune system, in the lungs of PF‐PH patients, compared with those of people with PF.

The team therefore hypothesized that increased levels of the Slug protein might promote deposits of extracellular matrix proteins — which come from the mesh-like scaffold surrounding cells —  that are involved in tissue scarring.

To test this hypothesis, the researchers developed a new rat model that developed PH after induction of PF. Most importantly, this new animal model recapitulated the features of human PF‐PH, namely lung scarring and pulmonary vascular remodeling. Moreover, the animal also showed increased levels of Slug protein.

Results showed that while inhibition of the Slug protein using a molecular approach had no effects on lung scarring, the thickness of blood vessels in the lungs was significantly lower in both fibrotic and non-fibrotic areas compared with control rats.

“Slug inhibition in the presence of a PH stimulus decreases PH severity in rats with pre‐existing PF by decreasing vascular remodeling and … vascular wall cell proliferation,” the researchers said.

The study “highlights histological and molecular differences” between PH and PF-PH, the team said.

“We demonstrate that Slug inhibition reduces PH severity in a pre‐clinical model of PF‐PH, which may pave the way toward a better understanding of this debilitating disease,” they concluded.