Mechanism Responsible for Development of Idiopathic Pulmonary Fibrosis Identified

A group of scientists from Helmholtz Zentrum München, in collaboration with colleagues from the University of Denver, have uncovered a contributing mechanism responsible for the development of idiopathic pulmonary fibrosis (IPF).

In the study published in the American Journal of Respiratory and Critical Care Medicine, the teams found that increased extracellular vesicles (EVs) function as carriers for signaling mediators, such as WNT-5A, in IPF and contribute to disease pathogenesis as a result. The team also concluded that novel approaches to diagnose and develop treatments for IPF may be possible with this characterization of EV secretion and composition.

"Simply put, extracellular vesicles are tiny pouches released by cells that can contain a large number of messenger substances, such as proteins and nucleic acids," explained Dr. Mareike Lehmann, one of the authors of the study, in a recent statement. "They are an important means of communication between cells and organs and help to ensure that the substances reach completely new sites."

In order to characterize EVs and evaluate the function of EV-bound WNT signaling in IPF, the teams “isolated EVs from bronchoalveolar lavage fluid (BALF) from experimental lung fibrosis as well as samples from IPF, non IPF-ILD, non-ILD and healthy volunteers from 2 independent cohorts,” authors of the study write. Through the use of transmission electron microscopy, nanoparticle tracking analysis, and Western Blotting (WB) investigators were able to characterize the EVs. Metabolic activity assays, cell counting, quantitative PCR, and WB upon WNT gain- and loss-of-function studies were used to analyze primary human lung fibroblasts (phLFs), which were used for EV isolation, the authors write.

Upon analysis, increased EVs, particularly exosomes, in BALF were found from experimental lung fibrosis and IPF patients. More specifically, TGF-β in primary human lung fibroblasts induced WNT-5A, which was secreted on EVs in lung fibrosis, according to the authors. In addition, phLF proliferation was found to be induced by the phLF-derived EVs. PhLF proliferation required an intact EV structure and was attenuated by WNT-5A silencing and antibody-mediated inhibition. Furthermore, phLF proliferation was found to be induced by EVs from IPF-BALF and mediated by WNT-5A.

“We were able to show in the study that increased levels of extracellular vesicles occur in IPF patients, which then act as carriers of WNT5A," concluded lead author, Aina Martin-Medina. "We were also able to confirm these results in our experimental model." Additionally, the teams also showed that reducing the number of vesicles decreated tissue scarring in Petri dish experiments.

For future preclinical studies, the teams hope to assess the suitability of extracellular vesicles as a pharmacological biomarker and possible therapeutic target.

IPF is a rare and incurable lung disease with limited treatment options and an unknown origin; it’s specific cause remains unidentified. The disease is characterized by an increased formation of connective tissue in the lungs that result in scarring, or fibrosis, of functional lung tissue. Drugs that can slow disease progression are available; however, to date, there are no therapies available that can permanently halt disease progression.