Small Group of Genes in Lung Fibroblasts May Help Promote IPF, Study Suggests

Researchers identified a small group of genes that may promote idiopathic pulmonary fibrosis (IPF) after analyzing gene expression profiles in fibroblasts isolated from the lungs of patients with the disease.

The study, “Global Gene Expression Analysis in an in vitro Fibroblast Model of Idiopathic Pulmonary Fibrosis Reveals Potential Role for CXCL14/CXCR4,” was published in the journal Scientific Reports.

“Our findings, present a possible therapeutic target for IPF and a model for the study and discovery of novel protein and processes in this terrible disease,” the research team said.

According to the researchers, fibroblasts are “the central effector cell of progressive fibrosis.” To gain a better understanding of these cells, they analyzed gene expression of pulmonary fibroblasts directly after isolating them from IPF patients and again after three weeks of culturing the cells in a lab, or in vitro culture. The team also analyzed gene activity in fibroblasts from nondisease donors.

Researchers found that although IPF fibroblasts have significantly different gene expression patterns than normal fibroblasts when first isolated, this difference decreases once the fibroblasts transition to an in vitro state, suggesting that the genes are altered by removing the fibroblasts from an IPF environment.

They then compared this subset of genes to four previously published gene expression analyses that used whole lungs. This allowed the team to identify a small cluster of genes that seem to be significantly altered only in fibroblasts from IPF samples.

“We identified a narrow subset of 59 IPF specific genes that we believe are indicative of the environmental impact on the fibroblast phenotype in disease,” they wrote.

Several of these genes indicate a dynamic crosstalk between the lung environment in IPF patients and its fibroblasts, which include significant enrichment for pathways that control cell migration and developmental processes.

Researchers identified an axis of three genes, CXCR4, CXCL12, and CXCL14, as potential players in the progression and/or activation of fibroblasts in the IPF lung.

“Of particular note is the observation that these three genes are all downregulated through the in-vivo to in-vitro transition of the IPF fibroblast,” the researchers wrote. They hypothesized that this reduction in gene expression was linked to the in vitro transition.

As hypothesized, when they incubated the IPF fibroblasts in an environment similar to that of IPF lungs (with high levels of oxidative stress), they were able to increase gene expression of the entire CXCR4/CXCL12/CXCL14 axis.

This response was only seen in IPF fibroblasts and not in normal fibroblasts, suggesting an increased sensitivity of the IPF fibroblast to oxidative stress.

Further analysis and experiments in IPF lungs suggested that the CXCL14/CXCR4 axis has a potential role in promoting the activation of fibroblasts. As a result, “we speculate that it may be possible to slow or inhibit fibroblast migration and activation by pharmacological intervention directed at the CXCR4/CXCL14 complex,” the researchers wrote.