A new model, produced by analyzing 10 different systemic sclerosis (SSc) gene expression data sets, showed that pulmonary fibrosis (PF) in SSc is likely the result of an initial insult activating the interferon signaling pathway. Researchers believe that the uncovered processes might reflect fibrotic processes in all SSc-affected tissues.
The research team, led by J. Taroni from the Geisel School of Medicine, along with collaborators both within the U.S. and from Brazil, presented their data at the 4th Systemic Sclerosis World Congress held in Lisbon, Portugal, on Feb. 18–20, 2016. The presentation was titled “Multi-organ systems biology analysis of systemic sclerosis reveals a macrophage signature associated with disease severity in multiple end-target tissues.”
Using a “big data” approach, the team performed an integrative meta-analysis of datasets identifying common disease drivers. The method could also predict a sequence of pathological events since data from both early and late-stage disease was used.
The new data mining procedure identified co-expression patterns shared across 10 datasets from four different tissues – skin, lung, esophagus, and blood. The patients from which the tissues were derived suffered a multitude of clinical SSc manifestations, such as pulmonary arterial hypertension (PAH) and PF, and had both localized and diffuse SSc subtypes.
The team first identified genes that were altered in the same way across all solid tissues and were highly expressed in manifestations of SSc involving the lungs. Then, they used the data to analyze tissue-specific gene interaction networks, and compared the skin and lung networks to find both common and tissue-specific fibrotic pathways.
Evidence showed that macrophages (a type of white blood cell) contribute to the process of extracellular matrix (ECM) re-organization that precedes fibrosis. The gene signature was found in both PAH and PF lung tissue, as well as in subsets of inflammatory molecules from the esophagus and skin. The team could observe indications of coupling between ECM and inflammatory processes in the solid tissues, but not in blood cells.
Researchers also noted a gene expression signature in early stage disease, showing increased movement of lung macrophage lipids, that was not present in later disease stages. In late-stage disease, an altered expression of genes involved in programmed cell death was observed.
The team believes that the changes leading to PF start with an insult activating inflammatory interferon signaling. This leads to a subsequent increase in lipid uptake by lung macrophages, which begin secreting the pro-fibrotic molecule TGF-β.
The results confirmed that fibrotic processes share features between the lungs and the skin, but that each tissue also has specific pathological characteristics. Moreover, the genes that were found to bridge pathological processes, such as ECM remodeling and programmed cell death, have been verified in experimental animal models of PF, and may be explored as targets for the development of new treatments.