Common pathway signature in lung and liver fibrosis

Abstract

Fibrosis, a progressive accumulation of extracellular matrix components, encompasses a wide spectrum of distinct organs, and accounts for an increasing burden of morbidity and mortality worldwide. Despite the tremendous clinical impact, the mechanisms governing the fibrotic process are not yet understood, and to date, no clinically reliable therapies for fibrosis have been discovered. Here we applied Regeneration Intelligence, a new bioinformatics software suite for qualitative analysis of intracellular signaling pathway activation using transcriptomic data, to assess a network of molecular signaling in lung and liver fibrosis. In both tissues, our analysis detected major conserved signaling pathways strongly associated with fibrosis, suggesting that some of the pathways identified by our algorithm but not yet wet-lab validated as fibrogenesis related, may be attractive targets for future research. While the majority of significantly disrupted pathways were specific to histologically distinct organs, several pathways have been concurrently activated or downregulated among the hepatic and pulmonary fibrosis samples, providing new evidence of evolutionary conserved pathways that may be relevant as possible therapeutic targets. While future confirmatory studies are warranted to validate these observations, our platform proposes a promising new approach for detecting fibrosis-promoting pathways and tailoring the right therapy to prevent fibrogenesis.

The extracellular matrix as a key regulator of intracellular signalling networks

“…These HSC‐derived myofibroblasts are responsible for the increased secretion and deposition of matrix components such as collagen and basement membrane proteins (Friedman et al, ), which then act to modulate signalling networks in all of the other cell types resident within the fibrosing liver. Similarly, idiopathic pulmonary fibrosis is characterized by dysregulation of, among others, the TGF‐β, MAPK and PI3K/Akt signalling pathways (Makarev et al, ), leading to aberrant tissue repair and extensive ECM remodelling which leads to the clinical loss of lung function. The activation of these pathways, which occurs in both forms of fibrosis, will enhance cell survival and proliferation (Wells, ) and acts to hyper‐activate a pro‐fibrotic cellular phenotype thus perpetuating further ECM remodelling and changes in signalling networks.…”

FibroAtlas: A Database for the Exploration of Fibrotic Diseases and Their Genes

“…Platelet factor 4 (PF4) is identified as a marker for fibrosis, levels of which are elevated in patients with systemic sclerosis and correlated with the presence and progression of pulmonary arterial hypertension [7]. Studies have suggested that multiple fibrotic diseases are usually triggered by the same irritation and share a number of common pathways, such as transforming growth factor beta (TGF-β), interleukin-6 (IL-6), and integrin-linked kinase signaling [8,9].…”

A noble TGF beta biogenesis inhibitor exhibits both potent anti-fibrotic and anti-inflammatory capabilities

“…Many of those genes were previously found to be fibrogenic, including those encoding NOX4, CTGF, PERIOSTIN, LOX, and CDH2. [15][16][17] Induction of NOX4, which encodes NADPH oxidase 4, is associated with the production of reactive oxygen species (ROS) and with several important signaling events, including LPS signaling and inflammasome activation. 18 These findings suggested that NOX4 plays an important role in the pathogenesis of myofibroblasts.…”