New Blocker of TGF-β1 Shows Promise as Potential Therapy for IPF Patients

New Blocker of TGF-β1 Shows Promise as Potential Therapy for IPF Patients

Blocking TGF-β1 — a known signaling pathway involved in tissue fibrosis — by compounds called trihydrophenolics halted fibrosis development and tissue stiffness in animal models of pulmonary fibrosis, new research shows.

The study, “Fibroblast-specific inhibition of TGF-β1 signaling attenuates lung and tumor fibrosis,” was published in the Journal of Clinical Investigation.

TGF-β1 signaling works through two cell-surface receptors called TβRI and TβRII. It results in the activity of genes that are involved in collagen production and leads to tissue accumulation during wound repair.

Scientists estimate that 80 percent of highly expressed genes in the lungs of patients with idiopathic pulmonary fibrosis (IPF) are TGF-β1 target genes, so there has been significant interest in targeting TGF-β1 signaling to treat IPF.

The main issue with targeting TGF-β1, however, is that it shuts down pathways that are critical to the functioning of normal cells. In fact, blocking TGF-β1 was found to cause skin tumors and autoimmune reactions.

To reduce the adverse events associated with targeting TGF-β1, researchers have been investigating molecules that only block TGF-β1 activation in specific cell types.

Researchers at the University of California, San Francisco also set out to develop a more restricted inhibitor of TGF-β1 signaling targeting collagen accumulation. They conducted image-based screens of small molecule inhibitors that would block a process called epithelial-mesenchymal transition (EMT). EMT refers to epithelial cells that begin to migrate and invade tissues; this process plays a role in the development of IPF. Therefore, a small molecule inhibitor that blocks EMT should benefit the treatment of IPF patients.

The UCSF researchers were able to discover that members of the ellagitannin and catechin families, which are trihydroxyphenolic compounds, were potent inhibitors of TGF-β1 signaling as well as collagen deposits in mouse models of IPF.

Interestingly, the pathway through which trihydroxyphenolics compounds work is also by blocking TGF-β1 signaling. The mechanism requires the presence of a protein called LOXL2 (lysyl oxidase-like 2) that is found mostly in fibroblasts, the most common cells of connective tissue that synthesize collagen and the extracellular matrix — the structural framework of tissues in animals. It also plays a critical role in the healing of wounds.

Trihydroxyphenolics react with LOXL2, causing the blockade of LOXL2. At the same time, through this reaction, trihydroxyphenolics are converted to a previously unknown molecule that directly inhibits TβRI, the receptor through which TGF-β1 signaling takes place.

Results using trihydroxyphenolics showed that blocking both LOXL2 and TGF-β1 signaling halted the accumulation of collagen without the adverse effects seen in other inhibitors of TGF-β1 signaling.

Overall, this study demonstrates a potential new approach to reduce fibrosis in IPF patients through the targeted blocking of TGF-β1.

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