Simultaneous Inhibition of TGF-beta1, Periostin Signals Can Halt PF Progression in Mice, Study Shows 

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by Steve Bryson, PhD |

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Simultaneous inhibition of two signaling pathways mediated by TGF-beta1 and periostin can halt progression of idiopathic pulmonary fibrosis in mice, a new study reveals. 

The study, “The Cross-Talk Between TGF-β and Periostin Can Be Targeted for Pulmonary Fibrosis,” was published in the American Journal of Respiratory and Critical Care Medicine.

Idiopathic pulmonary fibrosis (IPF) is thought to be caused by an abnormal wound-healing process, initially triggered by a response to injury, that leads to tissue scarring (fibrosis). Many pro-inflammatory and pro-fibrotic signaling proteins are activated during this process, of which transforming growth factor-beta1 (TGF-beta1) is the most well-known.

TGF-beta1’s role is to stimulate fibroblasts — the most common cells of connective tissue — to transform into a type of cell that mediates the wound healing process, called a myofibroblast. This cellular transformation is also associated with an increase of the levels of pro-fibrotic factors that are found in the lungs of people with IPF. 

Another protein, called periostin, has also been associated with IPF. This protein is highly present in the lungs of IPF patients, and high blood levels of periostin have been found to be correlated with decline in lung function.

Japanese and U.S. researchers conducted an early experimental study to better understand how TGF-beta1 and periostin could contribute to pulmonary fibrosis. 

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The team started by analyzing the protein content profile of cells in normal human lung fibroblasts (NHLFs) with or without TGF-beta1 stimulation, which had been modified to not have the periostin protein.

They could identify 258 proteins whose levels were significantly changed upon TGF-beta1 stimulation, as well as by the presence or absence of periostin. This particular protein profile confirmed that TGF-beta1 and periostin signals can cross-talk for a common outcome.

A closer look at the list of proteins identified revealed that it comprised many proteins found to be increased in lung tissue from people with IPF.

Further experiments allowed the team to identify which specific receptors were mediating periostin signals that lead to IPF protein signature. Reducing the levels of these receptors, called integrins alphaV/beta3 and alphaV/beta5, also showed to prevent the IPF protein profile. 

These results prompted researchers to determine whether inhibiting the binding of periostin to its integrin receptors could prevent TGF-beta1-periostin cross-talk. They screened 10 compounds that had been shown to have inhibitory activities against integrins and found one, CP4715, that successfully blocked TGF-β1-periostin, signaling via alphaV/beta3 integrin inhibition.

They then tested the effectiveness of CP4715 by treating mice with chemically induced IPF. After three weeks, the survival rate of untreated mice was 50%, whereas 80% of the CP4715-treated mice survived. An examination of the lung tissue revealed that CP4715 attenuated IPF development. 

The experimental inhibitor CP4715 also showed to effectively reduce TGF-β1-periostin cross-talk and modulate IPF-related proteins in lung fibroblasts isolated from IPF patients.

“These results suggest that the cross-talk between TGF-β and periostin can be targeted for pulmonary fibrosis and that CP4715 can be a potential therapeutic agent to block this crosstalk,” the researchers concluded.