Antifibrotic mechanism of avitinib in bleomycin-induced pulmonary fibrosis in mice

by Selleckchem | Dec 01 2023

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by alveolar epithelial cell injury and lung fibroblast overactivation. At present, only two drugs are approved by the FDA for the treatment of IPF, including the synthetic pyridinone drug, pirfenidone, and the tyrosine kinase inhibitor, nintedanib. Avitinib (AVB) is a novel oral and potent third-generation tyrosine kinase inhibitor for treating non-small cell lung cancer (NSCLC). However, the role of avitinib in pulmonary fibrosis has not yet been established. In the present study, we used in vivo and in vitro models to evaluate the role of avitinib in pulmonary fibrosis. In vivo experiments first verified that avitinib significantly alleviated bleomycin-induced pulmonary fibrosis in mice. Further in vitro molecular studies indicated that avitinib inhibited myofibroblast activation, migration and extracellular matrix (ECM) production in NIH-3T3 cells, mainly by inhibiting the TGF-β1/Smad3 signalling pathways. The cellular experiments also indicated that avitinib improved alveolar epithelial cell injury in A549 cells. In conclusion, the present findings demonstrated that avitinib attenuates bleomycin-induced pulmonary fibrosis in mice by inhibiting alveolar epithelial cell injury and myofibroblast activation.

Comments:

The study you described suggests that avitinib, a third-generation tyrosine kinase inhibitor, has potential therapeutic effects in pulmonary fibrosis. Pulmonary fibrosis is a condition characterized by the scarring of lung tissue, and it can be caused by various factors, including exposure to toxins or certain medications. Idiopathic Pulmonary Fibrosis (IPF) refers to cases where the cause of the condition is unknown.

In this specific study:

1. **In Vivo Experiments:** The researchers used mouse models induced with pulmonary fibrosis (using bleomycin) to test avitinib's effects. They found that avitinib significantly reduced pulmonary fibrosis in these mice. This suggests that avitinib has a protective effect on lung tissue in the presence of fibrosis-inducing factors.

2. **In Vitro Experiments:** The study also involved laboratory experiments using cell cultures. In NIH-3T3 cells (a type of fibroblast), avitinib inhibited myofibroblast activation, migration, and the production of extracellular matrix (ECM). Myofibroblasts are cells that play a key role in the development of fibrosis. In A549 cells (a type of alveolar epithelial cell), avitinib improved cell injury. Alveolar epithelial cells are crucial for maintaining the lung's function, and their injury is a common feature in pulmonary fibrosis.

3. **Mechanism of Action:** The study proposed that avitinib's effects were mediated through inhibiting the TGF-β1/Smad3 signaling pathways. TGF-β1 (Transforming Growth Factor Beta 1) is a molecule that plays a central role in the fibrotic process. By inhibiting this pathway, avitinib appears to prevent or reduce the development of pulmonary fibrosis.

In summary, this research suggests that avitinib has the potential to be a therapeutic option for pulmonary fibrosis. By inhibiting myofibroblast activation, migration, ECM production, and improving alveolar epithelial cell injury, avitinib seems to mitigate the progression of fibrosis. However, it's important to note that while these findings are promising, further research, including clinical trials, would be necessary to determine its safety and efficacy in humans.