SRC and TKS5 mediated podosome formation in fibroblasts promotes extracellular matrix invasion and pulmonary fibrosis

Abstract

The activation and accumulation of lung fibroblasts resulting in aberrant deposition of extracellular matrix components, is a pathogenic hallmark of Idiopathic Pulmonary Fibrosis, a lethal and incurable disease. In this report, increased expression of TKS5, a scaffold protein essential for the formation of podosomes, was detected in the lung tissue of Idiopathic Pulmonary Fibrosis patients and bleomycin-treated mice. Τhe profibrotic milieu is found to induce TKS5 expression and the formation of prominent podosome rosettes in lung fibroblasts, that are retained ex vivo, culminating in increased extracellular matrix invasion. Tks5+/- mice are found resistant to bleomycin-induced pulmonary fibrosis, largely attributed to diminished podosome formation in fibroblasts and decreased extracellular matrix invasion. As computationally predicted, inhibition of src kinase is shown to potently attenuate podosome formation in lung fibroblasts and extracellular matrix invasion, and bleomycin-induced pulmonary fibrosis, suggesting pharmacological targeting of podosomes as a very promising therapeutic option in pulmonary fibrosis.

Fibroblast Activation Protein Alpha (FAPα) in Fibrosis: Beyond a Perspective Marker for Activated Stromal Cells?

“…Numerous studies confirm that the maintenance of the invasive fibroblast phenotype in fibrosis is strictly necessary for the development of fibrosis. Although the mechanisms by which invasive cells contribute to the development of fibrosis are not fully understood, in general, the inhibition of factors associated with the invasive phenotype of stromal cells leads to a decrease in the development of fibrosis [54,[108][109][110]. Possible mechanisms may include an increase in the ability of cells to migrate to the site of injury [111,112], the destruction of the basement membrane and damage to epithelial cells [113,114], as well as the creation of new fibrotic foci in uninjured tissue [52,115].…”

Microneedle delivery system with rapid dissolution and sustained release of bleomycin for the treatment of hemangiomas

“…Our team has reported the effectiveness of intralesional bleomycin injection in treating hemangiomas resistant to propranolol [ 17 ]. However, the repeated use of BLM is associated with potential dose-related complications, such as pneumonitis and pulmonary fibrosis, significantly limiting its practical application [ 18 , 19 ]. In contrast, topical dermal application of BLM is considered a more favorable option for treating superficial hemangiomas.…”