Antifibrotic Effects of Focal Adhesion Kinase Inhibitor in Bleomycin-Induced Pulmonary Fibrosis in Mice

Abstract

Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase involved in various biological functions, including cell survival, proliferation, migration, and adhesion. FAK is an essential factor for transforming growth factor β to induce myofibroblast differentiation. In the present study, we investigated whether the targeted inhibition of FAK by using a specific inhibitor, TAE226, has the potential to regulate pulmonary fibrosis. TAE226 showed inhibitory activity of autophosphorylation of FAK at tyrosine 397 in lung fibroblasts. The addition of TAE226 inhibited the proliferation of lung fibroblasts in response to various growth factors, including platelet-derived growth factor and insulin-like growth factor I, in vitro. TAE226 strongly suppressed the production of type I collagen by lung fibroblasts. Furthermore, treatment of fibroblasts with TAE226 reduced the expression of α-smooth muscle actin induced by transforming growth factor β, indicating the inhibition of differentiation of fibroblasts to myofibroblasts. Administration of TAE226 ameliorated the pulmonary fibrosis induced by bleomycin in mice even when used late in the treatment. The number of proliferating mesenchymal cells was reduced in the lungs of TAE226-treated mice. These data suggest that FAK signal plays a significant role in the progression of pulmonary fibrosis and that it can become a promising target for therapeutic approaches to pulmonary fibrosis.

Dysregulated Collagen Homeostasis by Matrix Stiffening and TGF-β1 in Fibroblasts from Idiopathic Pulmonary Fibrosis Patients: Role of FAK/Akt

“…All these observations may have important translational consequences, for they support that targeting the FAK/Akt pathway may be a suitable therapeutic approach against IPF progression. In line with this hypothesis, different protein kinase inhibitors have successfully reduced collagen deposition and myofibroblast population (two critical markers of organ fibrosis) concomitantly with a reduction in the phosphorylation/activation of FAK and Akt in the bleomycin model of pulmonary fibrosis [ 39 , 63 , 65 ].…”

Mechanotransduction and fibrosis

“…Interestingly, the impact of FAK signaling on fibrosis formation has also been demonstrated in lung tissue using a bleomycin-induced pulmonary fibrosis model in mice (Lagares et al, 2012; Kinoshita et al, 2013). Bleomycin, originally developed as an anticancer agent, causes an inflammatory response resembling acute lung injury (ALI) and ultimately leads to the development of fibrosis, which can be markedly decreased by FAK inhibition (Moeller et al, 2008; Mouratis and Aidinis, 2011; Lagares et al, 2012).…”

Targeting Mechanotransduction at the Transcriptional Level: YAP and BRD4 Are Novel Therapeutic Targets for the Reversal of Liver Fibrosis

“…Indeed, several integrin-associated signaling proteins, including integrin-linked kinase (ILK, Zhang et al, 2006; Li et al, 2009; Kavvadas et al, 2010; Shafiei and Rockey, 2012; Radovanac et al, 2013), focal adhesion kinase (FAK, Wong et al, 2011; Lagares et al, 2012; Kinoshita et al, 2013; Lagares and Kapoor, 2013; Zhao et al, 2016), and regulators and effectors of Rho GTPases, such as P-Rex1 (Liang et al, 2016), PAK and Rho-activated kinase (ROCK, Knipe et al, 2015; Martin et al, 2016) have been identified as potential targets for anti-fibrotic therapy in a number of organs. Notably, activation of ILK, which links F-actin to focal adhesions and is required for integrin-mediated force generation, sustains nuclear YAP accumulation in pulmonary arterial vascular smooth muscle cells to promote cell proliferation in pulmonary arterial hypertension, a disease characterized by increased deposition of extracellular matrix and vascular stiffness (Kudryashova et al, 2016).…”