Lung epithelial cell focal adhesion kinase signaling inhibits lung injury and fibrosis

Abstract

Progressive pulmonary fibrosis is a devastating consequence of many acute and chronic insults to the lung. Lung injury leads to alveolar epithelial cell (AEC) death, destruction of the basement membrane, and activation of transforming growth factor-β (TGF-β). There is subsequent resolution of the injury and a coordinated and concurrent initiation of fibrosis. Both of these processes may involve activation of similar intracellular signaling pathways regulated in part by dynamic changes to the extracellular matrix. Matrix signaling can augment the profibrotic fibroblast response to TGF-β. However, similar matrix/integrin signaling pathways may also be involved in the inhibition of ongoing TGF-β-induced AEC apoptosis. Focal adhesion kinase (FAK) is an integrin-associated signaling molecule expressed by many cell types. We used mice with AEC-specific FAK deletion to isolate the epithelial aspect of integrin signaling in the bleomycin model of lung injury and fibrosis. Mice with AEC-specific deletion of FAK did not exhibit spontaneous lung injury but did have significantly greater terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling-positive cells (18.6 vs. 7.1) per ×200 field, greater bronchoalveolar lavage protein (3.2 vs. 1.8 mg/ml), and significantly greater death (77 vs. 19%) after bleomycin injury compared with littermate control mice. Within primary AECs, activated FAK directly associates with caspase-8 and inhibits activation of the caspase cascade resulting in less apoptosis in response to TGF-β. Our studies support a model in which dynamic changes to the extracellular matrix after injury promote fibroblast activation and inhibition of epithelial cell apoptosis in response to TGF-β through FAK activation potentially complicating attempts to nonspecifically target this pathway for antifibrotic therapy.

Phosphoproteome profiling provides insight into the mechanisms of ventilator‑induced lung injury

“…Therefore, exploring the molecular mechanisms underlying protein phosphorylation is critical in examining disease mechanisms and identifying potential therapeutic targets. Since approximately 30% of proteins in eukaryotic cells can be phosphorylated, each protein kinase selectively modifies a specific substrate protein to ensure signal transduction within a complex cellular environment (8,(10)(11)(12)(13)(14)(15)(16)(17). The results of the present study suggest that phosphorylated proteins are involved in VILI, in particular, phosphorylation of proteins involved in PI3K-AKT and MAPK signaling pathways.…”

“…Focal adhesion formation and behavior has been demonstrated to be pivotal to pulmonary epithelial function, and has been linked with modulation of ALI injury severity (15). Focal adhesions (FAs), large macromolecular complexes mediating interactions between cells and the extracellular matrix (ECM), have been linked to the development of pulmonary fibrosis and injury, as FAs play a part in mediating epithelial function, and epithelial dysfunction is a hallmark of pulmonary injury (16). The inhibition of focal adhesion kinase (FAK), a protein that is activated by integrin-ECM interactions and fibroblast-secreted transforming growth factor-β (TGF-β), has been shown to exacerbate bleomycin-induced lung injury in mice (16).…”

“…Focal adhesions (FAs), large macromolecular complexes mediating interactions between cells and the extracellular matrix (ECM), have been linked to the development of pulmonary fibrosis and injury, as FAs play a part in mediating epithelial function, and epithelial dysfunction is a hallmark of pulmonary injury (16). The inhibition of focal adhesion kinase (FAK), a protein that is activated by integrin-ECM interactions and fibroblast-secreted transforming growth factor-β (TGF-β), has been shown to exacerbate bleomycin-induced lung injury in mice (16). Moreover, FA formation, FAK phosphorylation, and FA arrangement and rearrangement have been shown to mediate preservation of pulmonary vascular barrier function (17).…”

Enhancement of FAK alleviates ventilator-induced alveolar epithelial cell injury

“…Conversely, Ghosh MC et al argue that migrating cells have decreased levels of FAK phosphorylation 14,23 . Therefore, we speculate that FAK may have different effects in different types of cells 7 . More research is needed to understand the role of FAK in lung injury.…”

“…Furthermore, FAK knockout makes mice susceptible to lung injury. In a study by Wheaton AK et al, the deletion of FAK increased sensitivity to apoptosis in lung epithelial cells, and the anti-apoptotic effect of FAK occurred via blocking caspase-8 7 . Therefore, FAK may be involved in VILI by contributing to epithelial cell survival.…”