Epithelial disruption of Gab1 perturbs surfactant homeostasis and predisposes mice to lung injuries

Abstract

GRB2-associated-binding protein 1 (Gab1) belongs to Gab adaptor family, which integrates multiple signals in response to the epithelial growth factors. Recent genetic studies identified genetic variants of human Gab1 gene as potential risk factors of asthmatic inflammation. However, the functions of Gab1 in lungs remain largely unknown. Alveolar type-II cells (AT-IIs) are responsible for surfactant homeostasis and essentially regulate lung inflammation following various injuries (3). In this study, in vitro knockdown of Gab1 was shown to decrease the surfactant proteins (SPs) levels in AT-IIs. We further examined in vivo Gab1 functions through alveolar epithelium-specific Gab1 knockout mice (Gab1). In vivo Gab1 deficiency leads to a decrease in SP synthesis and the appearance of disorganized lamellar bodies. Histological analysis of the lung sections in Gab1 mice shows no apparent pathological alterations or inflammation. However, Gab1 mice demonstrate inflammatory responses during the LPS-induced acute lung injury. Similarly, in mice challenged with bleomycin, fibrotic lesions were found to be aggravated in Gab1 These observations suggest that the abolishment of Gab1 in AT-IIs impairs SP homeostasis, predisposing mice to lung injuries. In addition, we observed that the production of surfactants in AT-IIs overexpressing Gab1 mutants, in which Shp2 phosphatase and PI3K kinase binding sites have been mutated (Gab1, Gab1), has been considerably attenuated. Together, these findings provide the direct evidence about the roles of docking protein Gab1 in lungs, adding to our understanding of acute and interstitial lung diseases caused by the disruption of alveolar SP homeostasis.

Surfactant replacement therapy reduces acute lung injury and collapse induration-related lung remodeling in the bleomycin model

“…It has been shown that in IPF, AE2 cells are subject of apoptosis, endoplasmic reticulum, and lysosomal stress (18) in line with the demonstrated impaired activity of lung surfactant (19). In this regard it has been demonstrated in animal models that an isolated injury of AE2 cells or disruption of the surfactant system is either sufficient to induce a fibrotic lung remodeling (40,51,62,71,72) or results in a higher susceptibility for injury and fibrotic remodeling (69). Although the role of mechanical stress resulting from alveolar R/D and volutrauma is appreciated as an aggravating factor of lung injury in the context of ventilator-induced lung injury (11,50,63), the relevance for disease progression from acute lung injury to tissue remodeling and fibrosis during spontaneous breathing is less clear and therefore represents a gap of knowledge in the context of human diseases characterized by high surface tension, ongoing lung injury, and remodeling (20).…”

LncRNA TUG1 alleviates sepsis-induced acute lung injury by targeting miR-34b-5p/GAB1

“…GAB1 is a scaffolding protein that belongs to the GRB2-associated binding family [40]. The alveolar epithelium-specific knockout of GAB1 in mice reduced the level of surfactant protein in alveolar type-II cells, promoted LPS-induced pulmonary inflammation, and aggravated bleomycin-triggered fibrotic lung injury, suggesting a vital role of Gab1 in the regulation of alveolar homeostasis [41]. In this study, we found that GAB1 was significantly downregulated in mice following CLP surgery, whereas the injection of TUG1 adenoviral vector significantly recovered the expression of GAB1 in CLPtreated mice.…”

Inhibition of microRNA-29a alleviates hyperoxia-induced bronchopulmonary dysplasia in neonatal mice via upregulation of GAB1

“…Similarly, a former conducted study revealed that GAB1 is a target gene of miR-29a (Ruan et al 2018). Moreover, a previous study showed that inhibition of GAB1 may impair surfactant protein homeostasis, subsequently predisposing mice to lung injuries, which suggests that GAB1 is involved in lung injury defense (Wang et al 2016). From the results above, it could be concluded that miR-29a may negatively regulate GAB1, and both miR-29a and GAB1 may be involved in BPD.…”

“…In a recent study, inhibition of miR-29a induces upregulation of GRB2associated-binding protein 1 (GAB1) to protect human osteoblasts from hydrogen peroxide (Ruan et al 2018). GAB1 belongs to the GAB adaptor family, and silencing of GAB1 might deregulate pulmonary surfactants and enhance pulmonary susceptibility to inflammatory responses (Wang et al 2016). Also, GAB1 has been suggested to be a novel ideal target for controlling epidermal growth factor receptor mutant lung cancer (Takeuchi et al 2012).…”