Keratinocyte growth factor induces Akt kinase activity and inhibits Fas-mediated apoptosis in A549 lung epithelial cells

Abstract

Acute respiratory distress syndrome (ARDS) is a syndrome characterized by the rapid influx of protein-rich edema fluid into the air spaces. The magnitude of alveolar epithelial cell injury is a key determinant of disease severity and an important predictor of patient outcome. The alveolar epithelium is positioned at the interface of the host response in the initiation, progression, and recovery phase of the disease. Keratinocyte growth factor (KGF) is a potent survival factor unique to the epithelium that promotes lung epithelial cell survival, accelerates wound closure, and reduces fibrosis. We therefore hypothesized that KGF preserves lung function by inhibiting apoptosis through activation of a signal transduction pathway responsible for cell survival. To test this hypothesis we determined that KGF inhibits death following Fas activation, a relevant apoptosis pathway, and then determined that cell survival is mediated through activation of the phosphatidylinositol 3'-kinase (PI3K)/Akt kinase signal transduction pathway. We found that KGF induces a dose- and time-dependent increase in Akt kinase activity and that, as expected, activation of Akt via KGF is PI3K dependent. KGF inhibited Fas-induced apoptosis as measured by a reduction in apoptotic cells and caspase-3 activity. This investigation supports our original hypothesis that KGF protects the lung epithelium by inhibiting apoptosis and that protection occurs through activation of PI3K/Akt-mediated cell survival pathway. Our results are in agreement with other reports that identify the PI3K/Akt axis as a key intracellular pathway in the lung epithelium that may serve as a therapeutic target to preserve epithelial integrity during inflammation.

Fibroblast‐specific perturbation of transforming growth factor β signaling provides insight into potential pathogenic mechanisms of scleroderma‐associated lung fibrosis: Exaggerated response to alveolar epithelial injury in a novel mouse model

“…Together with dysregulation of FGF-7 secretion by fibroblasts, it is conceivable that unopposed TGF␤-induced inhibition of type II AEC proliferation contributes to impaired AEC repair processes in this model (43). In addition to its mitogenic effects, FGF-7 may have a broader role as an epithelial survival factor and has been shown to inhibit Fas-mediated AEC apoptosis in vitro (44).…”

Intestinal trefoil factor activates the PI3K/Akt signaling pathway to protect gastric mucosal epithelium from damage

“…PI3K/Akt signaling pathway plays an essential role in regulating cell proliferation, differentiation, apoptosis and migration (12,13). In addition to its metabolic actions, PI3K/Akt signaling pathway has been shown to preserve epithelial integrity during inflammation (14). Numerous studies have indicated that growth factors participate in many important physiological and pathologic processes in gastrointestinal diseases via regulating downstream signaling pathways which could mediate cell survival, cell apoptosis, cell migration and immune response.…”

Toll-like receptor 9-mediated inhibition of apoptosis occurs through suppression of FoxO3a activity and induction of FLIP expression

“…In addition, the PI3K/Akt pathway has been reported as a very important signaling molecule in the anti-apoptosis effects of CpG ODN (Kuo et al, 2006). Furthermore, because Akt activity prevent the induction of apoptosis by cytokines, growth factors, and cellular stress (Bao et al, 2005), the effect of Akt pathway on FoxO3a activation, FLIP expression, and apoptosis was assessed. Use of the pharmacological inhibitor LY294002 enabled the examination of the role of the Akt signaling pathway in the regulation of the FoxO3a.…”