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EGFR-Activated Signaling and Actin Remodeling Regulate Cyclic Stretch–Induced NRF2-ARE Activation

Division of Physiology, Department of Environmental Health Sciences, Division of Pulmonary and Critical Medicine, and Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland; and University of Chicago, Chicago, Illinois

Correspondence and requests for reprints should be addressed to Sekhar P. Reddy, The Johns Hopkins University, Department of Environmental Health Sciences, Division of Physiology, Rm. E7610, 615 North Wolfe Street, Baltimore, MD 21205. E-mail: sreddy{at}jhsph.edu

Cyclic stretch (CS) associated with mechanical ventilation (MV) can cause excessive alveolar and endothelial distention, resulting in lung injury and inflammation. Antioxidant enzymes (AOEs) play a major role in suppressing these effects. The transcription factor Nrf2, via the antioxidant response element (ARE), alleviates pulmonary toxicant- and oxidant-induced oxidative stress by up-regulating the expression of several AOEs. Although gene expression profiling has revealed the induction of AOEs in the lungs of rodents exposed to MV, the mechanisms by which mechanical forces, such as CS, regulate the activation of Nrf2-dependent ARE-transcriptional responses are poorly understood. To mimic mechanical stress associated with MV, we have cultured pulmonary alveolar epithelial and endothelial cells on collagen I–coated BioFlex plates and subjected them to CS. CS exposure stimulated ARE-driven transcriptional responses and subsequent AOE expression. Ectopic expression of a dominant-negative Nrf2 suppressed the CS-stimulated ARE-driven responses. Our findings suggest that actin remodeling is necessary but not sufficient for high-level CS-induced ARE activation in both epithelial and endothelial cells. We also found that inhibition of EGFR activity by a pharmacologic agent ablated the CS-induced ARE transcriptional response in both cell types. Additional studies revealed that amphiregulin, an EGFR ligand, regulates this process. We further demonstrated that the PI3K-Akt pathway acts as the downstream effector of EGFR and regulates CS-induced ARE-activation in an oxidative stress–dependent manner. Collectively, these novel findings suggest that EGFR-activated signaling and actin remodeling act in concert to regulate the CS-induced Nrf2-ARE transcriptional response and subsequent AOE expression.

Key Words: oxidative stress • MAP kinases • mechanical stress • antioxidant response element • lung

CLINICAL RELEVANCE Our findings may have particular physiologic importance in clinical syndromes such as ventilator-induced lung injury where inflammation and oxidative stress (an imbalance between antioxidant and oxidant systems) are thought to play a preponderant role.