Human epidermal growth factor receptor signaling in acute lung injury

Abstract

Acute lung injury (ALI) is a syndrome marked by increased permeability across the pulmonary epithelium resulting in pulmonary edema. Recent evidence suggests that members of the human epidermal growth factor receptor (HER) family are activated in alveolar epithelial cells during ALI and regulate alveolar epithelial barrier function. These tyrosine kinase receptors, which also participate in the pathophysiology of pulmonary epithelial malignancies, regulate cell growth, differentiation, and migration as well as cell-cell adhesion, all processes that influence epithelial injury and repair. In this review we outline mechanisms of epithelial injury and repair in ALI, activation patterns of this receptor family in pulmonary epithelial cells as a consequence injury, how receptor activation alters alveolar permeability, and the possible intracellular signaling pathways involved. Finally, we propose a theoretical model for how HER-mediated modulation of alveolar permeability might affect lung injury and repair. Understanding how these receptors signal has direct therapeutic implications in lung injury and other diseases characterized by altered epithelial barrier function.

Figure 1.

Human epidermal growth factor receptor (HER) Signaling. HER ligands exist as surface-bound proteins, which are proteolytically shed to produce EGF-like domain containing free ligand (EGF has an EGF domain). The free growth factors are then able to bind individual receptors that homo- (HER1/HER1) or hetero- (HER2/3) dimerize, autophosphorylate, and initiate downstream intracellular signaling. Particularities of the HER family include HER2, which has no known ligand (orphan receptor), and HER3, which has a catalytically inactive tyrosine kinase domain.

Figure 2.

Proposed model of HER2/3 signaling in epithelial cells. Injurious stimuli, including IL-1β, induce protease-mediated ligand shedding, which is followed by autocrine or paracrine epithelial HER receptor activation. This induces activation of intracellular signaling pathways, including TGF-β and Rac, with subsequent modulation of tight junction and adherens junction proteins and regulation of epithelial cell–cell adhesion. IL-1β activation of HER2/3 through shedding ADAM17-induced shedding of neuregulin (NRG)-1 serves as a prototypical pathway.