EGFR Signaling in Lung Fibrosis

Abstract

In this review article, we will first provide a brief overview of the ErbB receptor-ligand system and its importance in developmental and physiological processes. We will then review the literature regarding the role of ErbB receptors and their ligands in the maladaptive remodeling of lung tissue, with special emphasis on idiopathic pulmonary fibrosis (IPF). Here we will focus on the pathways and cellular processes contributing to epithelial-mesenchymal miscommunication seen in this pathology. We will also provide an overview of the in vivo studies addressing the efficacy of different ErbB signaling inhibitors in experimental models of lung injury and highlight how such studies may contribute to our understanding of ErbB biology in the lung. Finally, we will discuss what we learned from clinical applications of the ErbB1 signaling inhibitors in cancer in order to advance clinical trials in IPF.

Keywords: ErbB-signaling; TGF-α; TGF-β; amphiregulin; epidermal growth factor; epidermal growth factor receptor; idiopathic pulmonary fibrosis; lung fibrosis; neuregulin 1; pulmonary fibrosis; tyrosine kinase inhibitor.

Figure 1

ErbB receptors and their ligands. ErbB2 has no known ligand, while ErbB3 lacks intrinsic kinase activity (indicated by a cross). Following ligand binding, the receptors activate several downstream signaling pathways thereby regulating cell growth, proliferation, and survival. These processes play an important role in development, wound healing and tissue regeneration. EGF, epidermal growth factor; TGFα, transforming growth factor-α; EPG, epigen; AREG, amphiregulin; EREG, epiregulin; BC, betacellulin; HB-EGF, heparin-binding EGF-like growth factor; NRG1-4, neuregulin 1-4; STAT, signal transducer and activator of transcription; MAPK/ERK, mitogen-activated protein kinase/extracellular signal-regulated kinase; PIK3/Akt, phosphoinositide 3-kinase/protein kinase B; PLCγ, phospholipase Cγ.

Figure 2

Overview of the in vitro, in vivo and clinical findings for the role of the ErbB/ligand system in lung fibrosis. LF, lung fibroblasts; TGFα, transforming growth factor-α; HB-EGF, heparin-binding epidermal growth factor-like growth factor; EREG, epiregulin; AREG, amphiregulin; HRG-α, heregulins; TGF-β, transforming growth factor-β; CCSP, Clara cell secretory protein; SP-C, surfactant protein-C; PI3K, phosphoinositide 3-kinase; MEK, mitogen-activated protein kinase kinase; IPF, idiopathic pulmonary fibrosis; ATII cells, alveolar type II cells; NRG1α, neuregulin-1α; BALF, bronchoalveolar lavage fluid; FVC, forced vital capacity; DL_CO, diffusion capacity of the lung for carbon monoxide; ILD, interstitial lung disease; NSCLC, non-small-cell lung cancer.