The role of epidermal growth factor receptor (EGFR) signaling in SARS coronavirus-induced pulmonary fibrosis

Abstract

Many survivors of the 2003 outbreak of severe acute respiratory syndrome (SARS) developed residual pulmonary fibrosis with increased severity seen in older patients. Autopsies of patients that died from SARS also showed fibrosis to varying extents. Pulmonary fibrosis can be occasionally seen as a consequence to several respiratory viral infections but is much more common after a SARS coronavirus (SARS-CoV) infection. Given the threat of future outbreaks of severe coronavirus disease, including Middle East respiratory syndrome (MERS), it is important to understand the mechanisms responsible for pulmonary fibrosis, so as to support the development of therapeutic countermeasures and mitigate sequelae of infection. In this article, we summarize pulmonary fibrotic changes observed after a SARS-CoV infection, discuss the extent to which other respiratory viruses induce fibrosis, describe available animal models to study the development of SARS-CoV induced fibrosis and review evidence that pulmonary fibrosis is caused by a hyperactive host response to lung injury mediated by epidermal growth factor receptor (EGFR) signaling. We summarize work from our group and others indicating that inhibiting EGFR signaling may prevent an excessive fibrotic response to SARS-CoV and other respiratory viral infections and propose directions for future research.

Keywords: EGFR; Fibrosis; SARS-CoV; Wound healing.

Fig. 1

Pathologic features of SARS-CoV infection in humans and mice. A. Transverse thin-section CT scan in 36-year-old man at follow-up (obtained at day 43 after admission, 26 days since discharge) shows evidence of fibrosis. Large areas of ground-glass opacification are still present, both surrounding the areas of fibrosis and in other regions. (Permission for reuse from Antonio et al., Radiology ; 228:810–815.) B. H&E stained lungs from either PBS or SARS-CoV (MA15) inoculated mice in wildtype 129/Sv or 129/STAT1-/- mice at 9 days post-infection. Note the resolution of lung damage and inflammation in the infected 129/Sv mice while 129/STAT1-/- mice display extensive inflammation, fibrotic lesions surrounding airways and occlusion of alveolar space with proteinaceous fluid and a mixed inflammatory infiltrate.

Fig. 2

The seven known ligands of EGFR are in a membrane bound inactive form. The ADAM family of proteases are activated in response to tissue injury and cleave the pro-ligands to release the EGF module containing soluble ligand. The ligand binds to the receptor causing it to dimerize and autophosphorylate its C-terminal tail at specific tyrosine residues. The phosphorylated active form aggregates several adaptor proteins leading to the activation of multiple signaling cascades. A range of different outcomes are produced by the activation of these pathways some of which are listed in the schematic above.

Fig. 3

The potential role of EGFR in fibrosis is illustrated above with the lung as an example. Physical injury or a pathogen (1) initiates the wound healing response by damaging healthy tissue, releasing EGFR ligands (2) and activating the EGFR pathway. A sustained activation of the EGFR pathway results in an exaggerated wound healing response leading to a fibrotic lung (3). The early use of tyrosine kinase inhibitors (4) could prevent the normal progress of wound healing and result in sustained injury and the development of fibrosis by alternate mechanisms.