The surface of the airway epithelium represents a battleground in which the host intercepts signals from pathogens and activates epithelial defenses to combat
infection.
Wound repair is an essential function of the airway epithelium in response to injury in chronic airway diseases, and inhaled pathogens such as Pseudomonas bacteria are implicated in the pathobiology of several of these diseases. Because
epidermal growth factor receptor (EGFR) activation stimulates
wound repair and because LPS activates EGFR, we hypothesized that LPS accelerates
wound repair via a surface signaling cascade that causes EGFR phosphorylation. In scrape
wounds of NCI-H292 human airway epithelial cells, high concentrations of LPS were toxic and decreased
wound repair. However, lower concentrations of LPS accelerated
wound repair. This effect was inhibited by treatment with a selective inhibitor of EGFR phosphorylation (
AG 1478) and by an EGFR neutralizing Ab.
Metalloprotease inhibitors and
TNF-alpha-converting enzyme (TACE)
small interfering RNA inhibited
wound repair, implicating TACE. Additional studies implicated
TGF-alpha as the active EGFR
ligand cleaved by TACE during
wound repair.
Reactive oxygen species scavengers,
NADPH oxidase inhibitors, and importantly
small interfering RNA of
dual oxidase 1 inhibited LPS-induced
wound repair. Inhibitors of
protein kinase C isoforms alphabeta and a TLR-4 neutralizing Ab also inhibited LPS-induced
wound repair. Normal human bronchial epithelial cells responded similarly. Thus, LPS accelerates
wound repair in airway epithelial cells via a novel TLR-4-->
protein kinase C alphabeta-->
dual oxidase 1-->
reactive oxygen species-->TACE-->
TGF-alpha-->EGFR phosphorylation pathway.