Pseudomonas lipopolysaccharide accelerates wound repair via activation of a novel epithelial cell signaling cascade.
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.
Koff
Jonathan L
JL
Cardiovascular Research Institute, Department of Medicine, University of California-San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143, USA.
Shao
Matt X G
MX
Kim
Suil
S
Ueki
Iris F
IF
Nadel
Jay A
JA
D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000502:physiology*; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology* / Q000627:therapeutic use; D010766:Phosphorylation; D011550:Pseudomonas aeruginosa / Q000737:chemistry*; D012137:Respiratory System / Q000166:cytology; D015398:Signal Transduction / Q000502:physiology*; D014945:Wound Healing / Q000187:drug effects*
D008070:Lipopolysaccharides; D066246:ErbB Receptors