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Pseudomonas Lipopolysaccharide Accelerates Wound Repair via Activation of a Novel Epithelial Cell Signaling Cascade¹

Jonathan L. Koff^*,, Matt X. G. Shao^*,, Suil Kim^*,, Iris F. Ueki^* and Jay A. Nadel^2,*,,

^* Cardiovascular Research Institute, Department of Medicine, and Department of Physiology, University of California, San Francisco, San Francisco, CA 94143

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--converting enzyme (TACE) small interfering RNA inhibited wound repair, implicating TACE. Additional studies implicated TGF- 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 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-4protein kinase C dual oxidase 1reactive oxygen speciesTACETGF-EGFR phosphorylation pathway.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Cardiovascular Research Institute funding.

² Address correspondence and reprint requests to Dr. Jay A. Nadel, University of California, San Francisco, 505 Parnassus Avenue, Room S-1183, San Francisco, CA 94143-0130. E-mail address: jay.nadel{at}ucsf.edu

³ Abbreviations used in this paper: EGFR, epidermal growth factor receptor; DPI, diphenyleneiodonium chloride; Duox1, dual oxidase 1; EGF, epidermal growth factor; HB-EGF, heparin-binding EGF; LDH, lactate dehydrogenase; NHBE, normal human bronchial epithelial; NMEA, N^G-monoethyl-L-arginine; Nox, NADPH oxidase; nPG, n-propyl gallete; PKC, protein kinase C; ROS, reactive oxygen species; siRNA, small interfering RNA; TACE, TNF--converting enzyme; TAPI-1, TNF- proteinase inhibitor-1.

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