| Summary: | Epithelial tissues play a critical role in maintaining systemic health by establishing a functional barrier that separates the external environment from the host to provide an innate defense against environmental insult. Epithelial barrier disruption is suspected to play a central role in the onset of chronic inflammatory disease, although, fundamental knowledge of the underlying pathogenesis remains poorly understood. Thus, identifying factors that mediate epithelial barrier loss is clinically relevant as it will open the possibility that novel interventional strategies may be developed to mitigate early disease-associated signaling events.
Lipopolysaccharide (LPS) is a Gram-negative bacterial virulence factor implicated in periodontal disease onset. Amphiregulin (AR) is a ligand for the epidermal growth factor receptor (EGFR) and downstream mediator of tumor necrosis factor-alpha (TNF-α) (Chokki et al., 2006) that is normally sequestered at cell-cell contacts in stable epithelial barriers. AR and corresponding signaling components modulating the EGFR pathway are altered in a rat model of periodontal disease that exhibited concomitant altered barrier architecture (Fujita et al., 2011; Firth et al., 2011). Treatment of this model with monoamine oxidase (MAO) inhibitors ameliorated disease indices (Ekuni et al., 2009).
This study employs an in vitro histiotypic model of epithelium to provide evidence that LPS-reduced epithelial barrier function associated with chronic inflammatory disease may be mediated by altered AR and TNF-α secretion. MAO-B inhibition by (−)-deprenyl enhanced barrier model transepithelial electrical resistance (TER), prevented LPS-, AR- and H₂O₂-induced reduction in TER and attenuated LPS-induced AR and TNF-α secretion and H₂O₂-induced AR secretion. Furthermore, immunostaining of barrier model cultures showed that markers of cell-cell junctions were altered by LPS challenge and treatment of the model with (−)-deprenyl protects against this disruption. This study addresses the underlying mechanism by which (−)-deprenyl protects against bacterial virulence factor-induced epithelial barrier disruption and points to a significant role for AR as a central mediator of barrier integrity. Ultimately, this project aims to provide in vitro evidence for the efficacy of (−)-deprenyl treatment of LPS-induced epithelial barrier disruption, which may promote development of enhanced MAO-B inhibitors and lead to an effective clinical treatment for disease-associated epithelial barrier loss.
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