ABSTRACT
Transient receptor potential vanilloid 1 (TRPV1) is implicated in cisplatin ototoxicity. Activation of this channel by cisplatin increases reactive oxygen species generation, which contribute to loss of outer hair cells in the cochlea. Knockdown of TRPV1 by short interfering RNA protected against cisplatin ototoxicity. In this study, we examined the mechanism underlying TRPV1-mediated ototoxicity using cultured organ of Corti transformed cells (UB/OC-1) and rats. Trans-tympanic injections of capsaicin produced transient hearing loss within 24 h, which recovered by 72 h. In UB/OC-1 cells, capsaicin increased NOX3 NADPH oxidase activity and activation of signal transducer and activator of transcription 1 (STAT1). Intratympanic administration of capsaicin transiently increased STAT1 activity and expression of downstream proinflammatory molecules. Capsaicin produced a transient increase in CD14-positive inflammatory cells into the cochlea, which mimicked the temporal course of STAT1 activation but did not alter the expression of apoptotic genes or damage to outer hair cells. In addition, trans-tympanic administration of STAT1 short interfering RNA protected against capsaicin-induced hearing loss. These data suggest that activation of TRPV1 mediates temporary hearing loss by initiating an inflammatory process in the cochlea via activation of NOX3 and STAT1. Thus, these proteins represent reasonable targets for ameliorating hearing loss.
Subject(s)
Capsaicin/pharmacology , Hearing Loss/metabolism , Inflammation/metabolism , NADPH Oxidases/metabolism , STAT1 Transcription Factor/metabolism , TRPV Cation Channels/metabolism , Animals , Capsaicin/administration & dosage , Cells, Cultured , Cochlea/drug effects , Cochlea/metabolism , Evoked Potentials , Hearing Loss/chemically induced , Immunohistochemistry , Inflammation/genetics , Male , Mice , Microscopy, Electron, Scanning , NADPH Oxidases/genetics , RNA, Small Interfering/drug effects , RNA, Small Interfering/genetics , Rats , Rats, Wistar , Reactive Oxygen Species/metabolism , Reverse Transcriptase Polymerase Chain Reaction , STAT1 Transcription Factor/genetics , TRPV Cation Channels/geneticsABSTRACT
Residual disfigurement is a common problem for patients who have undergone skin cancer reconstruction. Restoring form and function in these patients is an artistic and technical endeavor. The efficacy of surgical scar revision, dermabrasion, chemical peels, and laser resurfacing is predicated upon the skin's innate ability to regenerate over time in response to mechanical, chemical, and thermal or ablative stresses. The patient and surgeon should be accepting of a process that is often gradual and may proceed in stages. Achieving proficiency with the secondary procedures for improving scars and local flaps may allow the motivated surgeon to mold an initially passable surgical result into an excellent one.
