title: JAK2/STAT3 inhibition attenuates noise-induced hearing loss.
abstract: Signal transducers and activators of transcription 3 (STAT3) is a stress responsive transcription factor that plays a key role in oxidative stress-mediated tissue injury. As reactive oxygen species (ROS) are a known source of damage to tissues of the inner ear following loud sound exposure, we examined the role of the Janus kinase 2 (JAK2)/STAT3 signaling pathway in noise induce hearing loss using the pathway specific inhibitor, JSI-124. Mice were exposed to a moderately damaging level of loud sound revealing the phosphorylation of STAT3 tyrosine 705 residues and nuclear localization in many cell types in the inner ear including the marginal cells of the stria vascularis, type II, III, and IV fibrocytes, spiral ganglion cells, and in the inner hair cells. Treatment of the mice with the JAK2/STAT3 inhibitor before noise exposure reduced levels of phosphorylated STAT3 Y705. We performed auditory brain stem response and distortion product otoacoustic emission measurements and found increased recovery of hearing sensitivity at two weeks after noise exposure with JAK2/STAT3 inhibition. Performance of cytocochleograms revealed improved outer hair cell survival in JSI-124 treated mice relative to control. Finally, JAK2/STAT3 inhibition reduced levels of ROS detected in outer hair cells at two hours post noise exposure. Together, these findings demonstrate that inhibiting the JAK2/STAT3 signaling pathway is protective against noise-induced cochlear tissue damage and loss of hearing sensitivity.
authors.affiliation: Oregon Hearing Research Center, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Teresa
authors.initials: T
authors.lastname: Wilson
authors.affiliation: Virginia Merrill Bloedel Hearing Research Center, University of Washington, Seattle, Washington, United States of America.
authors.forename: Irina
authors.initials: I
authors.lastname: Omelchenko
authors.affiliation: Oregon Hearing Research Center, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Sarah
authors.initials: S
authors.lastname: Foster
authors.affiliation: Oregon Hearing Research Center, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Oregon Hearing Research Center, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Xiaorui
authors.initials: X
authors.lastname: Shi
authors.affiliation: Oregon Hearing Research Center, Oregon Health & Science University, Portland, Oregon, United States of America; Kresge Hearing Research Institute, The University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Alfred L
authors.initials: AL
authors.lastname: Nuttall
mesh_terms: D000818:Animals; D003051:Cochlea / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004848:Epithelium / Q000378:metabolism; D016057:Evoked Potentials, Auditory, Brain Stem; D005786:Gene Expression Regulation; D006198:Hair Cells, Auditory / Q000378:metabolism / Q000473:pathology; D006317:Hearing Loss, Noise-Induced / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D051379:Mice; D017084:Otoacoustic Emissions, Spontaneous; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D018836:Inflammation Mediators; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; D053614:Janus Kinase 2