Effects of TNF-alpha inhibition on inner ear microcirculation and hearing function after acute loud noise in vivo

摘要

Acute noise-induced inner ear hearing loss is characterized by microcirculatory disturbance in the stria vascularis. In addition to the immunomodulatory effect, inhibition of TNF-α activity might prevent vasoconstriction of the spiral modiolar artery by inactivation of Sphingokinase-1 in the S1P/S1P2 signaling system in vascular smooth muscle cells as well as reduce downregulation of NO-mediated vasodilation. Therefore, early treatment with TNF-α-inhibitors might prevent hearing impairment by restoring cochlear blood flow.In order to investigate acute effects of loud noise exposure on cochlear microcirculation and hearing function, we have established a new standardized animal model by using in vivo-fluorescence microscopy and auditory brainstem response. Fluorescent dextran as a blood plasma marker was given intravenously in guinea pigs under narcosis. On one ear, cochlea and stria vascularis were surgically exposed for microscopic analysis. On the contralateral ear, hearing threshold was measured by auditory brainstem response after exposure of both ears to loud noise (106 dB SPL, 30 min). Control animals were not exposed to noise. In contrast to control animals, cochlear blood flow was reduced by 44 % while the hearing threshold increased by 23 dB SPL at the end of the observation period (210 min) after loud noise exposure. After using this model for therapeutic evaluation, early treatment with a single dose of TNF-α-inhibitor – etanercept - was shown to restore cochlear blood flow and maintain hearing threshold. When cochlear blood flow was reduced by 36.0 % in saline-treated control animals, only 2.2 % reduction was observed under TNF-α-inhibition at the end of the observation. Similarly, when the total hearing threshold shift reached + 20 dB SPL in control animals, there was almost no threshold shift subsequent to TNF-α-inhibition therapy.In conclusion, these data clearly show that TNF-α-inhibition is a promising treatment strategy in acute noise-induced hearing loss.