Effects of TNF-alpha inhibition on inner ear microcirculation and hearing function after acute loud noise in vivo
Beschreibung
vor 14 Jahren
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.
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.
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