Article
TNFα compromises the inner ear microcirculation in a sphingosine kinase 1/sphingosine-1-phosphate dependent manner – a novel mechanism for sudden hearing loss (SHL)
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Published: | April 22, 2010 |
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This study establishes a link between inflammation and inner ear vascular dysfunction. Recovery of auditory function in sudden hearing loss (SHL) patients treated with a TNFα inhibitor were consistent with a vascular origin. We investigated the inner ear microcirculation using (1) an in vitro model of the spiral modiolar artery (SMA), the end artery feeding the inner ear, (2) intra vital microscopy of stria vascularis perfusion, and (3) in vitro measurement of cochlear lateral wall capillary constriction. We demonstrate that in all parts of the cochlear microcirculation (SMA, stria vascularis and cochlear lateral wall capillaries), TNFα induces a proconstrictive state via activation of sphingosine-1-phosphate (S1P). Analysis of the molecular signalling pathway identified the phosphorylation of sphingosine kinase 1 (the S1P generating enzyme activated by TNFα) as a new therapeutic target for SHL. We conclude that any pathology linked to the release of TNFα has the potential to reduce cochlear blood flow and cause SHL. The present study integrates SHL into the family of cardiovascular pathologies, with immediate implications related to risk stratification, diagnosis and treatment.
Supported by: CIHR-MOP-84402, CFI-11810, ORF-11810, CSN, KRICRFTUM-8758155, HSFO-NI, HSFO-CI, SFUT, Boehringer Ingelheim, DAAD, NIH-R01-DC04280.