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TNFα compromises the inner ear microcirculation in a sphingosine kinase 1/sphingosine‐1‐phosphate dependent manner ‐ a novel mechanism for sudden hearing loss (SHL)
Author(s) -
Scherer Elias Q.,
Yang Jingli,
Ivanov Karolina,
Diehl Christian David,
Reimann Katrin,
Wangemann Philine,
Pohl Ulrich,
Canis Martin,
Strieth Sebastian,
VoigtlaenderBolz Julia,
Lidington Darcy,
Bolz SteffenSebastian
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.590.17
Subject(s) - microcirculation , inner ear , sphingosine 1 phosphate , medicine , sphingosine , sphingosine kinase , sphingosine kinase 1 , microbiology and biotechnology , pathology , anatomy , biology , receptor
This study establishes a link between inflammation and inner ear vascular dysfunction. Recovery of auditory function in of 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 (SV) perfusion, and (3) in vitro measurement of cochlear lateral wall capillary (LWC) constriction. We demonstrate that in all parts of the cochlear microcirculation (SMA, SV and LWC), 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. CIHR‐MOP‐84402, CFI‐11810, ORF‐11810, CSN, KRICRF‐TUM‐8758155, HSFO‐NI, HSFO‐CI, SFUT, Boehringer Ingelheim, DAA, NIH‐R01‐DC04280.