Abstract
The molecular pathomechanisms in the majority of patients suffering from acute or progressive sensorineural hearing loss cannot be determined yet. The size and the complex architecture of the cochlea make biopsy and in-depth histological analyses impossible without severe damage of the organ. Thus, histopathology correlated to inner disease is only possible after death. The establishment of a technique for perilymph sampling during cochlear implantation may enable a liquid biopsy and characterization of the cochlear microenvironment. Inflammatory processes may not only participate in disease onset and progression in the inner ear, but may also control performance of the implant. However, little is known about cytokines and chemokines in the human inner ear as predictive markers for cochlear implant performance. First attempts to use multiplex protein arrays for inflammatory markers were successful for the identification of cytokines, chemokines, and endothelial markers present in the human perilymph. Moreover, unsupervised cluster and principal component analyses were used to group patients by lead cytokines and to correlate certain proteins to clinical data. Endothelial and epithelial factors were detected at higher concentrations than typical pro-inflammatory cytokines such as TNF-a or IL-6. Significant differences in VEGF family members have been observed comparing patients with deafness to patients with residual hearing with significantly reduced VEGF-D levels in patients with deafness. In addition, there is a trend toward higher IGFBP-1 levels in these patients. Hence, endothelial and epithelial factors in combination with cytokines may present robust biomarker candidates and will be investigated in future studies in more detail. Thus, multiplex protein arrays are feasible in very small perilymph samples allowing a qualitative and quantitative analysis of inflammatory markers. More results are required to advance this method for elucidating the development and course of specific inner ear diseases or for perioperative characterization of cochlear implant patients.
Highlights
The inner ear harbors the sensory organs responsible for balance and hearing
A homogeneous concentration range was observed in all samples with the insulin-like growth factor binding protein 1 (IGFBP1) and the plasminogen activator inhibitor 1 (PAI-1) at very high concentrations (>1,000 pg/ml) followed by four proteins higher than 500 pg/ml, i.e., the cytokine IL-6, the granulocyte-macrophage colony stimulating factor (GM-cerebrospinal fluid (CSF)), the IL-1 receptor antagonist (IL-1RA), and
This pattern further supported a tissuerelated microenvironment within perilymph fluid accompanied by several immune activation markers like the soluble Fas (CD95) ligand, the chemokine CCL2 (MCP-1), responsible for recruitment of myeloid cells, and the granulocyte colony stimulating factor G-SCF in the same concentration range
Summary
The inner ear was assumed to be an immune-privileged organ because the blood-labyrinth barrier largely excludes major systemic components of the inflammatory response from the cochlear microenvironment [1]. Despite this tight junction blood-labyrinth barrier and the absence of a lymphatic drainage, classical local, and systemic inflammatory mechanisms have been identified in the cochlea. Acute damage to the murine inner ear caused by noise or ototoxic medication was shown to induce inflammation [6, 7] and to increase cochlear macrophages and neutrophils in the stria vascularis and the spiral ganglion [4, 8]. An up regulation of immunerelated genes in the murine cochlea has been reported after noise exposure [10]
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