# Release of Mast Cell Mediators from Cochlear Tissue Following Short Exposure to Compound 48/80 or Cisplatin, and Their Damage to Cochlear Structure

## TL;DR

This study shows that mast cells in the cochlea release harmful substances when exposed to certain drugs, leading to hearing damage.

## Contribution

The study identifies mast cell degranulation as an early mechanism in cisplatin-induced hearing loss.

## Key findings

- Degranulated mast cell supernatants cause hair cell loss and cochlear tissue damage.
- Cochlear mast cells release chymase and histamine when exposed to cisplatin or Compound 48/80.
- Sodium cromolyn reduces the effects of mast cell activation by cisplatin.

## Abstract

What are the main findings?
The supernatant from degranulated BMMCs induces structural changes to coch-lear tissues.Cochlear tissues stimulated with Compound 48/80 or cisplatin release histamine and chymase.

The supernatant from degranulated BMMCs induces structural changes to coch-lear tissues.

Cochlear tissues stimulated with Compound 48/80 or cisplatin release histamine and chymase.

What is the implication of the main finding?
Mast cell mediators have a potential to remodel cochlear tissues.Resident cochlear mast cells can be stimulated during chemotherapy with cispla-tin to contribute to hearing loss by releasing proinflammatory mediators.

Mast cell mediators have a potential to remodel cochlear tissues.

Resident cochlear mast cells can be stimulated during chemotherapy with cispla-tin to contribute to hearing loss by releasing proinflammatory mediators.

The cochlea is susceptible to damage from ototoxic agents such as cisplatin, yet the mechanisms underlying cochlear injury remain incompletely understood. Mast cells (MCs), key immune players in allergic and inflammatory responses, have recently been identified in the rodent cochlea and implicated in cisplatin-induced ototoxicity. Our study investigated the role of MC degranulation in cochlear damage and evaluated the activation capacity of cochlear-resident MCs. Bone marrow-derived MCs (BMMCs) were cultured and induced to degranulate via IgE-anti-DNP/DNP stimulation, and the supernatants were applied to cochlear explants. Cochlear explants were also treated with Compound 48/80 (CP48/80) or cisplatin to assess MC activation. Morphological changes were assessed and hair cells (HC) quantified via phalloidin staining, while ELISA measured mediator release. Supernatants from degranulated BMMC induced a dose-dependent HC loss and tissue damage. A significant chymase and tryptase release was triggered by CP48/80 from cochlear MCs, with chymase elevation detected even at low concentrations. Cochlear MCs were rapidly activated by cisplatin exposure, elevating chymase and histamine levels, and the effects were attenuated by the MC stabilizer sodium cromolyn. Notably, tryptase remained undetectable post-cisplatin treatment, suggesting tissue-specific MC responses. These findings establish MC degranulation as an early event in cisplatin-induced cochlear injury, mediated by chymase and histamine. Our study highlights MCs as potential therapeutic targets for mitigating ototoxicity and underscores the need to explore MC-driven pathways in hearing loss.