Possible Involvement of Free Radicals in Lipopolysaccharide-Induced Labyrinthitis in the Guinea Pig: A Morphological and Functional Investigation

Abstract

Intratympanic injection of bacterial lipopolysaccharide impaired caloric responses and caused severe and widespread morphological damage to vestibular end organs and the endolymphatic sac in the guinea pig. These effects could be blocked with N-nitro-L-arginine methylester, a competitive inhibitor of nitric oxide synthase, with superoxide dismutase, an O₂ scavenger, with dexamethasone, and with ebselen, a scavenger of peroxynitrite. These observations indicate that enhanced nitric oxide and superoxide production, resulting in formation of peroxynitrite, is probably an important factor responsible for the pathological damage to vestibuli. If this is so, we may have found a way to study vestibular pathogenesis in inner ear disease.

Lipopolysaccharide-Induced Expression of Reactive Oxygen Species and Peroxynitrite in the Guinea Pig Vestibular Organ

“…The increased accumulation of nitrotyrosine in the vestibular organ indicates generation of peroxynitrite in the pathological process of LPS-induced labyrinthitis. In a series of experiments, we also demonstrated that removal of peroxynitrite by ebselen, a scavenger of peroxynitrite, could prevent its toxic effect, hence blocking the weakening of the caloric response [19]. These results strongly suggest that formation of peroxynitrite is responsible for the ototoxicity.…”

“…It has been suggested that NO mediates neurotransmission and may play an important role in regulating vascular tone, and also in maintaining endolymph and ion homeostasis [8,10,17]. On the other hand, recent studies have suggested that NO and its related oxygen radicals may under certain conditions even be responsible for certain pathological effects in the inner ear [9,12,13,17,19]. NOS II is usually not expressed constitutively but can be induced in almost every type of cell by stimulation with bacterial LPS and/or cytokines.…”

Free Radicals in the Guinea Pig Inner Ear following Gentamicin Exposure

“…It has been suggested that NO mediates neurotransmission and may play an important role in regulating vascular tone, and also in maintaining endolymph and ion homeostasis [4,6,31]. On the other hand, recent studies have suggested that NO and its related oxygen radicals may under certain conditions even be responsible for certain pathological effects in the inner ear [5,8,9,11,31]. NOS II is usually not expressed constitutively but can be induced in almost every type of cell by stimulation with bacterial lipopolysaccharide and/or cytokines.…”

“…After dissection of the organ of Corti and the vestibular end organs, the specimens were further fixed by immersion in the same fixative for 4 h, followed by conductive staining with 2% tannic acid and 1% OsO 4 . After dehydration with graded ethanols, the specimens were transferred to t-butyl alcohol for three changes, freeze-dried (Eiko ID-2 freeze drier) and plasma coated with OsO 4 (JOS-100D Osmium Plasma Coater ) for scanning electronmicroscopic observation and photography (Hitachi S-800 with an accelerating voltage of 20 kV) [11].…”

“…Recent studies have suggested that, in the inner ear, ROS and NO can give rise to certain pathological conditions [4][5][6][7][8][9][10][11]. ROS generation is believed to contribute to pathological changes in a wide variety of etiologies, including all classic categories of ototoxic agents.…”