Yong-Soo Park

Effects of Tumor Necrosis Factor Alpha Antagonist, Platelet Activating Factor Antagonist, and Nitric Oxide Synthase Inhibitor on Experimental Otitis Media with Effusion

Objectives: We studied the inflammatory responses in otitis media with effusion induced by lipopolysaccharide (LPS) in rats, and compared the preventive effects of tumor necrosis factor (TNF) soluble receptor type I (sTNFRI, a TNF-α antagonist), platelet activating factor antagonist, and the nitric oxide synthase inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME). Methods: We used 2 control groups of Sprague Dawley rats (untreated and saline-treated) and 4 experimental groups, which all received an intratympanic injection of LPS, followed in 3 groups by experimental treatment of the same ear. The LPS group had no additional treatment. The l-NAME group received intraperitoneal injection of L-NAME and was reinjected after 12 hours. The A-85783 group was first given an intraperitoneal injection of A-85783. The sTNFRI group was first given an intratympanic injection of sTNFRI. Twenty-four hours after the initial intratympanic injection of LPS, temporal bones from each group were examined histopathologically and the vascular permeability of the middle ear mucosa was measured by Evans blue vital dye staining. Results: The l-NAME, A-85783, and sTNFRI groups showed significantly reduced capillary permeability, subepithelial edema, and infiltration of inflammatory cells in comparison with the LPS group. There were no differences in capillary permeability, subepithelial edema, or infiltration of inflammatory cells between the A-85783 and sTNFRI groups. The l-NAME group showed no difference in vascular permeability or subepithelial edema in comparison with the A-85783 and sTNFRI groups, but showed more infiltration of inflammatory cells. Conclusions: We conclude that sTNFRI, A-85783, and l-NAME can be proposed as alternative future treatments for otitis media with effusion. However, l-NAME may be the least effective of these agents.

Effect of Leukotriene Inhibitor on Cochlear Blood Flow in Salicylate Ototoxicity

Our previous studies showed that salicylate ototoxicity is associated with decreased levels of vasodilating prostaglandins (PGs) and increased vasoconstricting leukotrienes (LTs) in the perilymph and reduced cochlear blood flow (CoBF). The purpose of this study was to test the hypothesis that leukotriene inhibitor prevents salicylate ototoxicity by preventing abnormal elevation of LT levels in the inner ear, thus averting a decrease in CoBF resulting from abnormal levels of arachidonic acid metabolites in the inner ear. Ototoxicity was induced in chinchillas by either local round window membrane (RWM) application or systemic treatment with salicylate both with and without pretreatment with leukotriene inhibitor (Sch 37224). A moderate reduction in CoBF was documented with both local RWM and systemic treatment with salicylate. Salicylate induced hearing loss and reduction in CoBF were prevented by pretreatment with a leukotriene inhibitor. This study suggests that leukotriene inhibitor prevents salicylate ototoxicity by averting a decrease in CoBF mediated by abnormal levels of arachidonic acid metabolites in the inner ear.

Effect of Inhibitor of Tumor Necrosis Factor-Alpha on Experimental Otitis Media with Effusion

Tumor necrosis factor (TNF)-α is important in the pathogenesis of otitis media with effusion (OME). The purpose of this study was to determine the effect of TNF-α antagonist on the outcome of lipopolysaccharide (LPS)-induced OME in rats. Otitis media was induced by injecting Pseudomonas aeruginosa LPS transtympanically. Another (combination) group was pretreated with TNF-α antagonist, soluble TNF receptor type I (sTNF RI), before transtympanic injection of LPS. Saline and phosphate-buffered saline solutions were used as controls. Twelve hours after the transtympanic injection, otoscopic examination and aspiration of middle ear effusion (MEE) were done. The temporal bones in each group were examined histopathologically, and the vascular permeability of the middle ear mucosa was measured by the Evans blue vital dye technique. In the LPS and combination groups, MEE developed in 90% and 0% of ears, respectively. The combination group showed less inflammation, less mucosal thickening, and significantly decreased vascular permeability as compared to the LPS group. Transtympanic administration of sTNF RI appears to suppress the development of LPS-induced OME. This study suggests that TNF-α antagonist, along with antibiotics, may have an adjunctive role in the future treatment of MEE.

Effect of corticosteroid treatment on salicylate ototoxicity.

Our previous studies showed that salicylate ototoxicity is associated with decreased levels of prostaglandins (PGs) and elevated levels of leukotrienes (LTs) in the perilymph. The purpose of this study was to determine whether or not pretreatment with corticosteroid, which suppresses both PGs and LTs in arachidonic acid metabolism, prevents salicylate ototoxicity. Salicylate ototoxicity was induced in chinchillas with or without treatment with dexamethasone. Hearing thresholds were measured by auditory brain stem response, and perilymph samples were assayed by high-performance liquid chromatography. Dexamethasone pretreatment, given by either systemic or local round window membrane application, partially prevented salicylate-induced hearing loss. Prevention of salicylate ototoxicity by dexamethasone seems to be correlated with increased PG levels and decreased LT levels in the perilymph. This is another piece of evidence that salicylate ototoxicity may be mediated by abnormal arachidonic acid metabolism in the inner ear.

Effects of platelet activating factor on vascular permeability of the middle ear mucosa

Platelet activating factor (PAF), a potent inflammatory mediator, seems to play a significant role in the pathogenesis of otitis media with effusion (OME), along with other inflammatory mediators such as leukotrienes and prostaglandins. The purpose of this study was to investigate the effect of PAF on the vascular permeability of middle ear mucosa, in an experimental OME model using chinchillas. We injected PAF in doses of 1, 4, 8, and 16 μg and normal saline as a control into the bullae of chinchillas. Vascular permeability was measured by the Evans blue vital dye technique. All the PAF-injected animals showed a significant increase in middle ear vascular permeability compared to the control group. This study demonstrated that PAF in the middle ear cavity contributes significantly to the development of OME by increasing the vascular permeability of the middle ear mucosa.

Effects of a Tumor Necrosis Factor-α Antagonist on Experimentally Induced Rhinosinusitis

This prospective, randomized, and controlled study examined the effects of tumor necrosis factor soluble receptor type I (sTNFRI, a TNF-α antagonist) on experimentally induced rhinosinusitis in rats. The experimental groups received an instillation of lipopolysaccharide (LPS) plus an intramuscular injection of amoxicillin/clavulanate (antibiotic group), an instillation of sTNFRI (sTNFRI group), an instillation of sTNFRI and an injection of amoxicillin/clavulanate (sTNFRI/antibiotic group), or no additional treatment (LPS group). Histopathological changes were determined using hematoxylin-eosin and periodic acid-Schiff (PAS) staining. Leakage of exudate was determined using fluorescence microscopy. Vascular permeability was measured using the Evans blue dye technique. Expression of MUC5AC was measured using reverse transcriptase PCR. The sTNFRI, antibiotic, and sTNFRI/antibiotic groups had significantly less capillary permeability, mucosal edema, PAS staining, and expression of MUC5AC than the LPS group. There were no differences in capillary permeability, mucosal edema, PAS staining, and MUC5AC expression between the sTNFRI and sTNFRI/antibiotic groups. The antibiotic group had PAS staining similar to that of the sTNFRI and sTNFRI/antibiotic groups but had a greater increase in capillary permeability, mucosal edema, and MUC5AC expression. This study shows that sTNFRI reduces inflammatory activity and mucus hypersecretion in LPS-induced rhinosinusitis in rats.

Effect of Corticosteroid on Salicylate-Induced Morphological Changes of Isolated Cochlear Outer Hair Cells

Our previous studies showed that pretreatment with corticosteroids, which inhibits release of arachidonic acid (precursor of prostaglandins and leukotrienes), partially prevented salicylate-induced hearing loss in vivo. The purpose of this study was to determine the effect of pretreatment with corticosteroid (dexamethasone sodium phosphate) on isolated cochlear outer hair cells (OHCs) exposed to salicylate in vitro. Isolated OHCs from the chinchilla cochlea were exposed to salicylate with or without pretreatment with dexamethasone. Images were stored and analyzed on the Image program. The OHCs exposed to salicylate demonstrated a significant shortening in cell length. The OHCs exposed to salicylate after pretreatment with dexamethasone exhibited no significant change in cell length. We conclude that corticosteroid treatment of isolated OHCs is effective in blocking the morphological changes induced by salicylate. This study gives additional evidence that salicylate ototoxicity is mediated by alteration in the levels of arachidonic acid metabolites.

Proteomic analysis of vestibular schwannoma: conflicting role of apoptosis on the pathophysiology of sporadic vestibular schwannoma.

Hypothesis In this study, we investigated the pathophysiology and mechanism underlying sporadic forms of vestibular schwannoma (VS) by comparing VS tissue with normal nerve tissue using proteomics. Background Proteomic analysis by two-dimensional electrophoresis and matrix-assisted laser desorption and ionization time-of-flight mass spectrometry facilitates identification and characterization of specific proteins related to the pathogenesis of various diseases. Methods Proteins were extracted from two vestibular nerve specimens and two VS specimens and analyzed in parallel using two-dimensional electrophoresis. We then analyzed 29 spots that were differentially expressed using matrix-assisted laser desorption and ionization time-of-flight mass spectrometry. Upregulated proteins associated with apoptosis were confirmed by Western blot analysis and immunohistochemistry. Results Twenty-nine proteins showing significant changes in the expression level between VS tissue and normal nerve tissue were identified. Of these, seven proteins were related to apoptosis. Conclusion Our findings indicate that apoptosis is associated in a complex manner with the pathophysiology of VS. The suppression of apoptosis is presumably involved in tumor occurrence and, conversely, increased apoptotic expression may contribute to the slow tumor growth rate and may be correlated with the Antoni type B area.

Benign Paroxysmal Positional Vertigo Is More Commonly Associated with Orthostatic Dizziness than Orthostatic Hypotension

Objectives: Orthostatic dizziness (OD) and positional dizziness (PD) are very common conditions in dizziness clinics, but those two conditions are not clearly separated. We aimed to evaluate the clinical significance of simple OD and OD combined with PD for the diagnosis of benign paroxysmal positional vertigo (BPPV) and orthostatic intolerance (OI). Methods: Patients presenting with OD (n = 102) were divided into two groups according to their symptoms: group PO, presenting with PD as well as OD; group O, presenting with OD. A thorough medical history, physical examination, and vestibular function tests were performed to identify the etiology of the dizziness. Orthostatic vital sign measurement (OVSM) was used to diagnose OI. Results: The majority of patients were in group PO (87.3%). BPPV was the most common cause of OD for all patients (36.3%) and group PO (37.1%), while OI was most common etiology for group O (38.5%). A total of 17 (16.7%) OI patients were identified by OVSM test. Orthostatic hypotension (n = 10) was most frequently found, followed by orthostatic hypertension (n=5), and orthostatic tachycardia (n = 2). Group O showed significantly higher percentage (38.5%) of OI than group PO (13.5%) (P = 0.039). Conclusions: It is suggested that orthostatic testing such as OVSM or HUTT should be performed as an initial work-up for patients with simple OD. Positional tests for BPPV should be considered as an essential diagnostic test for patients with OD, even though their dizziness is not associated with PD.

Effect of platelet activating factor with and without receptor antagonist (WEB2170) on morphology of isolated cochlear outer hair cells.

Platelet activating factor (PAF), generated from biologically active phospholipids, has been implicated as a potent inflammatory mediator and has been shown to be involved in many pathological processes, especially in inflammation and allergy. It has been suspected that PAF may be one of the inflammatory mediators in middle ear effusion that can induce sensorineural hearing loss, as observed in chronic otitis media. The PAF receptor antagonist WEB2170 has been studied extensively, and its inhibitory effects against various PAF actions are well proven in otologic systems. The purpose of our study was to determine the effect of superfusion of PAF and WEB2170 on morphological changes in isolated cochlear outer hair cells (OHCs). Isolated OHCs from adult chinchilla cochleas were exposed to albumin-phosphate-buffered saline solution (1 mg/mL), WEB2170 (5 mg/30 mL), PAF (1 μmol/L), or both PAF (1 μmol/L) and WEB2170 (5 mg/30 mL). All experiments were performed at an osmolality of 305 ± 5 mOsm at room temperature for 30 minutes. The cells were observed with an inverted microscope; the images were stored and analyzed on the Image Pro-Plus program. The OHCs exposed to control albumin-phosphate-buffered saline solution or to WEB2170 did not show any significant change in cell shape or length. The cells exposed to 1 μmol/L of PAF showed ballooning and significant shortening of the mean cell length in 15 to 20 minutes. These morphological changes in OHCs can be prevented by pretreating OHCs with WEB2170. This study demonstrated that exposure to PAF causes morphological changes in isolated OHCs that can be prevented by the PAF receptor antagonist WEB2170.