Prostaglandins, leukotrienes, and other arachidonic acid metabolites in the pathogenesis of otitis media.

Among the various inflammatory mediators of otitis media (OM), metabolites of arachidonic acid (AA) such as prostaglandins (PGs) and leukotrienes (LTs) appear to play an important role in the pathogenesis of otitis media. In an effort to investigate the role of AA metabolites on the pathogenesis of otitis media, concentrations of AA metabolites were measured in middle ear effusion (MEE) from human and paralleling animal models of otitis media and the effects of inhibitors of AA metabolism, antibiotics, and tympanostomy tube (TT) on the outcome of animal models of OM were studied. Concentrations of AA metabolites in MEE were higher in the younger age group. Levels of PGE2 and LTB4 in MEE seem to represent the degree of inflammation of OM best. Lipoxygenase products seem to be associated with the mucoid type of MEE. In the study of animal models of OM, combined models and ears with TT showed more inflammation than single models and ears without TT. Study of the therapeutic use of inhibitors of AA metabolism, penicillin, and TT showed that lipoxygenase products may be more important in the pathogenesis of OM than the cyclo-oxygenase products, and that the use of a combination of penicillin and corticosteroid produces the best results. It is clear from these studies that arachidonic acid metabolites are important inflammatory mediators in the pathogenesis of otitis media.

Experience with tympanoplasty for atelectatic ears.

Atelectasis is, unfortunately, still a common sequela of otitis media with effusion (OME)--including serous otitis media (SOM) and mucoid otitis media (MOM). When atelectatic ears provide a functional deficit, i.e., a conductive loss of sufficient magnitude or a residual conductive loss after aerating the middle ear with ventilation tube or early or strongly suspected attic cholesteatoma, a simple corrective procedure has been used which has stood the test of time. The procedure as well as experience with 51 patients (60 ears) will be described and discussed. The procedure consists of re-establishing the mesotympanic space, strengthening the tympanic membrane by an underplant fascial graft, cutting the tensor tympani, extirpation of any disease, re-establishment of ossicular mobility and continuity and the insertion of a ventilation tube in the anterior drumhead remnants along with silicone rubber sheeting and a moist Gelfilm implant. Methods and results are discussed.

Subepithelial space in otitis media.

The role of the subepithelial space (SES) has not received sufficient attention in assessing pathogenesis, pathology, and therefore, clinical diagnosis and treatment of the various forms of otitis media (OM). Temporal bones from patients with OM were classified as cases of acute purulent (POM), serous (SOM), mucoid or secretory (MOM), or chronic otitis media (COM). Controlled morphometric studies were made of cellular components of the SES, along with studies of the epithelium and middle ear space. Corollary studies of biochemistry, cellular components, and prostaglandins (PGs) were done on fluid from the human middle ear. Middle ear effusions (MEE) from animal models of SOM, MOM, and POM were analyzed biochemically. Findings are surprising in that the SES was more actively involved in all forms of OM than had been thought, especially in MOM and COM. Implications are discussed.

Prostaglandins in squamous cell carcinoma of the head and neck: a preliminary study.

It has already been demonstrated in human and animal systems that PGE2 is a suppressor signal for many immune functions. These include T-lymphocyte blastogenesis, natural killer cell activity, and cytolytic T-lymphocyte activity. These functions are important for destruction of tumor cells. Conceivably, suppression of these functions by excessive PGE2 restricts tumor cell kill, and reversal of suppression by an inhibitor of prostaglandin synthesis such as indomethacin could increase tumor cell kill. The purpose of this study was to determine the kind of prostaglandins (PGs) produced by tissues with squamous cell carcinoma of head and neck and to measure the concentrations of PGE2, 6-keto-PGF1 alpha, and thromboxane (Tx) B2 in the tumor tissue and in the corresponding control tissue. Tumor and normal control tissues at the margin of the resection were obtained from surgical specimens. The production of PGs was determined by incubation of tissue homogenates with 14C-arachidonic acid, by thin layer chromatography, autoradiography, and scintillation counting. Concentrations of PGs were measured by radioimmunoassay. Tumor tissues produced PGD2, E2, TxB2, F2 alpha, and 6-keto-F1 alpha, and 15-, 12-, and 5-monohydroxyeicosatetraenoic acid (HETE). Concentrations of PGE2 were four times higher in the tumor tissues compared to those in control tissues. There was no difference between the levels of TxB2 and 6-keto-PGF1 alpha in the tumor tissues and those in control tissues. The results of this study will serve as basic information necessary for the potential use of inhibitors of PG-synthesis in the treatment of head and neck carcinoma.

Prostaglandins, leukotrienes, and other arachidonic acid metabolites in nasal polyps and nasal mucosa.

Prostaglandins (PGs) and leukotrienes (LTs) are known to play an important role in allergic inflammatory reactions. The triad of aspirin sensitivity, nasal polyposis, and asthma led us to suspect that PGs, LTs and other arachidonic acid metabolites may be involved in the pathogenesis of nasal polyps. The purpose of this study was to determine arachidonic acid metabolites and to measure concentrations of PGs and LTs in nasal polyps and nasal mucosa. Samples of nasal polyps and nasal mucosa were obtained at the time of polypectomies and nasal procedures. Metabolites of arachidonic acid in tissue were determined by incubation of tissue-homogenates with 14C-arachidonic acid and analyses with thin-layer chromatography and high performance liquid chromatography (HPLC). Levels of PGE2, 6-keto-PGF1 alpha, thromboxane (Tx)B2, 15-hydroxyeicosatetraenoic acid (HETE), LTC4, LTB4 were measured by radioimmunoassay. The predominant arachidonic acid metabolite in both nasal polyps and mucosa with 15-HETE. The HPLC analysis showed that the predominant metabolite in nasal polyp was 15-HETE, especially in polyps from aspirin sensitive patients. Levels of 15-HETE and PGE2 were higher in polyps from patients with a history of allergy than from nonallergic patients. Levels of LTC4 and LTB4 in nasal polyps were determined. The findings of this study will help to explain biochemical basis of the pathogenesis of aspirin-sensitive nasal polyps and to develop better medical treatment for them.

Determination of ototoxicity of common otic drops using isolated cochlear outer hair cells.

OBJECTIVES: Otic drops are commonly used not only for otitis externa, but also for otorrhea in the presence of tympanostomy tubes or tympanic membrane perforations. Many studies have demonstrated the ototoxicity of common otic preparations such as Cortisporin otic drops (Monarch Pharmaceuticals, Bristol, TN). The purpose of this study was to assess the relative ototoxicity of common otic preparations by direct exposure to isolated cochlear outer hair cells (OHCs). METHODS: OHCs from adult chinchilla cochlea were exposed to standard bathing solution (control), acetic acid, Acetasol HC (Alpharma USPD Inc., Baltimore, MD), Gentacidin (CIBA Vision Ophthalmics, Atlanta, GA), and Tobradex (Alcon, Fort Worth, TX). The cells were observed using an inverted microscope, and the images were recorded in digital still-frame and video, and analyzed on the Image Pro-Plus 3.0 program (Media Cybernetics, Silver Spring, MD). RESULTS AND CONCLUSIONS: As measured by time to cell death and change in morphology of OHCs, acetic acid with or without hydrocortisone was most toxic to OHCs. Cortisporin was more cytotoxic than gentamicin and Tobradex.

Effect of tumor necrosis factor-alpha on experimental otitis media with effusion.

OBJECTIVES/HYPOTHESIS: Up to the present, many reports have demonstrated that local immune response is associated with maintenance and persistence of effusion in the middle ear cavity. Resulting retention of inflammatory cells and mediators in the middle ear results in ongoing effusion. The purpose of this study was to clarify the role of tumor necrosis factor in experimental otitis media with effusion, which was induced by transtympanic injection of tumor necrosis factor in the rats. STUDY DESIGN: Four groups were designed in two experiments. The purpose of experiment 1 was to confirm that transtympanic injection of TNF-alpha produces the middle ear effusion. In experiment 2, TNFsolRI was used to evaluate the possibility as an inhibitor in otitis media with effusion. METHODS: The histopathological changes were observed under light microscope, and the changes in microvascular permeability were examined using Evans blue vital dye technique. RESULTS: Middle ear effusion was developed in 70% of specimens, and histopathological changes, such as subepithelial edema and marked infiltration of neutrophils, were present in 100% at 24 hours after administration of tumor necrosis factor-alpha through transtympanic approach. Extravasation of Evans blue dye was found in all specimens injected by tumor necrosis factor-alpha, which was qualified using a fluorescence microscope and quantified using a spectrophotometer. These histopathological findings and changes in microvascular permeability were significantly reduced by tumor necrosis factor soluble receptor type I. CONCLUSIONS: Neutrophil infiltration, subepithelial edema, increased microvascular permeability, and resultant effusion were indirectly proved to be induced by tumor necrosis factor-alpha. We hope that this study may contribute to understanding the role of tumor necrosis factor-alpha in otitis media with effusion and clarifying the future role of tumor necrosis factor soluble receptor type I in preventing otitis media with effusion.

Primary and secondary tumors of the facial nerve. A temporal bone study.

Of 1400 temporal bones in the collection at the University of Minnesota, Minneapolis, 17 temporal bones from 15 patients were found to have tumors involving the facial nerve. The findings were as follows: one case of facial nerve schwannoma; two cases of invasion of the facial nerve by contiguous tumor; and 14 cases of metastatic tumors involving the facial nerve. Facial nerve paralysis was present in half of the cases (nine of 17). Facial nerve paralysis was present in the case of facial nerve schwannoma, in both cases of invasion of the facial nerve by contiguous tumor, and in six of 14 cases of metastatic tumors involving the facial nerve. The presence of the facial nerve paralysis correlated well with the degree of tumor infiltration into the nerve fibers and the segment of the tumor involvement in the facial nerve. In the patients with metastatic tumors, facial nerve paralysis was a sign of extensive intracranial tumor involvement and was usually accompanied by other cranial nerve palsies, most commonly involving the fifth nerve.

Intact-bridge tympanomastoidectomy.

In recent years closed-cavity (intact wall) tympanomastoidectomy has been described and recommended by many. The pendulum now is swinging back to open-cavity tympanomastoidectomy. The literature in this regard is reviewed. In all patients with chronic otitis media and mastoiditis with intractable tissue pathology, the primary objective is total eradication of disease with a dry, safe ear; a concomitant but secondary objective is hearing retention and restoration with tympanoplasty techniques. Over a 3-year period we have used a one-stage procedure called intact-bridge tympanomastoidectomy (IBM) that fulfills the desirable objectives of both open- and closed-cavity tympanomastoidectomy. The salient features include good exposure as in open-cavity tympanomastoidectomy, maintenance and widening of the middle ear space by bony bridge retention and facial buttress sculpturing to enhance grafting and ossiculoplasty such as TORP or PORP as in canal-up tympanomastoidectomy, and enhancement of mastoid obliteration for large cavities by blocking the aditus with bone paté or cartilage and by providing a separation between middle ear and mastoid. Specific methods, techniques, and results will be presented and discussed.

Arachidonic acid metabolites in experimental otitis media and effects of anti-inflammatory drugs.

Previous studies have shown that arachidonic acid (AA) metabolites are important in the pathogenesis of otitis media with effusion. The AA metabolites in 4 different experimental models for otitis media were analyzed, and the effect of anti-inflammatory drugs was studied. Purulent otitis media was induced in rats by inoculation of Streptococcus pneumoniae in the tympanic bulla, serous otitis media by blocking the tympanal orifice of the eustachian tube, and mucoid otitis media by combining the two procedures. Middle ear effusion was also induced by stimulating the external auditory canal with cold air. Indomethacin and hydrocortisone were used to inhibit AA metabolism in the latter model. Lipoxygenase products dominated in the purulent and cold air otitis media models. Cyclooxygenase products dominated in the mucoid and serous models. Indomethacin inhibited accumulation of middle ear effusion in the cold air otitis media model, whereas hydrocortisone did not. Apart from AA metabolites, other mechanisms and mediators appear to be responsible for the increased vessel permeability observed in the cold air otitis media model, such as interactions between mast cells and nerves in the middle ear mucosa.

Experimental otitis media with effusion induced by platelet activating factor.

This study tested the hypothesis that platelet activating factor (PAF) in the middle ear can induce otitis media with effusion (OME) and that PAF antagonists can prevent PAF-induced OME. An initial trial of 16 micrograms of PAF was injected into chinchilla bullae, and all ears developed middle ear effusion (MEE) within 48 hours. Subsequent trials were performed to test dose dependency. Interestingly, 1 or 16 micrograms of PAF caused more MEE and inflammation than did 4 or 8 micrograms. A dose of 0.5 micrograms PAF did not cause MEE. Middle ear effusion from injected bullae contained the full spectrum of lipoxygenase and cyclooxygenase products; additionally, more PAF was detected than was injected. Finally, a PAF antagonist (WEB 2170) injected intraperitoneally prevented PAF-induced OME. This study demonstrates that PAF injected into the middle ear can induce OME and that PAF antagonists effectively prevent PAF-induced OME. These findings suggest that PAF plays an important role in the pathogenesis of OME.

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 micrograms 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.

Effect of platelet activating factor and its antagonist on the mucociliary clearance of the eustachian tube in guinea pigs.

The purpose of this study was to test whether platelet activating factor (PAF) impairs the mucociliary clearance function of the eustachian tube (ET) in a dose-dependent manner and whether PAF antagonist can prevent the impairment of mucociliary function of the ET induced by PAF. Coomassie brilliant blue dye transport time (DTT) in normal guinea pigs was 69 seconds. The DTTs after the application of normal saline and PAF at I and 2 microg/mL into bullae were 66, 74, and 157 seconds. The time was over 15 minutes when 4, 8, and 16 microg/mL of PAF were applied. The DTT was 62 seconds when the animals were pretreated with PAF antagonist (WEB 2170). There were significant delays of the DTTs after treatment with 2, 4, 8, and 16 microg/mL of PAF. Histopathologic examination of ETs from groups with a significant delay in DTTs showed intact cilia, mucous plugs, increased inflammatory cells, and exfoliation of cells. This study demonstrated that PAF impaired the mucociliary clearance function of the ET in a dose-dependent manner. This impairment of mucociliary clearance function was prevented by pretreatment with PAF antagonist. The findings of the study suggest that PAF plays an important role in the pathogenesis of otitis media with effusion by impairing the ET clearance function.

Effect of inhibitor of tumor necrosis factor-alpha on experimental otitis media with effusion.

Tumor necrosis factor (TNF)-alpha is important in the pathogenesis of otitis media with effusion (OME). The purpose of this study was to determine the effect of TNF-alpha 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-alpha 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-alpha 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.

Effect of the radioprotector WR2721 on irradiation-induced injury to ciliated cells of eustachian tube.

Our previous studies revealed that injury to the ciliated cells of the eustachian tube may be the primary cause of irradiation-induced serous otitis media. The purpose of this study was to investigate the effects of the radioprotector WR2721 on irradiation-induced injury to ciliated cells of the eustachian tube (ET) in chinchillas. Twelve chinchillas were divided into two groups: the control group and the experimental group, which was pretreated with a single intraperitoneal dose of the radioprotector S-2-[3-aminopropylamino]ethylphosphorothioic acid (WR2721) 400 mg/kg. The two groups were exposed to 30 Gy of 13-MeV electrons in a single fraction to the area of the bullae and nasopharynx. Ciliary dysfunction was tested and ciliated cells of the ET were examined by scanning and transmission electron microscopy. Pretreatment with WR2721 was found to protect ciliated cells of the ET from irradiation injury.

Otolaryngologic approach to the diagnosis and management of otitis media.

Otitis media is a common childhood disease caused by multiple factors. Understanding the pathogenesis of otitis media is important in the diagnosis and management of it. The mode of therapy should be chosen depending on the type and stage of the disease. Treatment options available to an otolaryngologist include antibiotics, tympanocentesis, myringotomy and tympanostomy tube insertions, adenoidectomy with or without tonsillectomy, exploratory tympanotomy, atympanoplasty, and mastoidectomy.

Classification of otitis media and surgical principles.

Otitis media is an important disease of children and adults and is caused by multiple interrelated factors, including infection, eustachian tube dysfunction, allergy, and barotrauma. This article includes a pertinent review of the literature regarding otitis media. The pathogenesis, classification, and treatment of otitis media in children and adults are also reviewed in this article. Additionally, therapy is discussed with emphasis on the surgical options appropriate at each stage.

Ototoxicity of salicylate, nonsteroidal antiinflammatory drugs, and quinine.

Salicylates and most NSAIDS in high doses cause mild to moderate temporary hearing loss, either flat or greater in the high frequencies. Hearing loss is accompanied by tinnitus and suprathreshold changes. Salicylates may or may not exacerbate hearing loss and cochlear damage induced by noise. The mechanism of salicylate ototoxicity seems to be multifactorial. Morphologic studies suggest that no permanent cochlear damage occurs with salicylate ototoxicity. Electrophysiologic, morphologic, and in vitro data conclusively demonstrate that salicylate affects outer hair cells. In addition, salicylates appear to decrease cochlear blood flow. Salicylates and NSAIDs inhibit PG-forming cyclooxygenase, and recent studies suggest that abnormal levels of arachidonic acid metabolites consisting of decreased PGs and increased LTs may mediate salicylate ototoxicity. As with salicylate, quinine ototoxicity appears to be multifactorial in origin. The mechanism includes vasoconstriction and decreases in cochlear blood flow, as measured by laser Doppler flowmetry, motion photographic studies, and histologic studies. Reversible alterations of outer hair cells also appear to play an important role, as demonstrated by histology, electron microscopy, isolated hair cell studies, and cochlear potential evaluations. Unlike with salicylate, however, the role of prostaglandins in quinine ototoxicity has not been clearly demonstrated. Also, one of quinine's principal actions, antagonism of calcium-dependent potassium channels, has yet to be investigated for its potential role in ototoxicity.

Concentration of nitric oxide metabolites in middle ear effusion.

Free radicals such as nitric oxide (NO) seem to be important in the pathogenesis of otitis media with effusion (OME). NO can be quantitated by measuring its metabolites, nitrate (NO(3)(-)) and nitrite (NO(2)(-)). The purpose of this study is to determine the concentrations of NO in human middle ear effusion (MEE). Samples of human MEE were collected at the time of myringotomy and tympanostomy tube insertions. The type of MEE was classified as serous (SOM), mucoid (MOM) or purulent (POM) at the time of surgery. Samples of MEE were assayed for NO metabolites (nitrate and nitrite) with colorimetric assay (Griess method). Concentrations of NO metabolites were highest in MOM followed by SOM and POM. This study suggests that NO is present in human MEE and may play an important role in the pathogenesis of OME.