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.
Pathogenesis of otitis media was studied in humans and various animal models primarily from a pathological and chemical point of view. Findings were correlated and interpreted for various forms of otitis media in longitudinal and parallel studies, including acute purulent otitis media (POM), serous otitis media (SOM), mucoid or secretory otitis media (MOM), and chronic suppurative otitis media (COM), especially as regards the continuum or interrelated changes of various groups. Purulent otitis media was produced in chinchillas by direct inoculation of less than 100 pneumococci into the middle ear space. Serous otitis media was produced in chinchillas and cats following Eustachian tube obstruction with silicone. Mucoid otitis media followed the development of SOM in cats after two to four weeks of tubal occlusion. Samples of middle ear effusion (MEE) and serum, obtained from children with SOM and MOM after myringotomy for ventilation tube placement, were evaluated. The three components studied were MEE, epithelium and the subepithelial space (SES). Inflammatory changes in the SES were significant for all forms of otitis media, but especially for POM and SOM. Epithelial metaplasia to secretory cells was most prominent in MOM. Chemical factors involved in pathogenesis and defense were studied. Lactic dehydrogenase and lysozyme, chemical indicators of inflammatory activity, were greater in POM and MOM than in SOM. Immunoglobulins (A, G, & M) were greater in MOM than in SOM. The similarity of findings between the groups suggests a strong relationship between them. The ability of certain types of otitis media to evolve into another substantiates the concept of the continuum for some patients. Pathogenesis is dependent upon various extrinsic factors of etiopathogenesis, while the form that otitis media takes seems to rely mostly on relative activity of the SES and the epithelium.
Objective Otitis media is the most commonly diagnosed disease in ambulatory care and Streptococcus pneumoniae continues to be the most common bacterial agent. Bacterial resistance to antibiotics underscores the need for better vaccines. Current pneumococcal conjugate vaccines are modestly protective against otitis media; however, limited serotype coverage and serotype replacement have led to the investigation of pneumococcal proteins as potential vaccine candidates. Two proteins, pneumococcal surface proteins A (PspA) and C (PspC) are important virulence factors, expressed by virtually all strains. Although a number of pneumococcal proteins have been investigated in other infection sites, these proteins can have diverse organ-specific effects. In this study, we investigated the viability and virulence of single (PspA– and PspC–) and double (PspA–/PspC–) mutants of pneumococcal PspA and PspC proteins in the chinchilla middle ear. Methods Bullae of 24 chinchillas were inoculated with 0.5 ml of 106 colony forming units (CFUs)/ml bacteria: 6 with wild-type D39 strain; 6 with PspA–; 6 with PspC–; and 6 with PspA–/PspC– isogenic mutant strains. Bacterial CFU levels in middle ear effusions and light microscopic analysis of the number of inflammatory cells in the round window membrane (RWM) were compared 48 hours after inoculation. Results At 48 hours, CFUs in middle ears were increased for wild-type and PspC– strains compared to inoculum levels; however, they were significantly less for the group inoculated with the PspC– strain compared to wild-type strain. No bacteria were detected in the PspA– and PspA–/PspC– groups. The number of inflammatory cells in the RWM was significantly higher in wild-type compared to the PspA–, PspC–, and PspA–/PspC– groups. No significant difference in number of inflammatory cells was observed between any pairs of groups inoculated with mutant strains. Conclusion Viability and virulence of the PspC– strain were similar to the wild-type strain. The single PspA– and double PspA– /PspC– mutants were highly attenuated in the ear. Bacterial clearance of the PspA– /PspC– double mutant was indistinguishable from that of the PspA mutant. These studies provide no reason to exclude PspC from a multi-component protein vaccine containing PspA.
To determine whether mutants of Streptococcus pneumoniae that are deficient in pneumococcal surface protein A (PspA), pneumococcal surface antigen A (PsaA), or pneumolysin (Ply) are less virulent and less likely to penetrate the round window membrane (RWM). Design: Histopathologic comparison of wild-type S pneumoniae and its mutants deficient in PspA, PsaA, and Ply.
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