The anti-inflammatory effect of fusafungine during experimentally induced rhinosinusitis in the rabbit.

The short-term effects of local intranasal administration of fusafungine were studied for its anti-inflammatory and antimicrobial properties against experimentally induced bacterial rhinosinusitis. The maxillary sinuses of 20 rabbits were infected with encapsulated Streptococcus pneumoniae after mechanical occlusion of each animal's anatomic ostium. Either fusafungine solution or placebo was administered as a nasal spray through the nostrils twice daily for 10 days. Histopathological grading of inflammation, biochemical assay of inflammatory mediators, and the number of bacterial species isolated from the nasal cavities all showed significant recovery from inflammation after fusafungine treatment. The beneficial effects of fusafungine on inflamed sinus mucosa may possibly also be attributable to an initial alleviation of inflammation in the nasal cavity, which permitted entry of the drug to the sinus cavity through a partially reopened ostium. A reciprocal relationship between nasal and sinus reactivity involving generalization of inflammation and recovery was also thought to be of importance. The present findings indicate that local applications of fusafungine may effectively improve clinical conditions producing rhinitis and sinusitis.

Effects of surgery on mucosal pathologic changes following experimental sinusitis in rabbit.

In the present investigation, the regenerative capacity of the infected maxillary sinus mucosa following surgical procedures was studied in a rabbit model. Sinusitis was induced by occluding the ostium with and without the addition of Staphylococcus aureus or Bacteroides fragilis, or by provoking a prolonged bacterial infection with both pathogens. The surgical procedures performed were 1) widening of the natural sinus ostium (middle meatal antrostomy; MMA) and 2) removal of sinus mucosa without ostial interference (modified radical operation; MRO). The histologic features of the entire nose-sinus complex were studied, graded semiquantitatively, and compared with findings in untreated sinusitis, or after surgery only. Whereas MMA and MRO both led to a decrease of the inflammatory features of the sinus mucosa in induced sinusitis, persistent local histopathology was observed in the ostial region following MMA surgery. This indicates the importance of local pathologic changes resulting from interactions of bacterial colonization, inflammation, and surgery in chronic sinusitis.

Early stages in the development of goblet cells in the paranasal sinuses: a multimethodological study in the rabbit.

To evaluate the pattern of goblet cell differentiation in sinus mucosa in response to external stimuli, New Zealand White rabbits were subjected to either experimental sinusitis or topical capsalcin application. Sinus mucosa was examined by light microscopy after serial sectioning, whole-mount preparation or immunohistochemistry. The mucosa was also examined by electron microscopy after perfusion fixation or high-pressure freezing. While goblet cells were normally very scarce in the healthy rabbit maxillary sinus mucosa, such cells were frequent after experimental sinusitis or topical capsaicin application. The process of goblet cell differentiation seems to follow a sequential path where serous secretory cells start to produce an increasing amount of mucous granules which appear electron lucent after conventional fixation. Parallel to this shift in secretion production, the cell assumes a bulging appearance after conventional fixation. It is concluded that newly formed goblet cells are recruited from intermediate secretory cell stages rather than from ciliated cells.

Effect of systemic pretreatment with betamethasone on the bacterial flora, inflammatory response, and polyp formation in experimentally infected rabbit maxillary sinus mucosa.

To investigate possible effects of corticosteroids on polyp formation and local bacterial colonization, pneumococcal sinusitis was experimentally induced in rabbits pretreated with betamethasone or saline. After 7 days, macroscopic polyps were counted post-mortem and on histologic slides after serial sectioning. Histologic sections were also examined with light microscopy. Macroscopic polyps were significantly fewer in animals given betamethasone, while there was no difference regarding the number of microscopic polyps. Ingrowth of pathogenic microorganisms was found in five of eight rabbits given placebo but in none of the animals treated with corticosteroids (P < 0.05). The reduced number of pathogenic strains in these animals may be explained by a better-preserved local host defense. The lower number of macroscopic polyps in the same animals could be because of a delayed mucosal repair and subsequent polyp formation.

Recurrent primary pleomorphic adenomas of salivary gland origin: intrasurgical rupture, histopathologic features, and pseudopodia.

BACKGROUND: The rate of tumor recurrence after surgery for benign salivary gland pleomorphic adenoma varies considerably in different clinical settings and seems to depend to a great extent on the surgical technique used. The importance of tumor spillage for subsequent recurrence has recently been questioned. The current follow-up study was undertaken to ascertain whether intrasurgical rupture, tumor spillage, or any histopathologic feature might have had an impact on the rate of recurrence. METHODS: The medical records of all 255 patients operated on for benign salivary gland pleomorphic adenoma between the years 1974 and 1993 at the Department of Otorhinolaryngology, Huddinge University Hospital, were reviewed. All patients alive in April 1995 (n = 230) were sent a simple questionnaire. Two hundred thirteen of these patients received follow-up. All cases of tumor recurrence after surgery or intrasurgical rupture of the tumor capsule were reviewed histopathologically. RESULTS: Two (7.1%) of the 28 patients who had macroscopic capsule rupture during surgery experienced recurrence at a later stage. This was not a statistically higher rate than the 4.1% recurrence rate for the rest of the material. As many as 5 of the 9 primary tumors that subsequently recurred (56%) sent fingerlike tumor extensions or pseudopodia outside the pseudocapsule. The rate of occurrence of such structures was statistically higher than that of the tumors that ruptured during surgery (25%) and the examined uncomplicated cases (8%). CONCLUSIONS: Occurrence of pseudopodia--microscopic fingerlike formations of tumor tissue that extend beyond the main lump of the tumor--is a significant risk factor for local recurrence.

Expression of P-glycoprotein 170 in nasal mucosa may be increased with topical steroids.

The synthesis of P-glycoprotein 170 (P-gp), a "multidrug resistance" protein capable of extruding various drugs including 11-OH steroids from human cells, can be upregulated by certain glucocorticosteroids. This study demonstrates the presence of P-gp in the columnar surface epithelium and in glandular acini of healthy nasal mucosa with immunohistochemical technique. Furthermore, nasal polyps from 5 of 17 patients treated with clinical doses of a topical nasal steroid, budesonide, appear to show a stronger staining intensity for P-gp than polyps from 13 untreated patients. This suggests the possibility of local P-gp gene induction by topical glucocorticoid treatment. Upregulation of P-gp synthesis appears as a new possible cause of relative resistance to topical steroid medication in patients with nasal inflammatory disease.

Ciliary ultrastructure in experimental sinusitis.

Ultrastructure of respiratory cilia was observed in experimental sinusitis of rabbit maxillary sinuses. Sinus mucosa of 15 rabbits was inoculated with Streptococcus pneumonia bacteria and of 16 rabbits with Bacteroides fragilis bacteria. Specimens were taken during 12 weeks' observation time and they were studied by transmission electron microscopy from the cross-sections. A special emphasis was paid to the number of cilia, the ciliary orientation, the tubular anomalies, the presence of dynein arms and the compound cilia. It seems likely that pneumococcal sinusitis is a more toxic infection to the epithelium causing loss of ciliated cells and cilia than B. fragilis infection. In anaerobic infection ciliary ultrastructure remains normal and dynein arms as well as normal tubular ultrastructure were seen even after 12 weeks' infection.

Crystal containing membrane bound intracellular inclusion bodies in the epithelium of experimentally infected sinus mucosa.

The sinus mucosa of 16 rabbits was experimentally infected with Bacteroides fragilis. This paper describes and discusses large inclusion bodies, which were found in abundance by light and electron microscopy inside ciliated cells of the sinus epithelium in 3 of the studied animals. The spindle-shaped inclusions were located in the apical portion of the cytoplasm. They were bound by a trilaminar membrane with several coils to the interior as well as to the exterior. The interior of an inclusion body consisted to a large extent of electron-lucent, floccular substance, but fibrogranular aggregates and rod-shaped crystals with a line periodicity center-to-center of about 15 nm were also conspicuous. These peculiar formations may be constituted by abnormally stored material from defective synthesis of cilia.

A 13-year report on childhood sinusitis: clinical presentations, predisposing factors and possible means of prevention.

Two hundred and nineteen children with sinusitis treated as in-patients at Huddinge University Hospital during the period 1980-1992 have been reviewed. Epidemiological data, the clinical picture, treatment and complications are described. The prevalence of significant predisposing conditions (such as upper airway allergy, asthma, and immunoglobulin deficiency) has been estimated. Serious sinusitis complications are few, surgery is only rarely required, and previously-recognized important predisposing paediatric conditions are not significantly more common than in the general juvenile population. Improved medication and prevention may have reduced the incidence of serious sinus infections in risk groups today. Children with cystic fibrosis have been reviewed with regard to the necessity of both sinus and nasal polyp surgery. Aggressive medical therapy appears to have reduced their need for sinus surgery as well as polypectomy.

Zenker's diverticulum--a historical review and trends in therapy.

More than 200 years have passed since the pulsion diverticulum of hypopharynx was first described. This paper reviews different opinions on its etiology over the centuries. The German pathologist F.A. von Zenker, who successfully pursued research on a variety of topics, is often associated with this diverticulum through his classical work from 1867 "Krankheiten des Oesophagus", which deals with the pathogenesis and clinical presentations of this herniation of the posterior mucosal wall. Numerous surgical techniques, which have been practised mainly during this century, are also reviewed. Different options of endoscopic surgery, which is presently the preferred approach at many medical centers, are described and discussed. Our own experience of endoscopic surgery in patients with Zenker's diverticulum is also presented.

Experimentally induced polyps in the sinus mucosa: a structural analysis of the initial stages.

To document polyp formation in the sinus mucosa, the authors of this study subjected New Zealand white rabbits to different modes of manipulation intended to induce inflammation of the maxillary sinus. These manipulations included a combination of bacterial infection and mechanical trauma, the deposition of agarose into the sinus cavity, and the deposition of N-formyl-methionyl-leucyl-phenylalanine, a chemotactic peptide, into the sinus cavity. A majority of animals developed polyps, which were examined by light and electron microscopy. Polyp formation appears to involve epithelial disruption and the migration of immature branching epithelium. While part of the migrating epithelium eventually covers the mucosal defect, other branches spread into the underlying connective tissue, where intraepithelial microcavities with a differentiated, ciliated lining are formed. Fusing cavities separate the developing polyp body from the adjacent mucosa. With the described method, mucosal polyps can be induced with high reproducibility.

Microorganisms and leukocytes in purulent sinusitis: a symbiotic relationship in metabolism.

Since the exchange of gases, as well as metabolites, is greatly impeded in a paranasal sinus empyema, it is not unlikely that certain organic substances be retained and accumulated in purulent secretion. In this study, secretions aspirated from experimentally infected maxillary sinuses of 26 rabbits were analysed biochemically. Quantitatively, by far the most important acid accumulated in secretions was lactic acid. Lactate induces metabolic acidosis and exerts an inhibitory effect on mammalian defense mechanisms. Lactate may also be used as an energy source by certain microorganisms. In spite of its leukocytic origin lactic acid thus promotes the continuation of a bacterial infection. In addition, certain other organic acids of bacterial origin were found, which, in different ways, contribute to the impediment of antimicrobial defense functions.

The inflammatory response of the sinus and nasal mucosa during sinusitis: implications for research and therapy.

Since it is difficult to evaluate the state of an infected sinus mucosa by histopathology, much of the present knowledge of the morphology in sinusitis is based on animal experiments. When experimental sinusitis is induced in the rabbit, the inflammatory response in the nose appears to be more pronounced than that in the maxillary sinus. In the animal model, histological findings include epithelial desquamation, edema, goblet cell hyperplasia and, in severe cases, fibrosis, bone reaction and formation of polyps in the nose and in the antrum. These local pathological findings may persist in the nasal middle meatus and the paranasal sinuses for a considerable time and predispose the mucosa to recurrences of infection. By investigation with recently introduced advanced techniques such as magnetic resonance imaging (MRI), a protracted pathological state in the sinus mucosa can be recorded also in humans for months after an episode of acute sinusitis. Future human and experimental studies of the local inflammatory response and of the cellular pathology over time will yield further guidelines for improved therapy and prevention of acute sinusitis.

The efficacy of oxymetazoline administered with a nasal bellows container and combined with oral phenoxymethyl-penicillin in the treatment of acute maxillary sinusitis.

The efficacy of a new administration form of oxymetazoline, a nasal bellows container, was investigated in two separate studies by means of a combined treatment with phenoxymethyl-penicillin for acute maxillary sinusitis. In the first study (study 1), oxymetazoline administered with a bellows (OXBE) was compared both with a placebo belows (PLBE) as well as with oxymetazoline and placebo administered with a conventional nasal spray (OXSP respective PLSP) in 73 patients. In the second study (study 2), OXBE was compared only with PLBE in 48 patients. Objective evaluation was made by comparing the radiographical improvement in conventional plain sinus X-ray images. A scoring system corresponding to the outcome of antral irrigation was used for evaluating the X-ray pictures. Subjective symptoms; nasal stuffiness and pain, were assessed by registrations on visual analogue scales. Neither with regard to radiographical improvement nor to decrease in subjective symptoms could any significant differences be found between the different treatment modes. Oxymetazoline administered with a nasal bellows thus did not accelerate the rate of healing of acute maxillary sinusitis in these two studies. It is inferred from these results that decongestion of the sinus ostia is not of primary importance for the course of healing of a manifest acute sinusitis.

Formation of mucosal polyps in the nasal and maxillary sinus cavities by infection.

Unilateral maxillary sinusitis was experimentally induced in New Zealand White rabbits with Streptococcus pneumoniae serotype 3, Bacteroides fragilis NCTC 9343, and Staphylococcus aureus V8. In another group of rabbits, sinusitis was induced by blocking of the sinus ostium only. Bacteriologic and light microscopic analysis was performed after 5 days to 1 month. Granulation-like polyps developed after deep mucosal inflammatory trauma initiating fibroblast proliferation, angiogenesis, and epithelial migration to cover the polyp. In regions of a more superficial trauma-characterized by epithelial desquamation and fibroblast growth-proliferation and differentiation of basal cells resulted in the formation of microcavities dissecting off edematous polyps. Polyps could be found in all sinusitis groups, irrespective of inducing agent. The cellular events of polyp formation appear to be the result of a continuous inflammatory reaction and are not directly related to the presence of a certain microorganism. Instead, the potential of any microorganism to induce a deep mucosal trauma or epithelial desquamation seems essential for its ability to initiate polyp formation.

Mucosal fine structure in experimental sinusitis.

Rabbit maxillary sinuses were inoculated with Streptococcus pneumoniae and Bacteroides fragilis, and the histologic response in the sinus mucosa was observed over a 12-week period. An increased height of the cylindric cells and hyperplasia of the basal cells were frequent findings irrespective of the pathogen inoculated. The disease was found to influence the character of the secretory product from epithelial secretory cells and to degranulate the subepithelial glands. Ciliary loss was a transitional finding. A reduction in the number of mitochondria, the occurrence of deformed short microvilli, and cytoplasmic blebbing were seen in the cells devoid of normal cilia. It is inferred from this study that pneumococcal sinusitis in rabbits is a self-limiting process, and the mucosal sequelae of the acute infection are persisting goblet cells, slight focal fibrosis, and edema. Inoculation with B fragilis produces a chronic inflammatory process, with infiltration of mononuclear cells, luminal dilatation of the glands exhibiting zymogen granule depletion, and an increased thickness of the whole mucosal layer.

Pneumococcal antigens and serum antibody responses in experimentally induced sinusitis.

Maxillary sinusitis was induced in New Zealand White rabbits with Streptococcus pneumoniae serotype 3 and the serum antibody response was recorded by enzyme immunoassay. Activity of the three major immunoglobulin classes, viz. IgG, IgA and IgM, against the type-specific capsular polysaccharide, the cell wall C-polysaccharide as well as its subunit phosphorylcholine was analyzed. A pronounced increase in immunoglobulins reactive to the specific capsular antigen was observed throughout the study period, with the rise being particularly noticeable during the first 2 weeks. An increase in anti-C-polysaccharide antibodies was also evident, but no reaction to phosphorylcholine could be detected. Although the histological findings at 3 and 4 weeks varied in spite of similar serum antibody responses, a correlation appeared to exist between a more rapidly increasing anti-capsular IgG production and the prevalence of a purulent sinus secretion.

Lactic acid isomers and fatty acids in sinus secretion: a longitudinal study of bacterial and leukocyte metabolism in experimental sinusitis.

Concentrations of the two optic isomers of lactate (D- and L-form) as well as glucose, succinate, acetate, butyrate, isovalerate and valerate were examined in purulent sinus secretions. The samples were obtained from rabbit maxillary sinuses, experimentally infected with Streptococcus pneumoniae or Bacteroides fragilis. More soluble acids such as acetate displayed relatively low levels in the secretion, despite a high microbial production. A substantial increase in D-lactate concentration was found in secretions only the first day after induction of pneumococcal sinusitis, and not in bacteroides sinusitis. L-lactate levels were particularly high in secretions of a marked purulent character, and this isomer can be considered as indicator of anaerobic glycolysis in the leukocytes. Less diffusible fatty acids such as butyrate and isovalerate accumulated in the secretion, in spite of a relatively lower production rate, and are thus more reliable indicators of bacterial metabolism.

Experimental maxillary sinusitis induced by Bacteroides fragilis. A bacteriological and histological study in rabbits.

Experimental anaerobic maxillary sinusitis was induced in New Zealand White rabbits by blocking the ostium and inoculating Bacteroides fragilis, strain NCTC 9343. The animals were examined histologically and bacteriologically after 5 days, and 2, 3 and 4 weeks. All the infected sinuses displayed signs of moderate or severe inflammation throughout the study period. Ciliary damage and desquamation, hyperplasia and metaplasia of the epithelium were characteristic features. Furthermore, heavy leukocyte- and, particularly, round cell-infiltration, fibrosis, periosteal hyperplasia and bone degradation and -formation were also frequently encountered. The secretory cell count in the epithelium increased, including the regeneration of goblet cells. After 4 weeks no obvious recovery could be seen, and the inducing microorganism was re-isolated in the majority of cases. In comparison with experimental pneumococcal sinusitis, the B. fragilis infection exerts a more prolonged and severe inflammation.

Serum antibody response to Bacteroides fragilis in experimental sinusitis.

Maxillary sinusitis was induced in New Zealand white rabbits by local inoculation of 10(6) colony-forming units of Bacteroides fragilis NCTC 9343, and the serum IgG, IgA and IgM antibody responses to cell wall antigens were studied. Prior to inoculation, and one, two, three and four weeks after induction, serum samples were obtained and analysed for antibodies to the lipopolysaccharide and the capsular polysaccharide. Capsular polysaccharide from B. fragilis ATCC 23745 was used as control. The rise in IgG activity against NCTC 9343 capsular polysaccharide and lipopolysaccharide was most marked and sustained throughout the four weeks. The increases in IgA concentration were moderate and sometimes transient, and a more pronounced IgA increase was seen with IFA than with EIA. The IgM peak levels were weak and usually declined within two to three weeks. The development of antibody to the lipopolysaccharide was similar to that of the NCTC 9343 capsular polysaccharide antibodies, though somewhat delayed in time. No significant increase in antibody to the control capsular polysaccharide was seen.