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Chronic Bacterial Rhinosinusitis
Description of a Mouse Model
Abraham Jacob, MD;
Brian T. Faddis, PhD;
Richard A. Chole, MD, PhD
Arch Otolaryngol Head Neck Surg. 2001;127:657-664.
ABSTRACT
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Objectives To survey normal murine sinonasal anatomy and to create a mouse model
for chronic bacterial rhinosinusitis.
Design Anatomic, histologic, and pathophysiologic study displaying normal murine
sinonasal anatomy and surgically created unilateral sinonasal inflammation.
Subjects Twenty-one 6-week-old, male C57BL/6 mice.
Interventions Animals that underwent unilateral maxillary sinus ostial obstruction
using Merocel nasal packing, animals with unilateral Bacteroides
fragilis inoculation alone, and animals with both ostial obstruction
and bacterial inoculation were examined at 4 weeks for histologic evidence
of chronic sinonasal inflammation. Experimental interventions were compared
with contralateral control sinuses within each animal and with normal and
sham-operated controls.
Results Normal mouse paranasal sinuses include maxillary sinuses, ethmoid air
cells, and respiratory-type epithelium. In experimental animals, the lateral
maxillary sinus wall, nasal septum, and superior turbinelle of the maxillary
sinus were examined histologically. Epithelial thickening and disarray, goblet
cell hyperplasia, inflammatory infiltrates, and sinonasal fibrosis were present
in the experimental sinuses of animals packed with Merocel alone or Merocel
with bacterial inoculation. Changes seen with Merocel and bacteria were more
dramatic than those with Merocel alone. Sham-operated controls and sinuses
inoculated with bacteria alone did not differ significantly from the sinuses
of normal animals.
Conclusion Unilateral maxillary sinus ostial obstruction using Merocel nasal packing
along with B fragilis inoculation results in a persistent,
localized bacterial rhinosinusitis in mice.
INTRODUCTION
RHINOSINUSITIS affects more than 10% of the US population and is the
reason for approximately 12 million physician office visits annually. The
number of antibiotics prescribed and sinus surgical procedures performed have
increased significantly during the past decade.1
Sinus disease is divided clinically into acute (symptoms persisting
for less than 2 weeks), subacute (symptoms persisting for more than 2 weeks
but less than 3 months), and chronic (symptoms persisting for more than 3
months without return to baseline) based on the duration of disease.2 Patients with chronic sinusitis experience nasal obstruction,
rhinorrhea, postnasal discharge, headache, facial pain and pressure, and a
chronic cough. Obstruction to sinus drainage, immune dysregulation, and mucociliary
dysfunction result in mucosal disruption, hypersecretion, and a chronic infection.3 Given the obvious clinical significance of rhinosinusitis,
a systematic study of the pathogenesis and treatment of sinusitis is clearly
indicated. Without a good animal model, investigation into the basic molecular
mechanisms and pathophysiology of the disease is lacking. Important questions
remain about the mediation of this localized inflammatory response, histologic
changes, and potential therapeutic modulation.
Animal experiments in the study of sinus disease date back to the early
20th century.4, 5, 6, 7, 8
A variety of interventions have been attempted in dogs, cats, rabbits, and,
more recently, mice. Hilding4 pioneered the
development of a rabbit model for sinusitis, which subsequently became the
dominant tool with which researchers studied mucosal blood flow, lactic acid
accumulation, mucosubstance histochemistry, cellular histomorphology, local
and systemic humoral immune response, polyposis, and responses to a variety
of therapeutic measures.9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24
Although the rabbit model was helpful in simulating human disease, the relative
lack of experimental reagents and an inherent inability to manipulate these
animals genetically have made the transition to murine research necessary.1 To our knowledge, no mouse model for chronic bacterial
rhinosinusitis exists at this time. Although there are differences in sinus
anatomy between humans and mice, the mouse possesses clearly discernible nasal
cavities, maxillary sinuses, and ethmoidal air cells. At the histologic level,
the nasal and sinus epithelia are of a respiratory type. We intend to briefly
describe relevant normal mouse sinonasal anatomy and report a quantifiable
model of chronic murine rhinosinusitis.
MATERIALS AND METHODS
STUDY GROUPS
Six normal, 6-week-old, male C57BL/6 mice were used to define the relevant
normal anatomy of the murine sinonasal cavity. Then, in creating the rhinosinusitis
model, 15 six-week-old, male C57BL/6 mice (Jackson Laboratory, Bar Harbor,
Me) were used as follows: 2 normal controls without intervention, 2 sham-operated
controls, 3 animals with ostial obstruction alone using Merocel nasal packing
(Xomed Surgical Products, Jacksonville, Fla), 3 animals implanted with Merocel
plus 106 colony-forming units (CFU)/mL of Bacteroides
fragilis, 3 animals implanted with Merocel plus 108 CFU/mL
of B fragilis, and 2 animals without ostial obstruction
inoculated with 108 CFU/mL of B fragilis.
All mice were shipped directly from the Jackson Laboratory to the Animal Barrier
Facility at Washington University School of Medicine in St Louis, Mo. Bacteroides fragilis suspended in isotonic sodium chloride
solution at concentrations of 106 and 108 CFU/mL were
obtained from the Department of Microbiology, Barnes-Jewish Hospital/Washington
University School of Medicine. Merocel nasal sponge served as the obstructive
implant.
SURGICAL PROCEDURES
All procedures were performed in strict accordance with Animal Studies
Committee guidelines at the Washington University School of Medicine.
The surgical procedure was done under the operating microscope using
otologic microinstrumentation. After achieving a surgical plane of anesthesia
(80 mg/kg of ketamine hydrochloride with 15 mg/kg of xylazine hydrochloride,
intraperitoneal injection), a 5-mm midline incision was made over the nasal
dorsum from interocular plane to snout. Two-millimeter skin flaps were raised
laterally, and a dental microdrill was used to shave a 3-mm bony trough over
the right nasal cavity. A scalpel blade (No. 11 Bard-Parker; Becton-Dickinson,
Hancock, NY) was then used to enter this nasal cavity unilaterally. Bleeding
was carefully blotted away to prevent aspiration, and Merocel alone, bacteria
alone, or Merocel plus bacteria were inserted meticulously using otologic
picks and 27-gauge needles. A single drop of bacterial suspension from a standard
pipette was sufficient to saturate the sponge during insertion. The Merocel
sponge was placed in the middle third of the sinonasal cavity approximating
roughly 2 to 3 mm of the total anterior-posterior length (Figure 1 and Figure 2). The sham-operated controls had their right nasal cavity opened from above
in a similar manner. However, no Merocel was inserted in this group. Skin
flaps were reapproximated with 6-0 polypropylene sutures, and the anesthetic
reversed throughout 2 hours. Once awake and active, the animals were returned
to the rodent care facility. The duration of each surgical procedure ranged
from 10 to 15 minutes.
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Figure 1. Normal murine sinonasal anatomy.
Coronal 1.0-µm sections at 1-mm intervals demonstrate a maxillary sinus
persisting roughly 4 mm. Ethmoid air spaces develop posteriorly. MS indicates
maxillary sinus; ST, superior turbinelle; IT, inferior turbinelle; and NC,
nasal cavity (toluidine blue/basic fuchsin).
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Figure 2. Diagram of the lateral nasal wall
displaying the superior and inferior turbinelles, ethmoid spaces, snout, and
cranial cavity. The region of Merocel placement, roughly 2 to 3 mm of total
anterior-posterior length, is delineated. Numbers 1 through 6 correspond to
sections in Figure 1.
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Four weeks postoperatively, a euthanasia dose (200 mg/kg) of pentobarbital
was administered via intraperitoneal injection. The thoracic cavity was opened,
and intracardiac perfusion fixation was accomplished with 4% paraformaldehyde
and 0.05% glutaraldehyde in phosphate buffer. The animal was decapitated,
skin and soft tissues of the head were removed, and the mandible was excised.
A coronal cut was made 1 mm posterior to the eyes using a razor blade. In
this manner, the eyes and maxilla (including the sinonasal cavity) were isolated
for tissue processing.
HISTOLOGIC ANALYSIS
The tissues were immersed overnight in the same fixative at 4°C.
They were decalcified in buffered 0.35-mol/L tetrasodium EDTA solution at
4°C during 1 week and decanted daily. Tissues were then rinsed in phosphate-buffered
saline, dehydrated through a graded series of acetone, and embedded in an
Epon-araldite mixture. In the normal animals, sequential 1.0-µm sections
were taken in the coronal plane at 250-µm intervals. The animals' snout
and the anterior margin of the interocular plane defined the limits of sectioning.
These were stained with toluidine blue and basic fuchsin. For the sinusitis
experiment, the sinonasal cavity was divided into thirds, and 1-µm sections
(at 50- to 75-µm intervals) were taken from the middle segment. This
segment consistently contained the implanted Merocel, maxillary sinus, and
ostium. Five representative sections within this area were chosen at random
from each animal for analysis.
QUANTIFICATION
Anatomical observations were based on sequential sections through the
paranasal sinuses (Figure 1). For
the sinusitis experiment, the principal areas of analysis were in the middle
third of the sinonasal cavity (Figure 2).
The locations used for tissue morphometry include the lateral maxillary sinus
wall, nasal septum, and inner margin of the superior maxillary sinus turbinelle
(Figure 3). Epithelial thickness
and area and goblet cell number were quantified, whereas the presence or absence
of a luminal or submucosal mononuclear infiltrate, epithelial denudation or
disarray, and sinonasal fibrosis was evaluated qualitatively (Figure 4). Having experimental and contralateral unoperated-on control
sinuses within the same animal, within-animal and intergroup comparisons were
made.
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Figure 3. Normal murine sinonasal anatomy.
The lateral maxillary sinus wall, nasal septum, and superior turbinelle of
the maxillary sinus were used for histologic analysis and quantitation of
the sinonasal inflammatory response (toluidine blue/basic fuchsin).
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Figure 4. Characteristic histologic changes
in chronic bacterial rhinosinusitis: luminal and submucosal inflammatory infiltrate,
epithelial thickening or derangement, goblet cell hyperplasia, and sinonasal
fibrosis (toluidine blue/basic fuchsin).
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Given the presence or absence of Merocel within each section, image
analysis could not be done in a blinded fashion. Quantitative histologic analysis
was carried out as follows. Using SigmaScan Pro image analysis software (SPSS
Science Inc, Chicago, Ill), area measurements were traced directly on the
computer from digitally captured images. Once standardized to 1-mm distance
along the basement membrane, these measurements correlated directly with average
epithelial thickness. Goblet cell counts were then standardized to the same
1-mm distance. These were morphologically identified at x500 magnification
by their pale cytoplasm, shape, and characteristic nuclei. No special stains
were used. Qualitative histologic analysis based on a plus or minus scale
denoted the presence or absence of luminal or submucosal infiltrates, epithelial
disarray or sloughing, and presence of either luminal or submucosal fibrosis.
The experimental right-sided sinonasal cavity was compared with the contralateral
control within each section. Images were evaluated at x50, x125,
x250, and x500 magnifications from 5 sections chosen at random
from each intervention group.
All histologic figures presented herein were digitally captured, converted
to gray scale, and placed on white backgrounds in Adobe Photoshop 4.0 (Adobe
Systems Inc, San Jose, Calif). Figures were subsequently organized in Corel
Draw 7 (Corel, Ontario).
STATISTICAL ANALYSIS
All statistical analyses for quantitative histologic analysis were performed
using SigmaStat (SPSS Science Inc) statistical software. Within-animal comparisons
were evaluated with the 2-tailed t test, whereas
comparisons across interventions were evaluated using a 1-way analysis of
variance. Five data points from the middle third of each animal's sinonasal
cavity were used at the following locations: the lateral sinus wall, the nasal
septum, and the superior turbinelle. Data were pooled within each intervention
group, and means and SEs were calculated to make comparisons. For all comparisons, 
= .05. Mean data, SE bars, and P values are presented
in Figure 5, Figure 6, and Figure 7.
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Figure 5. Within-animal comparisons of mean
goblet cell number by intervention. P values  .05
are shown. 1 indicates left lateral wall; 2, right lateral wall; 3, left septum;
4, right septum; 5, left superior turbinelle; 6, right superior turbinelle;
and B fragilis, Bacteroides fragilis. Error bars
are SEs.
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Figure 6. Mean (SE) number of goblet cells
and epithelial thickness by treatment. 1 indicates normal controls; 2, sham-operated
controls; 3, Merocel only; 4, Merocel plus 106 colony-forming units
(CFU)/mL of Bacteroides fragilis; 5, 108 CFU/mL of B fragilis only; and 6, Merocel plus 108 CFU/mL
of B fragilis. Corresponding statistical data appear
in the Table 1.
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Figure 7. Within-animal comparisons of average
epithelial thickness by intervention. Area measures correlate with average
epithelial thickness. Statistically significant P
values are displayed. 1 indicates left lateral wall; 2, right lateral wall;
3, left septum; 4, right septum; 5, left superior turbinelle; 6, right superior
turbinelle; B fragilis, Bacteroides fragilis; and CFU, colony-forming units. Error bars are SEs.
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One-Way Analysis of Variance Across Interventions*
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RESULTS
NORMAL ANATOMY OF THE MOUSE SINUS
Anatomical studies revealed that a rudimentary maxillary sinus is present
within 1 mm of the cartilaginous snout and persists for approximately 4 mm.
A slitlike ostium is present throughout its course. About 1 mm anterior to
the interocular plane, ethmoid air spaces appear to develop bilaterally. The
epithelial lining of the maxillary sinus and superior turbinelle ranges from
cuboidal anteriorly to pseudostratified columnar more posteriorly. Goblet
cells with characteristic morphologic features appear to be present in greater
numbers posteriorly.
GOBLET CELL HYPERPLASIA AND METAPLASIA
Comparing experimental to contralateral control sinuses, the experimental
sinuses of animals with both Merocel placement and either 106 or
108 CFU/mL of B fragilis inoculation demonstrated
significantly increased goblet cell numbers (Figure 5). Increases were also observed in animals implanted with
Merocel alone and those inoculated with bacteria alone. Within-animal comparisons
showed no significant differences between experimental and control sinuses
in normal or sham-operated controls.
Comparisons of goblet cell number by intervention are displayed in Figure 6. Animals having undergone Merocel
placement and either 106 or 108 CFU/mL of B fragilis inoculation demonstrated significant increases in goblet
cell numbers at all locations when compared with normal or sham-operated controls
(Table 1). In addition, animals
with both Merocel placement and 106 CFU/mL of B fragilis inoculation displayed goblet cell hyperplasia at all locations
when compared with animals with Merocel placement alone. Animals with Merocel
placement plus 108 CFU/mL of B fragilis
inoculation displayed significant increases at the lateral wall and septum.
There were no differences between Merocel-only and bacteria-only animals vs
normal or sham-operated controls. Counts did not differ significantly between
normal controls and sham-operated controls.
EPITHELIAL THICKENING
Within-animal comparisons revealed statistically significant epithelial
thickening in the experimental sinuses of animals with Merocel placement and
106 CFU/mL of B fragilis inoculation,
Merocel placement with 108 CFU/mL of B fragilis inoculation, and Merocel placement alone (Figure 7). No statistically significant epithelial thickening was
found in intra-animal comparisons of normal controls, sham-operated controls,
or animals inoculated with bacteria alone.
Compared with the experimental sinuses of normal or sham-operated controls,
Merocel placement alone or Merocel placement with either 106 or
108 CFU/mL of B fragilis inoculation resulted
in statistically significant epithelial thickening at all locations analyzed
(Figure 6 and Table 1). Compared with Merocel alone, Merocel plus bacteria at
either concentration resulted in more dramatic epithelial thickening at the
lateral sinus wall and nasal septum. There were no differences between normal
controls, sham-operated controls, and animals inoculated with bacteria alone.
INFLAMMATORY INFILTRATE, EPITHELIAL DISARRAY, AND SINONASAL FIBROSIS
Animals with Merocel placement and 106 CFU/mL of B fragilis inoculation, Merocel placement with 108 CFU/mL
of B fragilis inoculation, and Merocel placement
alone displayed clear evidence of luminal or submucosal inflammatory infiltrates,
epithelial disarray, and fibrosis within their sinonasal cavities. Normal
controls, sham-operated controls, and bacteria-only animals did not. Representative
visual findings are demonstrated in Figure
4 and Figure 8. The changes
were dramatic.
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Figure 8. Comparison of experimental and
control sinuses within the same animal. Chronic right-sided rhinosinusitis
induced by foreign body ostial obstruction and Bacteroides
fragilis inoculation (toluidine blue).
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COMMENT
Unilateral maxillary sinus ostial obstruction with Merocel nasal packing
and B fragilis inoculation at either 106
or 108 CFU/mL resulted in a persistent, localized bacterial rhinosinusitis
in mice. With limited operative time and minimal morbidity and mortality,
histologic changes characteristic of chronic sinonasal disease were present
4 weeks after intervention. A 4-week end point was chosen to demonstrate the
chronicity of disease. A combination of quantitative and qualitative histology
focused on epithelial thickening, goblet cell changes, presence of a luminal
or submucosal inflammatory infiltrate, epithelial disarray, and sinonasal
fibrosis in the murine sinonasal cavity. Within-animal comparisons demonstrated
epithelial thickening and goblet cell hyperplasia in the experimental sinuses
of animals with Merocel only and Merocel plus bacteria. Epithelial disarray,
inflammatory infiltrates, and sinonasal fibrosis were present in these groups
as well. Comparison across interventions qualified these findings by noting
that changes seen with Merocel plus bacteria were more severe than those with
Merocel alone. No such changes were noted in normal controls, sham-operated
controls, or animals with bacterial inoculation alone. This represents the
first described murine model of chronic bacterial rhinosinusitis. There were
no operative mortalities within the present study group, and animal caregivers
did not report any evidence of postoperative suffering or behavioral dysfunction.
Merocel is used clinically in the control of epistaxis. A patient seen
in the emergency department may have this material inserted into his or her
nasal cavity if bleeding is diffuse and discrete sources cannot be identified
and cauterized. At our institution, the Merocel is then left in place for
3 days and patients are prescribed antibiotics during that time. If the Merocel
is left in longer, these patients often develop sinusitis on the obstructed
side. This is only one example of clinical sinusitis arising from foreign
body obstruction of the maxillary sinus ostium in humans. Another is the use
of nasogastric tubes. Patients intubated with nasogastric tubes often have
fluid in their maxillary sinuses. In fact, this is a frequent reason for otolaryngology
consultation at our institution. Most texts define rhinosinusitis as mucosal
and/or luminal inflammation in the sinonasal cavities. "Chronic" sinusitis
is further defined by duration of disease. To that extent, we believe that
epithelial thickening and disarray, luminal or submucosal inflammation, increased
goblet cell counts, and sinonasal fibrosis in our murine model qualify under
that definition.
Both the quantitative and qualitative findings presented herein were
dramatic. Therefore, quantitation required relatively few animals to discern
statistically significant differences. Qualitative analysis used straightforward
plus or minus designations. We believe that stratified scales (1+ to 4+) added
rather than reduced subjectivity in assessment and were therefore abandoned.
Although it would have been ideal to quantify the area of cellular infiltration,
fibrosis, and epithelial sloughing, we believe that tissue processing (decalcification,
dehydration, infiltration, and embedding) made such quantitation of luminal
findings suspect. Although it seemed unlikely that all such findings would
be washed away, it was certainly reasonable that some portion of it may be.
The plus or minus designation, indicating the presence or absence of findings,
was thought to be the most truthful representation of the data.
Although the rabbit model has dominated the scientific literature for
the past 5 decades, research at the molecular and genetic levels requires
a transition to murine models. Genetic knockouts and transgenic mice have
revolutionized animal research. Mice are pathogen free, demonstrate minimal
antigen priming, and have minimal sibling genetic variability. Cost and care
issues are simple. The ethics of animal experimentation oblige us to use the
least sophisticated animal species possible when gathering scientifically
relevant data.
To our knowledge, there is only one article in the literature on murine
bacterial rhinosinusitis. Using an inhalation technique with pneumococcal
suspensions, researchers successfully created an acute sinusitis in mice.1 An inflammatory response was noted by day 2, peaking
at day 5, and subsiding by day 14 to normal levels. Although the investigators
argued that recurrent acute attacks of sinusitis may progress to chronic disease,
their model was unable to sustain the sinonasal inflammatory response. We
have drawn on the osteomeatal hypothesis of human disease to solve this problem.
In humans, obstruction of the sinonasal osteomeatal complex and infection
are thought to impair sinus drainage, reduce ventilation, and generate an
acute inflammatory response.2 With persistent
obstruction to drainage, the body fails to clear the infection and chronic
sinusitis deveops. By providing both the infecting organism (B fragilis) and the obstruction to drainage (Merocel sponge), our localized
inflammatory response persisted for at least 4 weeks. Bacteroides
fragilis was used based on rabbit studies indicating that it exerted
a more prolonged inflammatory response than did pneumococcus.24
Furthermore, anaerobes are recovered frequently in human patients with protracted
sinus disease.25 Given that the anaerobic infection
itself may contribute to the chronicity of the disease, it was a reasonable
choice.
Clinical data on chronic sinusitis are abundant, but there is little
information on the disease at its molecular and genetic levels. Human studies
are limited by genetic and environmental variability, an inability to control
the specificity of intervention, small sample sizes, limits in surgical specimens,
and a lack of normal and internal controls. Murine research in this area could
be the foundation for a more thorough understanding of this unique inflammatory
process.
AUTHOR INFORMATION
Accepted for publication November 14, 2000.
This study was supported by an Institutional Training Grant (5T32DC0002213)
to the Department of Otolaryngology–Head and Neck Surgery at the Washington
University School of Medicine and grant DC00263 (Dr Chole).
Presented at the 2000 Midwinter Meeting of the Association for Research
in Otolaryngology, St Petersburg, Fla, February 23, 2000.
From the Department of Otolaryngology–Head and Neck Surgery,
Washington University School of Medicine, St Louis, Mo.
Corresponding author and reprints: Abraham Jacob, MD, Department
of Otolaryngology–Head and Neck Surgery, Washington University School
of Medicine, 660 S Euclid, Campus Box 8115, St Louis, MO 63110 (e-mail: Entsurgn{at}cs.com).
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