Inflammatory mediators and immunocompetent cells in the middle ear with particular regards to otitis media and tympanosclerosis
Author: Forséni Flodin, Marie
Date: 2000-06-15
Location: Aulan, Karolinska sjukhuset
Time: 9.00
Department: Institutionen för klinisk neurovetenskap / Department of Clinical Neuroscience
Abstract
Tympanosclerosis is a well known sequela after acute and chronic otitis
media. The pathologically calcified plaques are most commonly found in
the tympanic membrane and if located only at this site, it is termed
myringosclerosis. Other localizations where it can be found are the
epitympanon, the promontory and sometimes the middle ear ossicles are
involved leading to hearing impairment. The only treatment for these
patients is surgery but recurrencies are common and there is also a risk
for iatrogenic sensorineural hearing loss associated with this kind of
surgery. Hearing aids, thus, are then beneficial. It may be of great
interest if predictable factors could be found to prevent pathological
calcification. Earlier, tympanosclerosis has been investigated although
usually not with immunohistochemical methods which gives a new
possibility of a more exact identification of the cell types and the
mediators involved in the early stages of the process.
A rat model was used in order to illuminate the inflammatory response
after inoculation of a solution of Streptococcus pneumoniae into the
middle ear. The rats developed acute otitis media and the tympanic
membranes presented with sclerotic plaques in 30% of the inoculated
animals. Different methods for fixation, decalcification and embedding
were tested in order to find the best method for immunohistochemical
staining of this fragile tissue and to identify macrophages, T-cells,
B-cells, inducible nitric oxide synthase and interleukin-6 at different
timepoints after inoculation of bacteria. A new immunohistochemical
staining technique was developed, the free-floating technique. mRNA in
situ hybridization was used to show the timepoint for expression of
interleukin-6 mRNA.
Results indicated that macrophages and T-cells were found mostly in the
acute phase of the inflammatory process, three days postinoculation in
the rat middle ear. B-cells were seen to a low extent but found to be
most frequent at day six postinoculation. Inducible nitric oxide synthase
was seen at the same time and in the same pattern as the macrophages,
probably due to the fact that activated macrophages present inducible
nitric oxide synthase. Interleukin-6 was shown with immunohistochemical
technique from one hour postinoculation persisting throughout the study,
lasting until day five postinoculation. Expression of interleukin-6 mRNA
was seen at the earliest timepoint of sacrifice, one day postinoculation
but not thereafter.
Biopsies from two groups of patients, children with secretory otitis
media, a disease known to result in myringosclerosis and tympanosclerosis
in a high percentage, and patients with already established
tympanosclerosis associated with chronic otitis media, were analyzed with
immunohistochemical technique. Antibodies against the same
immunocompetent cells and parameters as in the rat studies were used.
Macrophages were found in both patient groups. B-cells were most
frequently seen in the biopsies from children with secretory otitis media
as compared to the biopsies from patient with already established
tympanosclerosis. There was no indication of T-cells. All biopsies from
the tympanosclerotic middle ears but only one from the group of secretory
otitis media patients showed labeling of inducible nitric oxide synthase.
Interleukin-6 was seen most frequently in the secretory otitis media
biopsies but not as often in the tympanosclerosis material.
The above mentioned immunocompetent cells and the two parameters,
interleukin-6 and inducible nitric oxide synthase, could be involved in
an inflammatory sequence leading to the development of tympanosclerosis.
Morphologically, tympanosclerosis has the appearance of bone and it is
tempting to speculate that the pathological calcification can be seen as
being ectopic production of bone. There are studies supporting
involvement of macrophages differentiating into bone remodeling cells
upon cytokine stimulation, among one is interleukin-6. Inducible nitric
oxide synthases may also be involved, since it is known to be expressed
in activated macrophages as well as in boneproducing cells. Predictive
factors for tympanosclerosis development could be, among others,
macrophages, T-cells, B-cells, interleukin-6 and inducible nitric oxide
synthase.
List of papers:
I. Forséni M, Eriksson A, Bagger-Sjöbäck D, Nilsson J, Hultcrantz M (1997). "Development of tympanosclerosis: can predicting factors be identified? " Am J Otol 18(3): 298-303
Pubmed
II. Forséni M, Hansson GK, Bagger-Sjöbäck D, Hultcrantz M (1999). "Infiltration of immunocompetent cells in the middle ear during acute otitis media: a temporal study" Am J Otol 20(2): 152-157
Pubmed
III. Forséni M, Hansson GK, Bagger-Sjöbäck D, Hultcrantz M (1999). "An immunohistochemical study of inducible nitric oxide synthase in the rat middle ear, with reference to tympanosclerosis" Acta Otolaryngol 119(5): 577-582
Pubmed
IV. Forséni M, Melhus Å, Ryan AF, Bagger-Sjöbäck D, Hultcrantz M (2000). "Detection and localization of interleukin-6 in the rat middle ear during experimental acute otitis media, using mRNA in situ hybridization and immunohistochemistry" (Submitted)
V. Forséni M, Bagger-Sjöbäck D, Hultcrantz M (2000). "A study of inflammatory mediators in human tympanosclerotic middle ear" Arch Otolaryngol Head Neck Surg (Submitted)
I. Forséni M, Eriksson A, Bagger-Sjöbäck D, Nilsson J, Hultcrantz M (1997). "Development of tympanosclerosis: can predicting factors be identified? " Am J Otol 18(3): 298-303
Pubmed
II. Forséni M, Hansson GK, Bagger-Sjöbäck D, Hultcrantz M (1999). "Infiltration of immunocompetent cells in the middle ear during acute otitis media: a temporal study" Am J Otol 20(2): 152-157
Pubmed
III. Forséni M, Hansson GK, Bagger-Sjöbäck D, Hultcrantz M (1999). "An immunohistochemical study of inducible nitric oxide synthase in the rat middle ear, with reference to tympanosclerosis" Acta Otolaryngol 119(5): 577-582
Pubmed
IV. Forséni M, Melhus Å, Ryan AF, Bagger-Sjöbäck D, Hultcrantz M (2000). "Detection and localization of interleukin-6 in the rat middle ear during experimental acute otitis media, using mRNA in situ hybridization and immunohistochemistry" (Submitted)
V. Forséni M, Bagger-Sjöbäck D, Hultcrantz M (2000). "A study of inflammatory mediators in human tympanosclerotic middle ear" Arch Otolaryngol Head Neck Surg (Submitted)
Issue date: 2000-05-25
Publication year: 2000
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