'Stuffy Nose' Mouse: A Promise To Help Treat 31 Million With Sinusitis
- From: rpautrey2 <rpautrey2@xxxxxxxxx>
- Date: Fri, 25 Jul 2008 09:01:08 -0700 (PDT)
'Stuffy Nose' Mouse: A Promise To Help Treat 31 Million With Sinusitis
Andrew Lane, M.D., with a 'stuffy nose' mouse. (Credit: Image courtesy
of Johns Hopkins Medical Institutions)ScienceDaily (July 23, 2008) —
Mice with inflamed nasal tissue being tested at a Johns Hopkins
laboratory may be unable to tell if something smells bad or good, but
their sensory deficit is nothing to turn up a nose at.
That is because, their developers say, the mice's reversible loss of
one of their key senses, which is essential to tasting food or sensing
danger from foul odors, sets them apart from all other mice and binds
them to an estimated 31 million Americans living with chronic
sinusitis, a persistent inflammation of the tissue that lines the
nasal and sinus cavities. Add to this group, millions of people with
other disorders that affect smell, including viral infections, head
traumas, tumors, Alzheimer's and Parkinson's diseases.
"A sense of smell in good working order is essential to our quality of
life, and these genetically engineered mice give us the first real
animal model for better understanding, treating and preventing people
from suffering a loss of olfactory function due to sinonasal
inflammation," says sinusitis expert Andrew Lane, M.D., who led the
team that developed the olfactory-compromised mice.
"And because we can turn on and off the inflammation in these mice, we
really can mimic how the most overlooked and very disabling aspect of
sinusitis, the loss of smell, or anosmia, plays out in people," says
Lane, an associate professor at the Johns Hopkins University School of
Medicine.
Lane will cite smell and sinus tissue data from his studies with mice,
and he will compare them to other clinical data, when he introduces
the inflammation-induced, anosmic mice to fellow experts July 22
during a presentation at the XV International Symposium on Olfaction
and Taste, in San Francisco, Calif.
"Until now, the lack of realistic animal models for each of the key
symptoms of chronic inflammation in the nasal tissue - such as the
growth of nasal polyps, the loss of the sense of smell, swollen sinus
tissue, or clogged and runny noses - has slowed sinusitis research and
hindered our search for therapies," says Lane, director of the Johns
Hopkins sinus center, where he treats hundreds of patients with the
condition.
New therapies are needed, he says, as an alternative to long-term
steroids, which block the inflammatory chemical pathway but also have
debilitating side effects, including loss of bone density, cataracts
in the eye and weight gain.
Another key advantage to the new sinusitis mouse, he points out, is
that it can be more easily studied than human olfactory tissue, which
is surgically difficult to cut out from deep inside the skull and
because the tissue sits dangerously close to the brain.
Johns Hopkins scientists began their quest for a "stuffy nose" mouse
with inflammation-produced anosmia in 2002.
Their first steps were performed in the lab, where researchers
genetically modified developing mouse cells to breed a family that
could secrete key cytokine proteins only in the olfactory, uppermost
part of the nose. An overproduction of cytokines, which are better
known for their role in the body's immune response to disease-causing
pathogens, are a telltale chemical signature in sinusitis.
Lane's team focused its efforts on one of hundreds of cytokines,
specifically, tumor necrosis factor alpha, or TNF±, because of its
many links to sinusitis. TNF± is overactive during all kinds of
inflammation, and the chemical is also known to accelerate olfactory
nerve cell turnover. Unlike most other kinds of nervous tissue, the
olfactory type can grow back, an evolutionary adaptation to the
constant shedding of skin cells that line the nasal cavity.
Researchers first injected mouse egg cells with a gene for TNF± and a
control system so that cells with the gene would secrete the cytokine
on demand and only if activated.
In a second set of mice, Lane's team planned to activate the control
system only in olfactory tissue, by genetically implanting the
controls to another gene, called CYP2G1, which is produced only in the
mouse nose, specifically in its nourishing sustentacular cells that
sit between nasal nerve cells.
Lane says the system had to be "nasally specific," so that secretion
of TNF± occurred in the mouse, much like it does in sinusitis in
humans.
After breeding the two groups of mice to get their animal test model,
of which there are 20 at any given time, scientists then turned on TNF
± production by stimulating the sustentacular cells with tetracycline,
an antibiotic trigger that was added to the mice's drinking water. The
system remained off when no tetracycline was added.
To make sure the model worked, mice were fed the drugged drinking
water for nearly two months, and samples of olfactory tissue were
tested weekly for any sense of smell in response to various odors.
Results showed that sense of smell, as gauged by minute electrical
currents in olfactory tissue, dropped progressively, by half (50
percent) within two weeks, and stopping completely after six. When
tissue was viewed under microscope, white blood cells were visible, a
telltale sign of inflammation. Olfactory nerve cells had nearly
disappeared.
But when researchers stopped the drug-induced sinusitis, olfactory
nerve cells rebounded and grew back within a couple of weeks, "proving
that what we have is a mouse with reversible olfactory loss due to
inflammation, which should speed up our learning more about the
disease and testing new therapies," says Lane. "Ultimately, we hope to
develop treatments that allow the sense of smell to recover, even in
the presence of a hostile inflammatory environment due to sinusitis."
His team's next steps will be to test different cytokines, either
alone or in combination, to clarify their roles in the loss of smell
in sinonasal inflammation.
Future studies are also planned to monitor the effects of current
steroid therapies on mouse olfactory tissue, in the hope of modifying
or bolstering the treatments and speeding up delivery of these
medications to inflamed tissue.
Another phase of research, he says, involves testing other anti-
inflammatory drugs, such as infliximab (Remicade), which is used to
treat arthritis, to see if they can spur growth of olfactory neurons
during sinusitis.
Lane also plans to add more sinusitis features to the animal model,
including progressive swelling of sinus tissue and rhinitis.
Funding for this study, conducted solely at Hopkins, was provided by
the National Institute on Deafness and Other Communication Disorders,
a member of the National Institutes of Health.
Besides Lane, other Hopkins researchers involved in this study were
Justin Turner, M.D.; Lindsey May, B.S.; and Randall Reed, Ph.D.
--------------------------------------------------------------------------------
Adapted from materials provided by Johns Hopkins Medical Institutions.
Johns Hopkins Medical Institutions (2008, July 23). 'Stuffy Nose'
Mouse: A Promise To Help Treat 31 Million With Sinusitis.
ScienceDaily. Retrieved July 25, 2008, from
http://www.sciencedaily.com; /releases/2008/07/080722225342.htm
.
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