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, and
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," said sinusitis expert
Andrew Lane, who led the team that developed the
"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," said Lane, an associate professor at the Johns
Hopkins School of Medicine.
Lane cited smell and sinus tissue data from his
studies with mice, and he compared them to
other clinical data, when he introduced the
inflammation-induced anosmic mice to fellow experts on
July 22 during a presentation at the XV International
Symposium on Olfaction and Taste in San
"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," said 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
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-alpha, because of its many links to
sinusitis. TNF-alpha 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-alpha 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-alpha occurred in
the mouse, much as 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-alpha
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
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 stopped completely after six. When
tissue was viewed under a 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," Lane said. "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."
The research 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
Future studies are 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, Lane 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 Johns
Hopkins, was provided by the National
Institute on Deafness and Other Communication Disorders, a
member of the National Institutes of
In addition to Lane, Johns Hopkins researchers
involved in this study were Justin Turner,
Lindsey May and Randall Reed.