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Vancouver,
BC--A new model that shows what is happening within an inflamed
sebaceous follicle has been developed at the University of Michigan,
and could lead to new acne treatments, said Sewon Kang, MD, at Dermatology
Update 2004.
Dr. Kang and colleagues, Drs. Gary J. Fisher and John J. Voorhees,
are known for their work on the physiology of photoaging. This led
them to an interest in how inflammation drives the dermal matrix
degradation that leads to acne scars.
"Actually, the two (photoaging and acne) can be viewed alike
with respect to signaling cascades that may be involved. So our
work began with this model," said Dr. Kang, professor and director
of clinical dermatology, University of Michigan, Ann Arbor.
Signaling
cascade
Dr. Kang presented in vivo data showing a transcription factor called
NF-kB to be activated in inflammatory acne. Once activated, NF-kB
moves from the cytoplasm to the nucleus where it affects gene transcription.
Inflammatory cytokines driven by this transcription factor are then
induced, and circulating cells (mostly neutrophils) move to the
inflammation site.
The inflammatory cytokines can now amplify the signaling pathways
that activate the AP-1 transcription factor, thus, AP-1 regulated
genes-MMP 1, 3 and 9-are induced. Dr. Kang's group has proven that
the MMP 1, 3 and 9 proteins are elevated in inflamed sebaceous follicles
and that they degrade the matrix.
"If the imperfection occurs long enough and with enough severity,
we predict acne scarring," he said.
Impact on
new drugs
"We need to expand our concept of how existing drugs work,"
Dr. Kang said.
For example, it is well known that retinoids act as an
anti-AP-1 agent.
Some retinoids can downregulate toll-like receptors, which are key
regulators of host responses to infection. Tetracycline might knock
out bacteria, but it has no anti-MMP activity.
"In the future, drugs that target things we didn't think about
before might be reasonable."
Based on the University of Michigan model, toll-like receptors,
NF-kB, AP-1 and MMPs are all rational targets for future drugs,
he said. DTC
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