Studies into the Pathogenesis of Human Interstitial Cystitis
(Funded by NIH RO1 DK44820-01)
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These investigations involves the role of
inflammatory cells
(particularly mast cells) and neuro-immune regulation of
inflammatory mediators in the genesis of interstitial cystitis
(IC).
The disease is an infliction of young and elderly females in
which
the etiologic agent and pathogenesis are poorly understood.
The quality of life of an affected individual is reported to be
worse than patients with end-stage renal failure with respect
to pain, urgency and ability to work. The estimated number of
diagnosed patients is 44,000 in the U.S. but only one in five
seeks
treatment or is recognized clinically. The expected annual cost
for
medical care and lost job time is $428 million per year for
these
44,000 patients that are recognized. Because of increasing
clinical
awareness of this disorder there have been concerted attempts to
find an appropriate small animal model to study its
pathogenesis.
Our team has described the pathology associated with detrusor
muscle infiltration by mast cells in interstitial cystitis (IC).
Detrusor mastocytosis in IC is associated with fibrosis, smooth
muscle fragmentation and proliferation of unmyelinated C-type
nerve fibers. Furthermore, ultrastructural studies provided
evidence
for chronic mast cell degranulation and associated nerve cell
injury
in IC. This evidence implicates detrusor mastocytosis and nerve
fiber proliferation in the pathogenesis of IC. Our studies have
helped to morphologically as well as experimentally characterize
this previously poorly understood condition. More importantly,
we have developed a clinical algorithm for the diagnosis of IC
that
employs quantitative image analysis and morphometry (QIAM) of
histochemically detected mast cells and immunohistochemically
detected nerve fibers to specifically diagnosis this disorder.
A prospective clinical trial is underway to further substantiate
our findings. We also recently have discovered that c-kit, the
glycoprotein receptor of the c-kit protooncogene, and SCF
(Stem Cell Factor or the Kit Ligand) are overexpressed in
bladders with IC when compared to controls. C-kit is present
in mast cells from both IC and controls but no other cell types.
SCF was also strongly expressed on nerve fibers in IC.
In control bladders the intensity of SCF was notably decreased
in the nerve fibers when compared to IC. SCF was also
expressed by smooth muscle cells of the detrusor muscle
and arterioles. Since SCF has been implicated as a potent
chemotactic and secretory regulator for mast cells our
findings suggest that nerve fibers may the promote detrusor
mastocytosis and chronic degranulation observed in interstitial
cystitis. Since mouse models with a mutant c-kit receptor
(white spotted mouse) and SCF ligand (Steel mouse) exist,
studying the role of nerve fibers in the modulation of detrusor
mastocytosis are planned. Further studies to characterize the
role of c-kit and SCF in human IC are currently underway and
should provide important clues into the pathogenesis of IC. |
