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KCa3.1-mediated effects on iNOS and proinflammatory cytokine produc-
tion and other Ca
2
รพ
-mediated effects.
4.3. Secretory leukocyte protease inhibitor
The classic model of wound healing in the skin has many of the hallmarks as
that observed after SCI (
Stadelmann, Digenis, & Tobin, 1998
): an inflam-
matory phase where the sequential infiltration of immune cells contributes
to the clearance of tissue debris; the proliferative phase where new blood
vessels are formed; and the remodeling phase where cells no longer needed
are removed by phagocytosis and collagen/epithelia are laid down forming
the scar tissue. This complex process is controlled by various mediators, both
pro- and anti-inflammatory as well as those involved in the resolution of
inflammation. These phases normally progress in a timely manner but if they
do not, the result is a chronic wound (
Nwomeh, Yager, & Cohen, 1998
),
which might also contribute to the ongoing secondary damage in the injured
spinal cord. This analogy brought our attention to SLPI, a 12-kD serine pro-
tease inhibitor involved in skin wound healing that is produced by activated
neutrophils and macrophages, and exerts an anti-inflammatory/resolving
effect (
Sallenave, 2010
). SLPI was also found to suppress the production of
proinflammatory mediators in LPS-stimulated macrophages (
Jin, Nathan,
Radzioch, & Ding, 1997; Zhang, DeWitt, McNeely, Wahl, & Wahl,
1997
). Mice deficient in SLPI show impaired skin wound healing while
exogenous application of recombinant SLPI (rSLPI) enhanced repair
(
Ashcroft et al., 2000
). Further, treatment with exogenous rSLPI reduced
inflammation and tissue damage in models of arthritis (
Song et al., 1999
)
and lung inflammation (
Lentsch et al., 1999; Stolk, Rudolphus, & Kramps,
1991
), and adenoviral expression in the CNS reduced lesion size after
cerebral ischemia (
Wang et al., 2003
). We therefore studied whether SLPI
could have a beneficial role in SCI (
Ghasemlou, Bouhy, et al., 2010
).
SLPI expression in the injured spinal cord mirrored closely the changes
seen in the skin after injury: protein levels peak early (3-7 days) after injury
and are found primarily in cells that will form the scar tissue (suprabasal epi-
dermal cells in the skin and astrocytes in the spinal cord). Some inflammatory
cells are also immunopositive for SLPI, although we observed little if any
staining in macrophages in the lesion core. Astrocytes surrounding the lesion
core had the most intense immunoreactivity (
Fig. 5.3
), suggesting that they
might play a role in dampening proinflammatory cytokine expression. We
then used two different methods to assess the role of SLPI in SCI. Transgenic
