Biology Reference
In-Depth Information
The use of SLPI to treat SCI may be fast-tracked as it has received orphan
drug status by the FDA for the treatment of cystic fibrosis and genetic
emphysema.
4.4. Phospholipase A
2
PLA
2
enzymes and downstream pathways play a role in a variety of inflam-
matory conditions. PLA
2
s hydrolyze membrane phospholipids at the
sn
-2
position to release a free fatty acid and generate a lysophospholipid. If the
fatty acid released is arachidonic acid, it can produce a variety of prostaglan-
dins and leukotrienes via cyclooxygenase-1 and 2 (COX-1 and 2) and
lipooxygenase enzymes, respectively. If the phospholipid is phosphatidyl-
choline, then the lysophospholipid released by the actions of PLA
2
will give
rise to LPC (also known as lysolecithin), a potent demyelinating agent. We
reported that LPC can induce rapid demyelination in the spinal cord within
4 days (
Ousman & David, 2000, 2001
). There are about 20 mammalian
forms of PLA
2
, which have different specificities, activation conditions,
intracellular or extracellular localization, and tissue distribution. There are
also about two dozen downstream bioactive metabolites of PLA
2
.
Therefore, PLA
2
s, the various downstream enzymes, and the metabolites
they produce comprise a major pathway controlling a wide variety of
inflammatory responses. In addition to proinflammatory mediators, this
pathway can also generate proresolution mediators that play a role in the
naturally occurring resolution of inflammation (
Serhan et al., 2008
). We
will focus here on our recent work on the expression and role of
different members of the PLA
2
superfamily in SCI.
There are two classes of PLA
2
—secreted (sPLA
2
) and intracellular. The lat-
ter include calcium-dependent (cPLA
2
) and calcium-independent (iPLA
2
)
forms. The former require micromolar concentrations of calcium and are
activated upon phosphorylation. These enzymes play a role inmembrane turn-
over and host defense (
Brown, Chambers, & Doody, 2003; Murakami,
Nakatani, Atsumi, Inoue, & Kudo, 1997
). We found increase in expression
at the mRNA and protein level after SCI in only 3 of the 14 PLA
2
s
examined (
Lopez-Vales et al., 2011
). These include sPLA
2
group IIA
(sPLA
2
GIIA), cPLA
2
GIVA and iPLA
2
GVIA, which showed differences in
the time-duration after injury when they are expressed, and differences in
the cell types that express them. The expression of sPLA
2
GIIA was detected
during the first week after spinal cord contusion injury in mice (mainly
between 3 and 7 days). The activated phosphorylated form of cPLA
2
GIVA,
