DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Analogous to the eicosanoids, PAF is not stored in cells but
is synthesized in response to stimulation. The major pathway, termed
the remodeling pathway, of PAF generation involves the precursor
1-O-alkyl-2-acyl-glycerophosphocholine, a lipid found in high concentrations
in the membranes of many types of cells. The 2-acyl substituents
include AA. PAF is synthesized from this substrate in two
steps (Figure 33–5). The first involves the action of PLA 2
, the initiating
enzyme for eicosanoid biosynthesis, with the formation of
1-O-alkyl-2-lyso-glycerophosphocholine (lyso-PAF) and a free fatty
acid (usually AA) (Prescott et al., 2000; Honda et al., 2002; Stafforini
et al., 2003). Eicosanoid and PAF biosynthesis thus is closely coupled,
and deletion of cPLA 2
in mice leads to an almost complete loss
of both eicosanoid and PAF generation. The second, rate-limiting
step is performed by the acetyl-coenzyme-A-lyso-PAF acetyltransferase.
PAF synthesis also can occur de novo; a phosphocholine substituent
is transferred to alkyl acetyl glycerol by a distinct
lyso-glycerophosphate acetyl-coenzyme-A transferase. This pathway
may contribute to physiological levels of PAF for normal cellular
functions. The synthesis of PAF may be stimulated during
antigen–antibody reactions or by a variety of agents, including
chemotactic peptides, thrombin, collagen, and other autacoids; PAF
also can stimulate its own formation. Both the phospholipase and
acetyltransferase are Ca 2+ -dependent enzymes; thus, PAF synthesis
is regulated by the availability of Ca 2+ .
The inactivation of PAF is catalyzed by PAF acetylhydrolyases
(PAF-AHs) (McIntyre et al., 2009) (Figure 33–5). This is a family of
Lyso-PAF
H
2C
O R´
HO CH O
H
2C
PAF
Acetylhydrolase
1-O-alkyl-2-acyl-glycerophosphocholine
O H
2C
O R´
R C O CH O
STIMULUS
H
2C
O P Choline
O -
Acyl
transferase
O P
O - Choline
H 3 C
H 3 C C O-
C
O
O
O
R C
H
2C
O CH
H
2C
O - H 3 C
O
CoA
O R´
O
O P Choline
O -
PAF
PLA 2
Lyso-PAF
H O R´
2C
HO CH O
H O P Choline
2C
O-
C CoA
Lyso-PAF
Acetyltransferase
Figure 33–5. Synthesis and degradation of platelet-activating
factor (PAF). RCOO – is a mixture of fatty acids but is enriched
in arachidonic acid that may be metabolized to eicosanoids.
CoA, coenzyme A.
four related Ca 2+ -independent phospholipases A 2
that show marked
specificity for phospholipids with short acyl chains at the sn-2 position.
Two PAF-AHs, which are group VII enzymes, are commonly known
as plasma PAF-AH (or lipoprotein-associated PLA 2
) and liver type II
PAF-AH. The remaining two are known as type I and II intracellular
PAF-AH. PAF is inactivated by PAF-AH-catalyzed hydrolysis of the
acetyl group, generating Lyso-PAF, which is then converted to a 1-Oalkyl-2-acyl-glycerophosphocholine
by an acyltransferase.
PAF is synthesized by platelets, neutrophils, monocytes, mast
cells, eosinophils, renal mesangial cells, renal medullary cells, and
vascular endothelial cells. Depending on cell type, PAF can either
remain cell associated or be secreted. For example, PAF is released
from monocytes but retained by leukocytes and endothelial cells. In
endothelial cells, PAF is displayed on the surface for juxtacrine signaling
and stimulates adherent leukocytes (Honda et al., 2002).
In addition to these enzymatic routes, PAF-like molecules can
be formed from the oxidative fragmentation of membrane phospholipids
(oxPLs) (Stafforini et al., 2003). These compounds are
increased in settings of oxidant stress, such as cigarette smoking,
and differ structurally from PAF in that they contain a fatty acid at
the sn-1 position of glycerol joined through an ester bond and various
short-chain acyl groups at the sn-2 position. oxPLs mimic the
structure of PAF closely enough to bind to its receptor (see
“Mechanism of Action of PAF”) and elicit the same responses.
Unlike the synthesis of PAF, which is highly controlled, oxPL production
is unregulated; degradation by PAF-AH, therefore, is necessary
to suppress the toxicity of oxPLs. Levels of plasma PAF-AH
are increased in colon cancer, cardiovascular disease, and stroke
(Prescott et al., 2002), and polymorphisms have been associated with
altered risk of cardiovascular events (Ninio et al., 2004). A common
missense mutation in Japanese people is associated disproportionately
with more severe asthma.
Mechanism of Action of PAF. Extracellular PAF exerts its actions by
stimulating a specific GPCR (Honda et al., 2002). The PAF receptor’s
strict recognition requirements, including a specific head group
and specific atypical sn-2 residue, also are met by oxPLs. The PAF
receptor couples to activation of the PLC-IP 3
–Ca 2+ pathway and to
inhibition of adenylyl cyclase, via G q
and G i
respectively. Activation
of phospholipases A 2
, C, and D give rise to second messengers.
These include AA-derived PGs, TxA 2
, or LTs, which may function
as extracellular mediators of the effects of PAF. In addition, p38
MAP kinase is activated downstream of PAF-receptor coupling to
G q
, while ERK activation can occur through a number of pathways,
including coupling to G q
, G o
, or G βγ
or via transactivation of the epidermal
growth factor receptor, leading to NF-κB activation
(Stafforini et al., 2003). Thus, the PAF receptor couples to a variety
of downstream signaling cascades in a cell-dependent manner.
PAF exerts many of its important pro-inflammatory actions
without leaving its cell of origin. For example, PAF is synthesized in
a regulated fashion by endothelial cells stimulated by inflammatory
mediators. This PAF is presented on the surface of the endothelium,
where it activates the PAF receptor on juxtaposed cells, including
platelets, polymorphonuclear leukocytes, and monocytes, and acts
cooperatively with P selectin to promote adhesion (Prescott et al.,
2000). This function of PAF is important for orchestrating the interaction
of platelets and circulating inflammatory cells with the
inflamed endothelium.
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CHAPTER 33
LIPID-DERIVED AUTACOIDS: EICOSANOIDS AND PLATELET-ACTIVATING FACTOR