The major constituent of cell membranes are phospholipids.
Cellular phospholipases, especially
phospholipase A
and C, are
activated during inflammation and degrade phospholipids to
arachidonic acid.
Arachidonic acid has a short half-life and can
be metabolized by two major routes, the cyclo-oxygenase and
lipoxygenase pathways. The
cyclo-oxygenase pathway produces
prostaglandins, prostacyclin, and thromboxanes; the
lipoxygenase pathway produces in one branch leukotrienes and in the second
branch lipoxins (Figure 1.1).
Figure 1.1:
The metabolic pathway of archidonic acid (HPETE:
hydroperoxy-eicosatetraenoic acid; HETE: hydroxy-eicosatetraenoic acid)
The
prostaglandins (PG) are a family of lipid-soluble
hormone-like molecules produced by different cell types in the
body. For example, macrophages and monocytes are large producers
of both PGE
and PGF
,
neutrophils produce moderate amounts of
PGE
, mast cells produce PGD
.
It is important to note that,
unlike histamine, prostanglandins do not exist free in tissues,
but have to be synthesized and released in response to an
appropriate stimulus. PGE
enhances vascular permeability, is
pyrogenic, increases sensitivity to pain, and stimulates leukocyte
cAMP, which can have an important suppressive effects on release
of mediators by mast cells, lymphocytes, and phagocytes.
Thromboxane A
(TXA
) is produced by monocytes and
macrophages, as well as by platelets. It causes platelets to
aggregate and constrict blood vessels and airways. These effects
are somewhat opposed by the action of
prostacyclin (PGI
)
which is a potent vasodilator.
Leukotrienes. LTB
and 5-hydroxyeicosatetranoate
(5-HETE), causes the chemotaxis (directed locomotion) and/or
chemokinesis (general cell movement) of a number of cell types
including neutrophils. The
synthesis of LTB
is inhibited by
colchicine, an anti-inflammatory agent used for treatment of gout.
The mixture of LTC
, LTD
and LTE
originally called slow
reacting substance of anaphylaxis (SRS-A), is produced by a wide
variety of cells, including monocytes and macrophages. They are
spasmogenic and cause contraction of smooth muscle, mainly in the
bronchus, and they have effects on mucous secretion.
Lipoxins LXA
and LXB
stimulate changes in
microcirculation. For example,
LXA
induces rapid arteriolar
dilation and can also antagonize
LTD
-induced vasoconstriction. It
suggest that LXA
may regulate the action of vasoconstrictor
leukotrienes. LXA
can block neutrophil chemotaxis induced by both
LTB
and N-formyl-oligopeptides.
Both LXA
and LXB
inhibit
cytotoxicity of natural killer cells.
Platelets produce a group of acetyl-alkylglycerol ether analogs of phosphatidylcholine called platelet-activating factors (PAFs). PAFs cause platelet aggregation and are potent phagocyte chemoattractants and stimuli of lysosomal enzyme release and reactive oxygen product formation by neutrophils, eosinophils, and macrophages. In addition, PAFs increase the stickiness of endothelial cells for leukocytes.
The basic activities of bioactive lipids are listed in Table 1.7.
Table 1.7: Lipid mediators and their basic activities