58
U N I T 1
Cell and Tissue Function
Several prostaglandins are synthesized from arachi-
donic acid through the cyclooxygenase metabolic path-
way.
15
The prostaglandins (e.g., PGD
2
, PGE
2
, PGF
2
α
, and
PGI
2
) induce inflammation and potentiate the effects of
histamine and other inflammatory mediators. The pros-
taglandin thromboxane A
2
promotes platelet aggrega-
tion and vasoconstriction. Aspirin and the nonsteroidal
anti-inflammatory drugs (NSAIDs) reduce inflammation
by inactivating the first enzyme in the cyclooxygenase
pathway for prostaglandin synthesis.
Like the prostaglandins, the leukotrienes are formed
from arachidonic acid, but through the lipoxygen-
ase pathway. Histamine and leukotrienes have similar
functions; however, histamine is produced rapidly and
transiently while the more potent leukotrienes are being
synthesized. The leukotrienes also have been reported
to affect the permeability of the postcapillary venules,
the adhesion properties of endothelial cells, and the
extravasation and chemotaxis of neutrophils, eosino-
phils, and monocytes. Leukotriene (LT) C
4
, LTD
4
, and
LTE
4
, collectively known as the
slow-reacting substance
of anaphylaxis
(SRS-A), cause slow and sustained con-
striction of the bronchioles and are important inflam-
matory mediators in bronchial asthma and anaphylaxis.
Omega-3 Polyunsaturated Fatty Acids.
There has
been recent interest in dietary modification of the
inflammatory response through the use of
omega-3
polyunsaturated fatty acids.
These include
eicosapentae-
noic acid
and
docosahexaenoic acid
, which are present
in oily fish and fish oil,
17,18
but can be derived in limited
quantities from
α
-linolenic acid.
The
α
-linolenic acid
,
which is present in flax seed, canola oil, green leafy veg-
etables, walnuts, and soybeans, is an essential omega-3
fatty acid that cannot be produced in the body and must
be obtained through the diet. The omega-3 polyun-
saturated fatty acids, which are considered antithrom-
botic and anti-inflammatory, are structurally different
from the prothrombotic and proinflammatory omega-6
polyunsaturated fatty acids, which are present in most
seeds, vegetable oils, and meats. Typically, the cell mem-
branes of inflammatory cells contain high proportions
of omega-6 arachidonic acid, which is the source of
prostaglandin and leukotriene inflammatory mediators.
Eating oily fish and other foods that are high in omega-3
fatty acids results in partial replacement of omega-6
arachidonic acid in inflammatory cell membranes by
eicosapentaenoic acid, a change that leads to decreased
production of arachidonic acid–derived inflammatory
mediators. This response alone is a potentially beneficial
effect of omega-3 fatty acids. However, omega-3 fatty
acids may have a number of other anti-inflammatory
effects that occur downstream of altered eicosanoid pro-
duction or might be independent of this function.
Platelet-Activating Factor.
Originally named for its
ability to cause platelet aggregation and granulation, PAF
is another phospholipid-derived mediator with a broad
spectrum of inflammatory effects. Platelet-activating fac-
tor is generated from the membrane phospholipids of vir-
tually all activated inflammatory cells and affects a variety
of cell types. In addition to activating platelets, PAF stim-
ulates neutrophils, monocytes/macrophages, endothelial
cells, and vascular smooth muscle. Platelet activating
Injured tissue,
inflammatory mediators
Cell membrane phospholipids
Corticosteroid
medications
Arachidonic acid
Lipoxygenase
pathway
Cyclooxygenase
pathway
Aspirin, NSAIDs
Prostaglandins
(PGI
2
, PGF
2a
)
Thromboxane
(TxA
2
)
Leukotrienes
(LTC
4
, LTD
4
, LTE
4
)
Induces smooth muscle
contraction
Constricts pulmonary
airways
Increases microvascular
permeability
Induces vasodilation and
bronchoconstriction
Inhibits inflammatory
cell function
Vasoconstriction
Bronchoconstriction
Promotes platelet
function
FIGURE 3-4.
The cyclooxygenase and
lipoxygenase pathways and sites where the
corticosteroid and nonsteroidal anti-inflammatory
drugs (NSAIDs) exert their action.
