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Arachidonic Acid (AA)

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Arachidonic Acid (AA)

Cytochrome P450

PGH,

\COOH

COX-1 or COX-2

PGD,

PGD,

l/hPGD2

synthase

h l/hPGD2

synthase

th nty

TXA2 synthase

TXA2 synthase

COOH

15-deoxyA12-14PGJ2

Figure 1 The arachidonic acid cascade. In resting cells arachidonic acid (AA) is esterified to membrane phospholipids. However, upon cell activation and the subsequent action of phospholipase A2, AA can be liberated from the sn-2 position of the glycerol backbone. There are several types of PLA2 including cytosolic PLA2 (c PLA2), calcium-independent PLA2 (i PLA2), and several isoforms of secretory PLA2 (s PLA2). AA is then oxidized to PGG2, which is then rapidly reduced to PGH2 by either cyclooxygenase (COX) isoform. PGH2 acts then as a substrate for several other synthases leading to the synthesis of specific prostanoids (see main text for more details).

COOH

COOH

COOH

Biological Properties of Prostaglandins

Thrombosis

Platelet COX converts AA to TxA2, along with comparatively smaller amounts of PGE2 and PGF2a TxA2 has a halflife of about 30 seconds and breaks down to inactive TxB2. TxA2 constricts large blood vessels, has variable vasoconstrictor activity in the microcirculation, and is a potent stimulus for platelet aggregation. PGi2, on the other hand, is the main AA metabolite of endothelial cell lining the larger arteries and veins, but is also formed by the endothelial cells of the microvessels. Prostacyclin (PGI2) is a vasodilator and a potent inhibitor of platelet aggregation. It also exerts other potential protective effects on the endothelium by promoting the outflow of free cholesterol from endothelial cells, inhibiting the release of growth factors from endothelial cells, platelets, and macrophages, and reducing the release of free radicals from leukocytes [2].

A number of thrombotic diseases have been associated with an imbalance in the prostacyclin-thromboxane system. Platelets from patients with arterial thrombosis, deep vein thrombosis, or recurrent venous thrombosis produce more prostaglandin endoperoxides and TxA2 than normal platelets. Also, platelets from rabbits made atherosclerotic by a high-fat diet or from patients who have survived myocardial infarction are abnormally sensitive to aggregating agents and upon stimulation produce higher amounts of TxA2 than controls. In general terms, it seems that in diseases where there is a tendency for thrombosis to develop, TxA2 production is elevated whereas PGI2 production maybe either maintained or reduced. The opposite is found in some diseases associated with increased bleeding tendency [3, 4].

Vascular Dynamics

Prostaglandins of the E-series along with PGI2 potently dilate arterioles in the microcirculation (Figure 2). On the other hand, prostaglandins of the A, D, and F series only produce negligible changes in vascular permeability in guinea-pig or rabbit skin even when given at high doses. Thus, in general, it is considered that prostaglandins do not contribute significantly to edema formation by a direct effect on blood vessel permeability; rather, it is believed that vasodilator prostaglandins synergize with other inflammatory mediators to cause inflammatory edema. For instance, the effects of bradykinin or histamine on plasma exudation in guinea-pig skin or edema in the rat paw are potentiated by low doses of E-series prostaglandins. Moreover, PGE2 causes a dose-dependent increase in blood flow with little or no plasma exudation in the rabbit skin, but when mixed with bradykinin or histamine causes a marked increase in plasma exudation [5, 6].

Pain

Like their effects on the vasculature, none of the COX products cause pain directly, but some eicosanoids potentiate the pain-causing effects of histamine and bradykinin.

This finding has led to the suggestion that prostaglandins can sensitize the afferent pain nerve endings, leading to the hyperalgesia characteristic of inflammation.

Cell Recruitment

Another critical component of the inflammatory response is the recruitment of inflammatory cells. However, it is generally accepted that the COX pathway is not involved in the recruitment of these inflammatory leukocytes. In fact, it is likely that PGE2 or PGI2 attenuates leukocyte migration by inhibiting leukocyte motility and preventing adherence to vascular endothelial cells [7].

Essentials of Human Physiology

Essentials of Human Physiology

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