10.02.2 Actions of Eicosanoids
Figure 10.6 Prostaglandins and acid production (Copyright QUT, Sheila Doggrell)
PGE2 and PGI2 give protection from the damaging effects of acid in the stomach. Thus, acid secretion induced by histamine, gastrin and food is countered by PGE2 and PGI2, which inhibit the acid secretion (Figure 10.6). In addition to inhibiting acid secretion, PGE2 and PGI2 stimulate the production of mucus, which protects cells from acid.
Finally, PGE2 and PGF2α, with the hormone oxytocin, contract the uterus to initiate labour and childbirth. If these PGs are produced too early, labour occurs prematurely leading to preterm birth.
The leukotrienes, produced by the lipooxygenase pathway, have a major role in immediate type hypersensitivity. Thus, after an antigen-antibody reaction, mast cells release histamine and leukotrienes. Histamine causes a histamine H1-receptor mediated bronchoconstriction, but this is minor compared to the effects of leukotrienes. As the histamine H1-receptor antagonists are only effective against histamine, not leukotrienes, this explains why histamine H1-receptor antagonists are not effective in severe hypersensitivity, where leukotrienes are the major players. The leukotrienes LTC4, LTD4 and LTE4 are potent bronchoconstrictors, which can lead to bronchospasm, and LTB4 is a chemotractant for neutrophils and eosinophils, which are cells prominent in inflammation. The leukotrienes also stimulate mucous production.
Figure 10.5 Prostacyclin and platelet aggregation (Copyright QUT, Sheila Doggrell)
Thromboxanes do the opposite to prostacyclin i.e. TXA2 causes platelet aggregation. When there is damage to a blood vessel, the area is no longer protected by endothelium released PGI2, and the platelets stick to collagen. Once activated platelets produce TXA2, which initiates more platelet aggregation, by having the opposite effect on the platelet to prostacyclin. Thus, TXA2 inhibits adenylate cyclase, to decrease levels of cAMP, and increase platelet aggregation.
Platelet aggregation has an important role in blood vessel repair. When the blood vessel is damaged, platelet aggregation is the first step in blood vessel repair, which takes place under the protection of the clot. Unfortunately, excessive platelet aggregation is quite common, and can be part of several cardiovascular conditions. Excessive platelet-platelet aggregation can partially block the blood vessel. Blood flow can then dislodge the clump of platelets and they can move downstream to block a smaller vessel, the blockage is known as a thrombus, and the condition is thrombosis. Coronary thrombosis underlies myocardial infarction (heart attacks). Thus, it is important to avoid excessive platelet aggregation, which can be done by decreasing the levels of TXA2.
Thirdly, prostaglandins are cytoprotective in the stomach.
Figure 10.4 Eicosanoids and inflammation (Copyright QUT, Sheila Doggrell)
There are 3 components to inflammation; pain, erythema (redness) and oedema (swelling). The pain is partly due to prostaglandins E2 and I2 which sensitive afferent nerve endings (the sensory nervous system), and this causes an amplification of pain. The erythema is due to both leukotrienes and prostaglandins, with the redness being due to vasodilation and congestion of blood vessels, with localised high concentrations of red blood cells. The oedema is due to the leukotrienes increasing vascular permeability, and causing proteins to leave blood vessels in much the same way as histamine causes oedema (Figure 10.4). To overcome eicosanoids-induced inflammation, drugs must inhibit both the cyclooxygenase and lipooxygenase pathways.
The other actions of eicosanoids discussed here are those of the cyclooxygenase pathway only. Firstly, PGE2 has a major role in fever. Fever is associated with disease states, infections, tissue damage, and malignancy. Fever involves increased PGE2 synthesis in hypothalamus, and PGE2 increases set point of body temperature to give the fever. In some situations this can be useful, e.g. increased body temperature probably helps fight bacterial infections by killing the bacteria. However, excessive increases in temperature are harmful to a body designed to act at 370C. To reduce fever, drugs need only inhibit the cyclooxygenase pathway.
Secondly, the products of the cyclooxygenase pathway have important roles on the cardiovascular system. PGs cause vasodilation of most vascular beds. An important role for PGE2 and PGI2 is to keep a specialised blood vessel, the ductus arteriosus (lung bypass), open prior to birth. Often the effects of PGI2 and TXA2 oppose each other, thus whereas PGI2 causes vasodilation, TXA2 causes vasoconstriction of most vascular beds.
Platelets are a form of blood cells produced in the bone marrow. Platelet aggregation is the first step in coagulation, and PGI2 prevents platelet aggregation, whereas TXA2 increases platelet aggregation. The PGI2 is produced by the activity of the COX in the endothelial cells that line the inside of the blood vessels. PGI2 activates the IP receptors on the platelet cells to increase the activity of adenylate cyclase and levels of cAMP, which prevents platelet aggregation (Figure 10.5).
The eicosanoids have many, many actions. The actions discussed here are those that we modify with medicines.
Eicosanoids from both the cyclooxygenase and lipooxygenase pathways have a major role in inflammation. With a variety of physical, chemical, bacterial, and immunological stimuli, phospholipase A2 is activated, and the cyclooxygenase pathway is activated to produced prostaglandins, and the lipooxygenase pathway to produced leukotrienes, and this combination leads to inflammation (Figure 10.4).
