Porth's Essentials of Pathophysiology, 4e

58

Cell and Tissue Function

U N I T 1

Injured tissue, inflammatory mediators

Cell membrane phospholipids

Corticosteroid medications

Arachidonic acid

Lipoxygenase pathway

Cyclooxygenase pathway

Aspirin, NSAIDs

Leukotrienes

(LTC 4

, LTD 4

, LTE 4

)

Thromboxane (TxA 2 )

Prostaglandins (PGI 2 , PGF 2a )

Induces smooth muscle contraction Constricts pulmonary airways Increases microvascular permeability

Vasoconstriction Bronchoconstriction Promotes platelet function

Induces vasodilation and bronchoconstriction Inhibits inflammatory cell function

FIGURE 3-4. The cyclooxygenase and lipoxygenase pathways and sites where the corticosteroid and nonsteroidal anti-inflammatory drugs (NSAIDs) exert their action.

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