Histamine causes dilation of arterioles and increases the permeability of venules. Histamine is considered the principal mediator of the immediate transient phase of increased vascular permeability, producing interendothelial gaps in postcapillary venules, as discussed earlier. Its vasoactive effects are mediated mainly via binding to receptors, called H1 receptors, on microvascular endothelial cells. The antihistamine drugs that are commonly used to treat some inflammatory reactions, such as allergies, are H1 receptor antagonists that bind to and block the receptor. Histamine also causes contraction of some smooth muscles, but leukotrienes, described later, are much more potent and relevant for causing spasms of bronchial muscles, for example, in asthma.
Serotonin (5-hydroxytryptamine) is a preformed vasoactive mediator present in platelets and certain neuroendocrine cells, such as in the gastrointestinal tract, and in mast cells in rodents but not humans. Its primary function is as a neurotransmitter in the gastrointestinal tract. It also is a vasoconstrictor, but the importance of this action in inflammation is unclear.
The lipid mediators prostaglandins and leukotrienes are produced from arachidonic acid present in membrane phospholipids, and they stimulate vascular and cellular reactions in acute inflammation. Arachidonic acid is a 20-carbon polyunsaturated fatty acid that is derived from dietary sources or by conversion from the essential fatty acid linoleic acid. Most cellular arachidonic acid is esterified and incorporated into membrane phospholipids. Mechanical, chemical, and physical stimuli or other mediators (e.g., C5a) trigger the release of arachidonic acid from membranes by activating cellular phospholipases, mainly phospholipase A2. Once freed from the membrane, arachidonic acid is rapidly converted to bioactive mediators. These mediators, also called eicosanoids (because they are derived from 20-carbon fatty acids; Greek eicosa = 20), are synthesized by two major classes of enzymes: cyclooxygenases (which generate prostaglandins) and lipoxygenases (which produce leukotrienes and lipoxins) (
Fig. 3.9 ). Eicosanoids bind to G protein-coupled receptors on many cell types and can mediate virtually every step of inflammation (
Table 3.6