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The major LO product of neutrophils is LTB4

, though macrophages may also synthesize this

compound. This compound is potently chemotactic for both neutrophils and eosinophils. By

upregulating endothelial cell surface adhesion molecules it promotes leukocyte recruitment. It increases

vascular permeability, either directly or through interaction with neutrophils and endothelial cells. LTB4

has also been shown to induce hyperalgesia.94,180

LTC4

, LTD4

, and LTE4 comprise the family of slow-reacting substances of anaphylaxis (SRSA),

compounds synthesized by mast cells during anaphylactic reactions. LTC4

is the major eicosanoid

product of eosinophils and the only mast cell–derived product of LO. These three LTs are potent

vasoconstrictors and the most powerful bronchoconstrictors in humans, being three orders of magnitude

more potent than histamine. They also increase vascular permeability and are vasodilatory in skin.43,180

Lipoxins are biosynthesized by several routes in a tissue-specific manner. Current evidence implicates

the eosinophil. A 5(6)-epoxytetraene intermediate can be formed by 5-LO activity on 15-HPETE. This

reaction, when carried out in blood vessels, requires the interaction of platelets and neutrophils. On

mucosal surfaces, 12-LO and 5-LO activity on LTA4 can result in the formation of this lipoxin

intermediate through leukocyte–epithelial interactions. The 5(6)-epoxytetraene intermediate is then

converted to lipoxin A4

, lipoxin B4

, or lipoxin C4

, the last of which serves as the precursor for lipoxins

D4 and E4

.92,184,185

Table 7-8 Prostanoid Effects

Though many of the functions of lipoxins have yet to be elucidated, they appear to counterregulate

the actions of LTs. They inhibit LT production by downregulating 5-LO as 15-LO is upregulated. The

anti-inflammatory cytokines IL-4 and IL-13 further contribute to suppression of inflammatory responses

by enhancing 15-LO activity. In addition to inhibiting synthesis, lipoxins inhibit the actions of LTB4 and

LTD4

. Lipoxins A4 and B4 are potent vasoactive compounds. Lipoxins influence smooth muscle and

vascular tonus by increasing NO and prostacyclin production, increasing arachidonate release, and

reversing endothelin-induced vasoconstriction. Counterinflammatory functions of lipoxin A4

include

inhibition of LTs, fMLP, and other chemoattractants. Lipoxin A4 also downregulates LTB4

-mediated

delayed type hypersensitivity reactions.92,184–186

A large number of anti-inflammatory drugs, many of which are in clinical use, act by interfering with

eicosanoid synthesis. The anti-inflammatory properties of corticosteroids are mediated at least in part

by the inhibition of PLA2

through the induction of lipocortin. They have been shown to selectively

inhibit COX2 activation without affecting COX1. NSAIDS block the synthesis of both prostaglandins and

thromboxanes by inhibiting COX activity. In contrast to the other NSAIDS, aspirin inhibits COX in an

irreversible manner, and restoration of platelet function necessitates the administration of platelets.

Aspirin, by either acetylating COX2 or by inducing the oxidation of arachidonic acid by cytochrome

p450 or 5-LO, has been shown to stimulate the formation of 15R-HETE in endothelial or epithelial cells.

These 15-epilipoxins exhibit higher potency in suppressing inflammation because of their prolonged

half-lives. A potential complication of NSAID use and COX inhibition is the shunting of arachidonate

through the 5-LO pathway and subsequent greater production of proinflammatory LTs (asthma). Such

consequences minimize any benefit achieved from reducing other eicosanoid levels. In addition, NSAIDs

act systematically in a nonselective manner, so that inhibition of prostaglandin synthesis can result in

dangerous side effects in locations where prostaglandins normally exert cytoprotective effects

(stomach).181,185,187

PLATELET-ACTIVATING FACTOR

PAF is a heterogeneous mixture of 1-0-alkyl-2-acetyl-sn-glycero-3-phosphocholines that plays a

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prominent role in both physiologic and pathologic inflammatory states. It does not exist preformed, but

is rapidly produced by activated cells. Synthesis involves either the remodeling of membrane

phospholipids by PLA2

, usually more important under inflammatory conditions, or by de novo synthesis

as occurs in resting cells. De novo synthesis is regulated by substrate availability and involves a

constitutively active enzyme that produces PAF in small basal amounts.188 The membrane phospholipid

precursor is present in high amounts in neutrophils. Other cells that can synthesize PAF include

platelets, basophils, monocytes, eosinophils, mast cells, and vascular endothelial cells. Similar to

eicosanoid production, the synthesis of PAF is initiated by calcium-dependent activation of PLA2

, which

yields 1-0-alkyl-sn-glycerophosphocholine (lyso-PAF); subsequent acetylation generates PAF. PAF may

be released from the cell, or it may be converted back to lyso-PAF by an acetylhydrolase and to the

precursor ether-phosphatidylcholine.188

The actions of PAF are mediated by G-protein activation. As the name implies, PAF induces platelet

aggregation and degranulation; yet also possesses many other critical functions for inflammation. Its

vasoactive properties include vasodilation and increased permeability, and it is an equally potent

bronchoconstrictor. PAF enhances arachidonic acid metabolism, leading to increased leukocyte motility,

degranulation, and free radical formation. PAF plays an integral role in promoting activation and

adherence of inflammatory cells to the endothelium.189 During the early inflammatory response,

activated endothelial cells synthesize and express PAF on the cell surface. Leukocytes tethered by

selectins to the endothelium are activated by endothelial PAF, which results in the induction of tight

integrin-dependent adhesion and subsequent emigration and chemotaxis toward the inflammatory focus.

Acyl-PAF, the major acetylated lipid from mast cells, basophils, and endothelial cells, is a less potent

derivative of PAF that likely plays a similar role in the regulation of neutrophil recruitment. PAF also

promotes platelet and neutrophil aggregation, thereby contributing to the prothrombotic state of acute

inflammation. In circumstances of persistent pathologic stimuli, PAF may be liberated systemically,

thereby causing the sequelae of an excessive inflammatory response. As a mediator of sepsis, PAF

augments endotoxin-induced hypotension and neutrophil and platelet accumulation in the lungs. There

is evidence that the NO-induced hypotension in experimental models of endotoxemia is mediated by

PAF.190 PAF infusion leads to a shock state that is similar to septic shock in that there is tissue

hypoperfusion despite adequate fluid resuscitation. In animal studies, PAF has been shown to contribute

many manifestations of sepsis including coronary vasoconstriction, reduced cardiac contractility,

reduced preload, peripheral vasodilation, pulmonary vasoconstriction, increased microvascular

permeability, gastrointestinal hemorrhage, and thrombocytopenia.181 Two prospective randomized,

placebo-controlled trials of PAF inhibition in sepsis have suggested a benefit.181

PAF acetylhydrolase, an enzyme regulated by dexamethasone, estrogen, and PAF itself, is the enzyme

responsible for degradation of PAF.

Kinins

Kinins (i.e., bradykinin and lysyl bradykinin) are small vasoactive peptides generated during the

inflammatory response (Fig. 7-11). Three sources and mechanisms of kinin formation occur during

inflammation: (1) plasma proteins; (2) tissue proteins; (3) cellular proteinases.191–194

Production of Bradykinin

Biosynthesis commences with the activation of Hageman factor (HF), or factor XII of the coagulation

cascade (Fig. 7-11). HF is activated by exposure to anionic surfaces such as the basement membrane of

injured endothelium, heparin, or lipid A of endotoxin. It can also be proteolytically cleaved and

activated by kallikrein. Prekallikrein circulates complexed with HMWK, a nonenzymatic protein.

Kininogen enhances the binding of prekallikrein to negatively charged surfaces. Activated HF converts

prekallikrein to kallikrein, which in turn activates more HF in a positive feedback cycle. HFf, a cleavage

product of activated HF, is also capable of activating prekallikrein. Kallikrein in plasma, tissues, and

secretions specifically cleaves HMWK to release the nonapeptide bradykinin. In addition to bradykinin

production, kallikrein participates in the activation of plasminogen and C1q of the complement system;

yet another link between inflammation and the coagulation system. The only major plasma inhibitor of

activated HF is C1 inhibitor. The primary inhibitors of kallikrein in plasma are C1 inhibitor and α1

macroglobulin.39,191

Kinin Production in Tissue

Lysyl-bradykinin (kallidin) is the cleavage product of either HMWK or LMWK by tissue kallikreins,

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