Neutrophil granulocytes are the most abundant cell population in inflammatory exudates as well as in inflamed and ischemic tissues. Neutrophils cause tissue injury by two mechanisms: generation of free oxygen centered radicals and products thereof and release of tissue destructive enzymes, such as elastase and peroxidase. These reactions are amplified by LTB4 release from activated neutrophils, which mediates leukocyte recruitment to the site of tissue injury. In this context, it should be noted that vasodilatory prostaglandins, most notably PGE2 but not PGI2, are potent inhibitors of neutrophil function  as might be aspirin via ATL formation (see below). Interestingly, there is evidence for a synergistic inhibitory effect of E-type prostaglandins and salicylate on neutrophil function . An alternative explanation for the inhibition of leukocyte accumulation to an inflamed area by aspirin and salicylates is the local accumulation of adenosine in granulocytes after enhanced ATP breakdown  and/or preventing its rephosphor-ylation by inhibition of oxidative phosphorylation (Section 2.2.3). In this context, inhibition of leukocyte accumulation by salicylates was shown in one study to be independent of inhibition of prostaglan-din synthesis and was suggested to be adenosine mediated .
Protection of Endothelial Function Inflammation and infections do profoundly affect the function of vascular endothelial cells. Endothelial dysfunction might be a common link between inflammation and the enhanced cardiovascular risk in patients suffering from chronic inflammatory diseases such as rheumatoid arthritis (Section 4.2.2). Inflammatory cytokines upregulate endothelial COX-2 and iNOS and enhance generation of reactive oxygen species (Section 2.2.2). Experimental systemic inflammation in healthy individuals, caused by S. typhi vaccination, was associated with endo-thelial dysfunction as seen from reduced endothe-lium-dependent relaxation that could be prevented by previous aspirin treatment (1.2 g). Aspirin treatment after vaccination had no effect, suggesting that these actions of aspirin were mediated by inhibition of the cytokine (IL-1) cascade . In inflammatory conditions, treatment with aspirin might result in generation of 15-(R)-HETE that can be transformed to 15-epi-lipoxin A4 or aspirin-triggered lipoxin (Section 2.2.1) by interaction with the 5- and 15-lipoxygenase of white cells, respectively (Figure 2.33). ATL, like other lipoxins, is a potent anti-inflammatory compound. It inhibits the neutrophil-induced increase in vascular permeability  and leukocyte recruitment to the inflammatory site. This last action might also involve
Figure 2.33 Generation of aspirin-triggered lipoxin, an anti-inflammatory mediator, by acetylation (Ac) of COX-2 in the presence of white-cell 5-lipoxygenase (5-LOX). Coxibs and traditional NSAIDs solely block COX-2 activity to a variant extent. ATL stimulates eNOS with subsequent NO formation and antagonizes the activation of neutrophils and their recruitment to the injured (inflamed) area.
NO formation via stimulation of the eNOS , possibly similar to the improved endothelium-dependent relaxation in patients with advanced systemic atherosclerosis (see Figure 2.30). Lipoxins will also improve endothelial oxygen defense by transcriptional upregulation of heme oxygenase-1  (see Figure 2.20) and might be important as agents that terminate the "killing" phase ofinflam-mation and initiate the healing process .
This mode ofaction of aspirin differs fundamentally from that of selective or nonselective COX inhibitors that rather tend to reduce ATL formation because of inhibition of COX-2 and cannot induce generation of the 15-(R)-HETE precursor because of their inability of target protein acetylation. In any case, the clinical significance of this attractive hypothesis of a central function of aspirin-generated ATL and other lipoxins for resolution ofinflamma-tion still needs to be confirmed in men.
Leukocyte Adhesion and Transmigration A prerequisite fortissue-destructing actions ofleukocytes is their adhesion to and transmigration through the endothelial lining of blood vessels. This leukocyte traffic is controlled by signaling and adhesion molecules that also regulate leukocyte function. Sali-cylates inhibit cytokine-induced expression of adhesion molecules on endothelial cells [162,341] and integrin-mediated neutrophil adhesion [342, 343]. No such effects were seen with indomethacin . In healthy volunteers, inhibition of adhesion and transmigration of T lymphocytes to cultured cyto-kine-stimulated human endothelial cells were found exvivo after one single i.v. injection of500 mg soluble aspirin. This anti-inflammatory activity of salicylates was at least partially due to an interference with the integrin-mediated binding ofresting T lymphocytes to "activated" endothelium with subsequent reduction of specific T-cell recruitment to the inflammatory site . Finally, there is also evidence for inhibition ofTNF a-induced monocyte adhesion to endothelial cells by aspirin. This action appears to be NFkB-mediated (Section 2.2.2) but requires salicylate concentrations of 5-10 mM in vitro for a significant effect .
Modulation ofCytokines Cytokines mediate many inflammation-associated immune reactions. However, they also mediate host defense, for example, by generation of antibodies or activation of lymphocytes [345,346]. IL-1 and the related tumor necrosis factor (TNFa) from macrophages induce secretion of further cytokines and function as endogenous pyrogen. Aspirin has complex actions on cytokine-induced inflammatory and immunogenic responses in healthy man . Interestingly, rebound phenomena on cytokine-induced cytokine synthesis have been described after short-term low-dose aspirin treatment and were possibly prostaglandin dependent since similar changes were seen after ibuprofen .
An interesting recent finding was the selective inhibition of IL-4 gene expression in human T cells by aspirin at therapeutic concentrations (<1 mM). IL-4 is the proto-typic cytokine expressed in CD4+ T cells and involved in several inflammatory diseases, such as juvenile rheumatoid arthritis and Kawasaki's disease. Salicylates inhibit IL-4 promoter activation in vitro. This action does not involve inhibition of prostaglandin biosynthesis or inhibition of NFkB activation .
Overall, the available data on the modification of cytokines by salicylates are complex and partly controversial. In some cases, this can be explained by the high concentrations of salicylates, required to obtain these actions in many in vitro studies. At higher levels, salicylates have multiple actions on C/CBP-b, NFkB, and other transcription factors in the promoter region of inducible genes, for example, those for cytokines (C/EBP-b), COX-2, and iNOS (Section 2.2.2). Another explanation for variable results is the different experimental settings, that is, different cell types, duration, and intensity of stimulation as well as complex interactions with other mediators such as immunomodulating prostaglandins. For example, PGE2 generation might significantly alter cytokine release and activity in vivo but is virtually absent in many in vitro assays. Overall, available data show that aspirin and salicylates have multiple biochemical and pharmacological actions on important mediators of inflammation. This also includes prostaglandins. However, the full spectrum of putative antiinflammatory actions of aspirin and salicylate might not solely be explained by inhibition of prostaglandin biosynthesis and is also not shared by traditional NSAIDs or coxibs, respectively.
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