Increased lipopolysaccharide-induced tissue factor activity and tumour necrosis factor production in monocytes after intake of aspirin

Østerud, Bjarne; Jo, Olsen; Wilsgård, Line

doi:10.1097/00001721-199206000-00011

Cited by 23 publications

(35 citation statements)

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“…9 -11 Although toxic concentrations of ASA and salicylate have been shown to inhibit LPSstimulated TF expression on isolated monocytes, 9 experiments in whole blood have demonstrated that ASA at substantially lower doses stimulates TF expression. 10 Attempting to address these controversial findings and to put them into a clinically relevant context, we studied whether 1000 mg of ASA would inhibit TF expression and subsequent generation of thrombin in vivo. The human LPS model, which resembles the early phase of sepsis-induced DIC, was chosen because it allows investigation of the complex interplay between coagulation, platelets, leukocytes, and endothelium within human vasculature.…”

Section: Discussionmentioning

confidence: 99%

“…9 Conversely, whole-blood experiments showed that ASA enhanced TF activity on monocytes. 10,11 Furthermore, TF expression on human monocytes is enhanced by the presence of granulocytes and activated platelets, suggesting an even more complex regulation of TF in vivo. [12][13][14][15][16] In addition, results of animal studies suggest that inhibition of thromboxane A 2 -mediated platelet activation may improve DIC induced by LPS.…”

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confidence: 99%

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Endotoxin-Induced Activation of the Coagulation Cascade in Humans

Pernerstorfer

Stohlawetz

Hollenstein

et al. 1999

ATVB

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Abstract-During Gram-negative septic shock, lipopolysaccharide (LPS, endotoxin) induces tissue factor (TF) expression.TF expression is mediated by nuclear factor B and amplified by activated platelets. TF forms a highly procoagulant complex with activated coagulation factor VII (FVIIa). Hence, we hypothesized that aspirin, which inhibits LPS-induced, nuclear factor B-dependent TF expression in vitro and platelet activation in vivo, may suppress LPS-induced coagulation in humans. Therefore, we studied the effects of aspirin on systemic coagulation activation in the established and controlled setting of the human LPS model. Thirty healthy volunteers were challenged with LPS (4 ng/kg IV) after intake of either placebo or aspirin (1000 mg). Acetaminophen (1000 mg) was given to a third group to control for potential effects of antipyresis. Neither aspirin nor acetaminophen inhibited LPS-induced coagulation. However, LPS increased the percentage of circulating TF ϩ monocytes by 2-fold. This increase was associated with a decrease in FVIIa levels, which reached a minimum of 50% 24 hours after LPS infusion. Furthermore, LPS-induced thrombin generation increased plasma levels of circulating polymerized, but not cross-linked, fibrin (ie, thrombus precursor protein), whereas levels of soluble fibrin were unaffected. In summary, a single 1000-mg dose of aspirin did not decrease LPS-induced coagulation. However, our study showed, for the first time, that LPS increases TF ϩ monocytes, substantially decreases FVIIa levels, and enhances plasma levels of thrombus precursor protein, which may be a useful marker of fibrin formation in humans. ). 1,2 DIC is defined by enhanced activity of coagulation factors, exhaustion of endogenous coagulation inhibitors, and activation and depletion of platelets by formation of thrombi in the vasculature. 3 Results of several studies suggest that initiation of coagulation in sepsis is driven primarily by the tissue factor (TF)-dependent pathway of coagulation. 4,5 Inhibition of the TF-dependent activation of coagulation using antibodies against TF or activated factor VII (FVIIa) completely prevents LPS-induced activation of coagulation in animals. 6 -8 Thus, inhibition of TF expression on monocytes during endotoxemia may present a promising therapeutic option for dampening the coagulation cascade. A recent in vitro study showed that acetylsalicylic acid (ASA) reduces LPS-induced TF expression on isolated monocytes. 9 Conversely, whole-blood experiments showed that ASA enhanced TF activity on monocytes. 10,11 Furthermore, TF expression on human monocytes is enhanced by the presence of granulocytes and activated platelets, suggesting an even more complex regulation of TF in vivo. [12][13][14][15][16] In addition, results of animal studies suggest that inhibition of thromboxane A 2 -mediated platelet activation may improve DIC induced by LPS. 3 Besides in vitro studies and experiments in animals, infusion of small doses of LPS into humans has emerged as a valuable tool to explore the pathogenesis ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Endotoxin-Induced Activation of the Coagulation Cascade in Humans

Pernerstorfer

Stohlawetz

Hollenstein

et al. 1999

ATVB

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“…Interestingly, aspirin caused a significant increase in the TNF-␣ response, an effect that has been observed in experimental studies previously; in whole-blood models, aspirin increases lipopolysaccharide-induced TNF-␣ release, and administration of oral aspirin to healthy volunteers increases TNF-␣ production by lipopolysaccharidestimulated monocytes. 8,9 Prostaglandin E 2 reduces TNF-␣ production in isolated cell models, and therefore inhibition of cyclooxygenase may be the mechanism by which aspirin increases TNF-␣ levels. 10 Although TNF-␣ induces endothelial dysfunction in various models, the observation that there is no increase in this cytokine in the placebo-treated group and that there is an increase seen after aspirin in the absence of endothelial dysfunction suggests that TNF-␣ is not the major mediator of vaccine-induced endothelial dysfunction.…”

Section: Aspirin Pretreatment Preserves Endothelial Functionmentioning

confidence: 99%

“…However, it is possible that the effects of aspirin to increase TNF-␣ production during inflammation may exert other detrimental effects, including procoagulant effects. 8,9 Elevation of IL-6 is of particular interest in relation to cardiovascular risk, and IL-6 is presumed to be an important if not the principal stimulus to the synthesis of C-reactive protein, levels of which are predictive of the risk of cardiovascular events. 11,12 However, our data show that aspirin protects endothelial function without modulating systemic IL-6.…”

Section: Aspirin Pretreatment Preserves Endothelial Functionmentioning

confidence: 99%

Prevention of Inflammation-Induced Endothelial Dysfunction

Kharbanda

Walton²,

Allen³

et al. 2002

Circulation

155

101

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Background — Inflammation and infection may initiate and promote atherosclerosis or its complications by adverse effects on the vascular endothelium. The mechanisms by which aspirin reduces cardiovascular risk might involve anti-inflammatory actions or direct effects on the endothelium in addition to its antiplatelet action. We investigated the role of aspirin in modulating endothelial dysfunction induced by an experimental inflammatory stimulus. Methods and Results — An inflammatory response was generated in healthy volunteers by Salmonella typhi vaccination. Venous occlusion plethysmography was used to assess resistance vessel responses (16 hours before and 8 hours after vaccination) to the endothelium-dependent dilator bradykinin (BK) and the endothelium-independent dilator glyceryl-trinitrate (GTN). Twelve subjects were randomized to receive either aspirin 1.2 g orally or placebo 2 hours before vaccination. After vaccination alone there was suppression of the response to BK in the placebo group ( P =0.01), with no change in response to GTN. In the aspirin group there was no change in the response to either BK or GTN after vaccination. Aspirin treatment prevented vaccine-induced elevation of interleukin-1 receptor antagonist but enhanced the generation of tumor necrosis factor-α compared with placebo. In an additional 5 individuals, local intrabrachial aspirin (10 mg/min for 15 minutes) failed to restore responses to BK after vaccination. Conclusions — Experimental inflammation produces endothelial dysfunction, which can be prevented by pretreatment with aspirin. Locally administered aspirin does not reverse vaccine-induced endothelial dysfunction once established. The protective effects of aspirin on inflammation-induced endothelial dysfunction may be through modulation of the cytokine cascade.

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“…Monocytes can be stimulated by various agents, such as endotoxin, phorbol ester, lipoteichoic acid, and C-reactive protein, to express TF molecules on their membranes, thereby generating TF activity (TFA) (9,25,26,30,31). We have shown that monocytes also express TFA when they adhere in vitro to fibrin matrixes containing bacteria, in particular bacteria that are known to cause the endovascular disease bacterial endocarditis (BE) (1)(2)(3)(4)38).…”

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Interleukin-10 Regulates the Tissue Factor Activity of Monocytes in an In Vitro Model of Bacterial Endocarditis

et al. 2001

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Monocytes are important effector cells in the pathogenesis of bacterial endocarditis since they provide the tissue factor that activates the coagulation system and maintains established vegetations. Monocytes secrete cytokines that can modulate monocyte tissue factor activity (TFA), thereby affecting the formation and maintenance of vegetations. In this study, we show that monocytes cultured for 4 h on a Streptococcus sanguis-infected fibrin matrix mimicking the in vivo vegetational surface express high levels of TFA. This was accompanied by secretion of the proinflammatory cytokines tumor necrosis factor alpha (TNF-␣), interleukin-1␣ (IL-1␣), and IL-1␤. After a 24-h incubation period the anti-inflammatory cytokine IL-10 could also be detected. Our data show that, whereas TNF-␣ and IL-1 have a minor role in the induction of TFA by monocytes cultured on a fibrin matrix, TNF-␣ but not IL-1 plays an important role in the induction of IL-10 by these cells. In turn, our data show that IL-10 is an important factor in the downregulation of monocyte TFA. In summary, we conclude that IL-10 is an important factor in the control of monocyte TFA in endocardial vegetations.Tissue factor (TF), a transmembrane glycoprotein, is the most important factor in the initiation of the extrinsic coagulation pathway (25). Monocytes can be stimulated by various agents, such as endotoxin, phorbol ester, lipoteichoic acid, and C-reactive protein, to express TF molecules on their membranes, thereby generating TF activity (TFA) (9,25,26,30,31). We have shown that monocytes also express TFA when they adhere in vitro to fibrin matrixes containing bacteria, in particular bacteria that are known to cause the endovascular disease bacterial endocarditis (BE) (1-4, 38). With respect to the pathogenesis of BE, Drake and coworkers (13) have shown that in vivo TF is a crucial factor in the formation of an endocardial fibrin clot, called endocardial vegetation, in which the infecting microorganisms and blood cells are embedded (33). In a rabbit model of BE it was found that the TF needed to maintain the endocardial vegetation is generated by monocytes that settle from the circulation onto the infected endocardial lesion (2,3,6,38).Monocyte TFA can be regulated by cytokines. Proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-␣) and interleukin-1 (IL-1), induce TFA on monocytes (15,17,18,22,24,25). Monocytes isolated from patients with atherosclerosis, a disease in which TNF-␣ and IL-1 play a significant role, express TF on their membranes (24). Furthermore, macrophages in atherosclerotic plaques express TF (32). Anti-inflammatory cytokines, such as IL-10 and transforming growth factor beta, inhibit or suppress monocyte TFA (14,18,20,24,29,30).It is well known that pro-and anti-inflammatory cytokines each control the other's production (5, 33). TNF-␣ and IL-1, which are examples of the earliest cytokines produced by monocytes upon appropriate stimulation (15, 28), are able to stimulate monocyte IL-10 production (15,27,28,40). In turn, IL...

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Increased lipopolysaccharide-induced tissue factor activity and tumour necrosis factor production in monocytes after intake of aspirin

Cited by 23 publications

References 0 publications

Endotoxin-Induced Activation of the Coagulation Cascade in Humans

Endotoxin-Induced Activation of the Coagulation Cascade in Humans

Prevention of Inflammation-Induced Endothelial Dysfunction

Interleukin-10 Regulates the Tissue Factor Activity of Monocytes in an In Vitro Model of Bacterial Endocarditis

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