Anti-inflammatory Effects Of Aspirin Research Articles

Regular use of aspirin and statins reduces the risk of cancer in individuals with systemic inflammatory diseases.

Aspirin has shown potential for cancer prevention, but a recent large randomized controlled trial found no evidence for a reduction in cancer risk. Given the anti-inflammatory effects of aspirin, systemic inflammatory diseases (SIDs), such as osteoporosis, cardiovascular diseases, and metabolic diseases, could potentially modify the aspirin-cancer link. To investigate the impact of aspirin in people with SIDs, we conducted an observational study on a prospective cohort of 478,615 UK Biobank participants. Individuals with at least one of the 41 SIDs displayed a higher cancer risk than those without SIDs. Regular aspirin use showed protective effects exclusively in patients with SID, contrasting an elevated risk among their non-SID counterparts. Nonetheless, aspirin use demonstrated preventative potential only for 9 of 21 SID-associated cancer subtypes. Cholesterol emerged as another key mediator linking SIDs to cancer risk. Notably, regular statin use displayed protective properties in patients with SID but not in their non-SID counterparts. Concurrent use of aspirin and statins exhibited a stronger protective association in patients with SID, covering 14 common cancer subtypes. In summary, patients with SIDs may represent a population particularly responsive to regular aspirin and statin use. Promoting either combined or individual use of these medications within the context of SIDs could offer a promising chemoprevention strategy.

Blood-brain barrier penetrating carbon dots with intrinsic anti-inflammatory and drug-loading properties.

The blood-brain barrier (BBB) is the major obstacle limiting the reach of therapeutic drugs into the brain. Herein, an aspirin-based anti-inflammatory replenisher (aspCD) was fabricated by carbonizing aspirin to deliver drugs into the brain visually. The as-prepared aspCD combined the BBB-penetrating and anti-inflammatory effects of aspirin with the fluorescent and drug-loading properties of carbon dots (CDs), thereby delivering therapeutic drugs into the brain and acting as imaging agent as well as anti-inflammatory replenisher. In vivo experiments of mice and zebrafish revealed that fluorescence aspCD could effectively penetrate BBB. In vitro and in vivo inflammatory models demonstrated that aspCD could be regarded as an excellent anti-inflammatory replenisher. In addition, as a functional carrier, aspCD was proved to be capable of loading drugs with different polarity. In summary, carbonization of active precursors (therapeutic drugs) into CDs could be a promising strategy to achieve the loading and visualization of drugs as well as the retainment of their biological activities.

The 15-Epilipoxin-A4 Pathway with Prophylactic Aspirin in Preventing Preeclampsia: A Longitudinal Cohort Study.

The benefit of aspirin in preventing preeclampsia is increasingly recognized; however, its mechanism of action remains unclear. Nonobstetric studies have described an anti-inflammatory effect of aspirin through the 15-epilipoxin-A4 pathway (aspirin-triggered lipoxin [ATL]). However, the anti-inflammatory mechanism of aspirin in the prevention of preeclampsia remains unknown. To examine (1) the difference in longitudinal endogenous lipoxin-A4 (En-Lipoxin-A4) concentration in low-risk (LR) and high-risk (HR) pregnancies, and (2) the effect of aspirin on endogenous ATL concentration and the associated effect on cytokine profile of HR women. Plasma from 220 HR women was collected at 12, 16, 20, 24, 28, 32, and 36 weeks of gestation. Adherence to aspirin was biochemically verified. Plasma En-Lipoxin-A4 and ATL concentrations were analyzed using liquid chromatography mass spectrometry, and cytokines, interleukin (IL)-10, tumor necrosis factor-α, interferon-γ, IL-8, and IL-1β, with the high-sensitivity multibead Luminex® assay. HR women have up to 70% lower plasma concentration of En-Lipoxin-A4 (P < 0.001) than LR women. HR women with adequate aspirin adherence (HR-AA) (n = 82) had higher plasma concentration of ATL (P < .001), lower concentration of IL-8 from 16 to 36 weeks of gestation (P < .001), and increased IL-10 concentration from 16 to 28 weeks of gestation (P = .03) compared with high-risk women who were not on aspirin (HR-NA). HR-AA who did not develop preeclampsia had higher plasma En-lipoxin-A4 (P < .001), ATL (P = .02), and IL-10 concentrations (P < .001) with lower IL-8 concentration (P = .004) than HR women who developed preeclampsia. Plasma concentration of En-Lipoxin-A4 is lower in HR women than in LR controls. Adequate adherence with aspirin results in an increase in ATL and IL-10 with reduced IL-8 plasma concentration. This study suggests a potential anti-inflammatory role of aspirin through the ATL pathway with prophylactic aspirin in HR pregnant women.

The association between aspirin use and depression: a systematic review and meta-analysis of observational studies.

Many clinical trials and observational studies have been conducted under the premise that the anti-inflammatory effect of aspirin may prevent depression. These studies, however, showed inconsistent results. To inspect the association between aspirin use and depression, we conducted a meta-analysis of observational studies. In August 2019, two authors independently searched PubMed, EMBASE, and PsycINFO to retrieve observational epidemiological studies presenting an association between aspirin use and depression. Case-control and cohort studies were included, and odds ratios (ORs) or relative risks (RRs) with 95% confidence intervals (CIs) for the risk of depression were estimated using a random-effects model. In addition, number needed to harm (NNH) was calculated to measure the rates of depression. In total, 12 observational studies-five case-control studies and seven prospective cohort studies-were included in this meta-analysis. The random-effects model demonstrated a significant association between aspirin use and depression (OR/RR 1.10; 95% CI: 1.05-1.16) with insignificant heterogeneity (I2 = 23.3%). The risk estimates of depression from prospective cohort studies were similar (RR 1.11; 95% CI: 1.08-1.14), and heterogeneity was not observed (I2 = 0.0%). In the subgroup meta-analysis, a duration of aspirin use ≥5 years and a dosage ≥500 mg daily were also associated with depression. The NNH for depression with aspirin use >5 years was 103 (95% CI 91-111) indicating that observed event is rare. Aspirin use was associated with depression in the present meta-analysis. One of the major limitations is the lack of detail and consistency with respect to exposure verification in the included papers. Another limitation is the lack of randomized controlled studies and prospective cohort studies.

Editors' note: Association between aspirin dose and subarachnoid hemorrhage from saccular aneurysms: A case-control study

In their retrospective case–control study of nearly 5,000 patients with saccular aneurysms, Can et al. found a protective effect of aspirin use with regard to aneurysm rupture. Furthermore, there appeared to be a dose–response relationship, which added to the biologic plausibility of their findings. The investigators postulated that the anti-inflammatory effect of aspirin may attenuate rupture risk in these patients. Vilanilam et al. mention that the data of Can et al. corroborate at least 2 prior investigations. Dr. Juvela, of the University of Helsinki, contends that the protective effect in this study may be confounded by selection bias—in which sicker, older patients were more likely to have taken aspirin prior to aneurysm identification or be on antihypertensive medications. At the request of Dr. Juvela, Can et al. also evaluate statin use and prior stroke as potential confounders, and find no significant association with aneurysm rupture. While aspirin may attenuate the risk of the index rupture event, the investigators found that aspirin use was associated with a significant, 8-fold higher odds of rerupture prior to definitive aneurysm treatment, although event rates were small. Vilanilam et al. question the relationship between aspirin dose and risk of rerupture; however, only 4 of 17 patients who reruptured were on aspirin prior to the index event, limiting a formal dose–response assessment. In their retrospective case–control study of nearly 5,000 patients with saccular aneurysms, Can et al. found a protective effect of aspirin use with regard to aneurysm rupture. Furthermore, there appeared to be a dose–response relationship, which added to the biologic plausibility of their findings. The investigators postulated that the anti-inflammatory effect of aspirin may attenuate rupture risk in these patients. Vilanilam et al. mention that the data of Can et al. corroborate at least 2 prior investigations. Dr. Juvela, of the University of Helsinki, contends that the protective effect in this study may be confounded by selection bias—in which sicker, older patients were more likely to have taken aspirin prior to aneurysm identification or be on antihypertensive medications. At the request of Dr. Juvela, Can et al. also evaluate statin use and prior stroke as potential confounders, and find no significant association with aneurysm rupture. While aspirin may attenuate the risk of the index rupture event, the investigators found that aspirin use was associated with a significant, 8-fold higher odds of rerupture prior to definitive aneurysm treatment, although event rates were small. Vilanilam et al. question the relationship between aspirin dose and risk of rerupture; however, only 4 of 17 patients who reruptured were on aspirin prior to the index event, limiting a formal dose–response assessment.

The Anti- Inflammatory Effects of Spinacia Oleracea Leaf Extract on Carrageenan Induced Inflammation in Rats

Context: Use of herbal medicine throughout the world is increasing. Plants still remaining the primary source of supply of many important drugs used in modem medicine. Spinacia Oleracea i,e spinach leaves contain more number of anti-inflammatory phytochemcicals such as carbohydratie, tanins and phenolic compounds, saponins, flavinoids and steroid. Better collagenation seen under the influence of the flavinoids, phenolic compound and saponins which is responsible for the free radical scavenging activity and are believed to be some of the most important component for wound healing and antioxident activity. Spinacia Oleracea scavenges free oxygen redicals and increases the catalase level in granulation tissue. Plants still remaining the primary source of supply of many important drugs used in modem medicine. Considering its medicinal value and availability in our country this study was undertaken to evaluate the antiinflammatory effect of the Spinacia Oleracea leaf extract in rat models.&#x0D; Material and Methods: The experiments were carried out on 30 (thirty) Swiss male albino rats. They were collected from the ICDDRB, Dhaka. The rats were of male weighing between 150- 200gm which were divided randomly into 5 groups each having 6 rats. Groups were labeled as group-I, group-II, group-III, group-IV and group-V. The anti inflammatory effect of Spinacia Oleracea leaf extract in experiment rat were evaluated and compared with the anti inflammatory effects of aspirin and hydrocortisone. The study was prospective experimental type and was conducted in the department of Pharmacology, Dhaka Medical College, Dhaka, from July 2011 to June 2012.&#x0D; Result : Administration of mathanolic extract and water extract of Spinacia Oleracea leaf at a dose of 200mg/kg body weight orally produced a significant (P&lt;0.05) anti-inflammatory effect, and the percentage of inhibition of oedema formation was 28.75% and 40.79% respectively. There were highly significant (P&lt;0.05) percentage of inhibition of oedema formation was observed in aspirin (40.52%) and in hydrocortisone (47.71%).&#x0D; Conclusion: Spinacia Oleracea leaf extract, possess significant anti-inflammatory activity in rats.&#x0D; J Dhaka Medical College, Vol. 27, No.1, April, 2018, Page 88-93

P3774Novel endothelial anti-inflammatory effects of aspirin and metformin - Role of the transcription factors NFkB and FOXO3a

P3774Novel endothelial anti-inflammatory effects of aspirin and metformin - Role of the transcription factors NFkB and FOXO3a

Abstract 5247: Aspirin use and estrogen receptor-negative breast cancer risk in African American women

Abstract Introduction: Use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been hypothesized to be associated with reduced risk of breast cancer; however, results of epidemiological studies have been mixed. Further, few previous studies investigated these associations among African American women and no studies that included African Americans evaluated whether associations differ by estrogen receptor (ER) status. Methods: To assess the relation of aspirin use to risk of ER+ and ER- breast cancer in African American women, we conducted a prospective analysis within the Black Women's Health Study, an ongoing nationwide cohort of 59,000 black women that began in 1995. On baseline and biennial follow-up questionnaires, women reported regular aspirin use (defined as use at least three days per week) and years of use. Acetaminophen use was queried similarly. Among women with available information on aspirin use, 1701 invasive breast cancers occurred during follow-up through 2015, including 962 ER+ and 492 ER- tumors. All cancers were confirmed through pathology reports or state cancer registry data. We used age-stratified Cox proportional hazards regression models to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for associations of aspirin use with risk of ER+ and ER- breast cancer. All models adjusted for age at menarche, oral contraceptive use, parity, age at first birth, estrogen plus progestin use, body mass index, alcohol consumption, and use of other NSAIDs. Results: Compared to never use, current regular use of aspirin was associated with lower risk of breast cancer overall (HR 0.87; 95% CI 0.76, 1.00). The association was driven by a statistically significant inverse association for ER- breast cancer (HR 0.76; 95% CI 0.58, 0.99); for ER+ breast cancer, the corresponding HR was 0.92 (95% CI 0.77, 1.09). In contrast, we found no associations with acetaminophen use. Conclusions: Our observation of reduced risk of ER- breast cancer in relation to current regular use of aspirin is consistent with anti-inflammatory effects of aspirin, rather than hormone-dependent pathways. Aspirin may represent a potential opportunity for chemoprevention of ER- breast cancer; however, these findings require corroboration in additional studies. Citation Format: Kimberly A. Bertrand, Traci N. Bethea, Hanna Gerlovin, Patricia Coogan, Lucile L. Adams-Campbell, Lynn Rosenberg, Julie R. Palmer. Aspirin use and estrogen receptor-negative breast cancer risk in African American women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5247.

Effects of aspirin on immobile behavior and endocrine and immune changes in the forced swimming test: Comparison to fluoxetine and imipramine

Aspirin (ASP) is the most commonly used non-steroidal anti-inflammatory drug in the world. Recent clinical and preclinical evidence suggests that ASP may also exert psychoactive effects. It remains unclear whether ASP has antidepressant-like activity, and any molecular mechanisms underlying such activity have yet to be elucidated. Using the forced swimming test (FST), a well-established animal model of depression widely used to screen potential antidepressants in rodents, we investigated the effects of subacute treatment with ASP (0, 6, 12, 25, and 50mg/kg, i.p.) on immobility in the FST, and on FST-induced changes in endocrine and immune parameters in rats, in comparison to the clinical antidepressants imipramine (IMI) and fluoxetine (FLU). Serum levels of corticosterone, pro-inflammatory cytokine interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were determined by enzyme-linked immunosorbent assay. ASP dose-dependently decreased immobility in the FST, without altering the locomotor activity in the open-field test. The inhibitory effects of higher doses (25 and 50mg/kg) of ASP on immobility were similar to that of FLU and IMI at a dose of 10mg/kg. In addition, the levels of corticosterone, IL-6, and TNF-α in peripheral blood were significantly increased after the FST exposure. IMI, but not FLU and ASP at any dose tested, significantly attenuated corticosterone responses in the FST. Both FLU and IMI treatment reduced the increase of IL-6 and TNF-α levels following the FST exposure. ASP dose-dependently decreased FST-induced increase of cytokine levels, as manifested by significantly stronger effects on IL-6 and TNF-α levels at higher doses (25 and 50mg/kg) than the lowest dose of ASP (6mg/kg). In all, these results indicate that ASP treatment dose-dependently decreased the immobility time and the release of pro-inflammatory cytokines in the FST, suggesting that the anti-inflammatory effects of ASP might be involved in the antidepressant-like effect.

AMP-activated protein kinase: a key regulator of energy balance with many roles in human disease.

The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that regulates cellular and whole-body energy balance. A recently reported crystal structure has illuminated the complex regulatory mechanisms by which AMP and ADP cause activation of AMPK, involving phosphorylation by the upstream kinase LKB1. Once activated by falling cellular energy status, AMPK activates catabolic pathways that generate ATP whilst inhibiting anabolic pathways and other cellular processes that consume ATP. A role of AMPK is implicated in many human diseases. Mutations in the γ2 subunit cause heart disease due to excessive glycogen storage in cardiac myocytes, leading to ventricular pre-excitation. AMPK-activating drugs reverse many of the metabolic defects associated with insulin resistance, and recent findings suggest that the insulin-sensitizing effects of the widely used antidiabetic drug metformin are mediated by AMPK. The upstream kinase LKB1 is a tumour suppressor, and AMPK may exert many of its antitumour effects. AMPK activation promotes the oxidative metabolism typical of quiescent cells, rather than the aerobic glycolysis observed in tumour cells and cells involved in inflammation, explaining in part why AMPK activators have both antitumour and anti-inflammatory effects. Salicylate (the major in vivo metabolite of aspirin) activates AMPK, and this could be responsible for at least some of the anticancer and anti-inflammatory effects of aspirin. In addition to metformin and salicylates, novel drugs that modulate AMPK are likely to enter clinical trials soon. Finally, AMPK may be involved in viral infection: downregulation of AMPK during hepatitis C virus infection appears to be essential for efficient viral replication.

Modulation of the CX3CL1/CX3CR1 signaling pathway by acetylsalicylic acid (aspirin) in human trophoblast (1096.9)

Aspirin inhibits cyclooxygenase (COX), acting stronger on the COX‐1 than the COX‐2. COX‐independent antiinflammatory effects of aspirin were also reported. Signaling pathway related to the chemokine CX3CL1 and its receptor CX3CR1 was proposed as a new target for aspirin. CX3CL1 modulates inflammatory response within the feto‐placental unit, influencing both adhesion and chemotaxis. HT produces CX3CL1 and expresses the CX3CR1. We examined the effects of aspirin on CX3CL1 production and CX3CR1 expression in HT obtained from normal term pregnanies (N = 24). The cytotrophoblasts were isolated using Kliman’s method based on trypsin, DNase and a 5‐70% Percoll gradient centrifugation, and cultured in normoxia. Secretion of CX3CL1 was augmented by lipopolysaccharide (1μg/ml). Next, the cultures were continuously exposed to aspirin, given in 6 different concentrations (1mM to 6mM) in respective groups. CX3CL1 levels in the culture media were measured using ELISA. After 5 days the cultures were fixed and immunostained for CX3CR1. CX3CR1 expression was examined by quantitative morphometry. Aspirin administered in higher doses (4.0mM and above) produced significant (p &lt; 0.05) inhibition of CX3CL1 production in HT. This effect was inversely proportional to significantly increased (p &lt; 0.02) expression of CX3CR1. Thus, influencing CX3CL1/CX3CR1, aspirin interferes with placental chemokine signaling network.Grant Funding Source: Supported by WUM grant: 2M2‐W2‐13.

Aspirin for Prevention of Subarachnoid Hemorrhage

Aspirin for Prevention of Subarachnoid Hemorrhage

Modifying action of heavy metal salts on an-ti-inflammatory aspirin action

Nowadays pollution of the environment is one of the major problems of mankind. Moreover, studying of the effect of different kinds of med- icine on selected, specially bred, non-exposed to external pollutants animals is becoming distant from reality. Thus in this work we have investigated the modifying action of heavy metals on anti-inflammatory effect of aspirin. The investigation were carried out on rats which were injected during 7 days intraperitoneally by PbCl3, HgCl2, CdCl2 in concentration of 100, 20, 1 mg/kg accordingly, modulating accumulation of the metals in the organism tissues. On the 8 days inflammation was invoked by formalin. As anti-inflammatory medicine was use aspirin. Judging by obtained results the conclusion can be drawn that cadmium in concentration 1 mg/kg significantly increases anti-inflammatory aspirin activity. The observed outcome can be explained in the following way. It is generally known that zinc in a certain concentration demonstrates anti-inflammatory properties. Be- ing an element of the same group cadmium has similar properties and also can have anti-inflammatory action. Lead and mercury suppre- ssed anti-inflammatory aspirin activity. Obvious inhibitory action of mercury and lead salts on aspirin action related to the fact that these elements by themselves were inflammation factors. From the obtained results the following conclusion can be drawn: a definite dose of anti-inflammatory medicine (aspirin) which is sufficient in normal conditions became less effective against the background of accumulation of ions of some heavy metals in an organism.

Recommendations for special populations: diabetes mellitus and the metabolic syndrome

Cardiovascular diseases (CVD) are the major causes of mortality in persons with diabetes, and many factors, including hypertension, contribute to this high prevalence of CVD. The incidence of hypertension in patients with diabetes is approximately twofold higher than in age-matched subjects without the disease, and conversely, individuals with hypertension are at increased risk of developing diabetes compared with normotensive persons. Furthermore, because up to 75% of cases of CVD in patients with diabetes can be attributed to hypertension, aggressive management of elevated blood pressure (BP) (ie, to <130/85 mm Hg) in these patients is essential for reduction in cardiovascular morbidity and mortality. The renin-angiotensin system is an important regulator of both BP and obesity, and its pharmacologic modulation may thus translate into significant cardiovascular benefits. Apart from hypertension and obesity, the important risk factors for CVD in patients with diabetes include atherosclerosis, dyslipidemia, microalbuminuria, endothelial dysfunction, platelet hyperaggregability, and coagulation abnormalities. Therefore, effective prevention of major cardiovascular events in patients with diabetes requires combination therapy with agents that target key factors contributing to cardiovascular morbidity and mortality. The antiplatelet and anti-inflammatory effects of aspirin, the lipid-lowering activity of statins, as well as the antihypertensive effects of various agents (eg, diuretics, β-blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin-II receptor blockers) have all been demonstrated to provide substantial reductions in cardiovascular events.

Adjunctive pharmacotherapy before percutaneous coronary intervention in non-ST-elevation acute coronary syndromes: the role of modulating inflammation.

Vascular inflammation is central to the pathogenesis of acute coronary syndromes (ACS) and the response to vascular injury after percutaneous coronary intervention (PCI). For both ACS and PCI, the magnitude of vascular inflammation is linked to adverse late clinical outcomes (e.g., death, recurrent myocardial infarction [MI] or ischemia, and restenosis). Many pharmacologic therapies with demonstrated efficacy for the treatment of ACS have anti-inflammatory properties, which are distinct from their perceived primary mechanism of action. The anti-inflammatory effects of aspirin, clopidogrel, low-molecular-weight heparin (LMWH), platelet glycoprotein (GP) IIb/IIIa receptor inhibitors, statins, and angiotensin converting enzyme (ACE) inhibitors are reviewed, and the hypothesis is generated that modulation of vascular inflammation at least in part contributes a common basis for the long-term clinical benefit ascribed to these medications. A therapeutic algorithm based on clinical risk stratification and coronary revascularization strategy is proposed for incorporating the current American College of Cardiology (ACC)/American Heart Association (AHA) guideline recommendations for treatment of patients who present with non-ST-elevation ACS.

Localization of cyclooxygenase-2 protein expression in lung cancer specimens by immunohistochemical analysis.

AbstractCyclooxygenase-2 (COX-2) inhibitors comprise a group of compounds that show promise as cancer preventives. COX-2 is an inducible enzyme that catalyzes the rate-limiting step in the synthesis of prostaglandins from arachidonic acid. The anti-inflammatory effects of aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) are a result of their inhibition of this enzyme. A role for this enzyme in cancer development was first hypothesized when it was noted that people who ingest NSAIDs regularly for long periods of time have a significantly reduced risk of colon cancer (1). Subsequently COX-2 was found to be expressed at high levels in about one-half of colorectal adenomas and most colorectal adenocarcinomas (2). And more importantly, NSAIDs and other COX-2 inhibitors significantly reduced colon tumor number in both animal (3,4), and clinical studies (5). KeywordsTissue SectionHumid ChamberColorectal AdenomaQuantitative Reverse Transcriptase Polymerase ChainAtypical Adenomatous HyperplasiaThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Non-prostaglandin effects of aspirin III and salicylate: inhibition of integrin-dependent human neutrophil aggregation and inflammation in COX 2- and NF kappa B (P105)-knockout mice.

Two, non-prostaglandin effects of antiinflammatory levels of salicylates (i.e. aspirin III) are shown here: 1) Exposure of neutrophils to aspirin or sodium salicylate inhibited Erk activity and integrin-dependent aggregation of neutrophils, consistent with antiinflammation but not COX inhibition. Inhibition of Mek (proximal activator of Erk) also blocked stimulation of Erk and neutrophil aggregation by FMLP and arachidonic acid. Thus, the antiinflammatory effects of salicylates may be mediated by inhibition of Erk signaling required for integrin-mediated responses. 2) Acute inflammation was induced in murine air-pouches of wild-type mice and mice rendered deficient in either COX-2 or p105, the precursor of p50 of NF kappa B. The antiinflammatory effects of aspirin and sodium salicylate were independent of the presence of COX-2 or p105 component of NF kappa B or the levels of prostaglandins at the inflammatory site. In contrast, glucocorticoid action depended on the p105.

Sites of action for future therapy: an adenosine-dependent mechanism by which aspirin retains its antiinflammatory activity in cyclooxygenase-2 and NFκB knockout mice

The antiinflammatory action of aspirin is generally attributed to inhibition of cyclooxygenases 1 and 2, but additional mechanisms are at work. These include inhibition of NFκB translocation to the nucleus and the capacity of aspirin to promote accumulation of adenosine, a potent antiinflammatory autocoid. We tested these hypotheses in the murine air pouch model of acute inflammation in wild type mice and in cyclooxygenase 2 or NFκB knockouts. The antiinflammatory effects of aspirin, sodium salicylate and indomethacin did not correlate with inhibition of cyclooxygenase in either group. Indeed, aspirin retained its antiinflammatory properties even in COX-2 knockouts. Similarly, aspirin was no less antiinflammatory in mice rendered deficient for NFκB (p105) than in wild type controls. In contrast, dexamethasone lost its antiinflammatory capacity in NFκB knockouts. Aspirin and sodium salicylate dramatically increased concentrations of adenosine in exudates, a property shared with methotrexate and sulfasalazine. Removal of adenosine by adenosine deaminase or specific antagonism of adenosine at A2receptors completely reversed the antiinflammatory effects of aspirin and sodium salicylate, but not those of dexamethasone. This adenosine-dependent, antiinflammatory effect of aspirin points to another target of drug development.

Salicylates and sulfasalazine, but not glucocorticoids, inhibit leukocyte accumulation by an adenosine-dependent mechanism that is independent of inhibition of prostaglandin synthesis and p105 of NFkappaB.

The antiinflammatory action of aspirin generally has been attributed to direct inhibition of cyclooxygenases (COX-1 and COX-2), but additional mechanisms are likely at work. These include aspirin's inhibition of NFkappaB translocation to the nucleus as well as the capacity of salicylates to uncouple oxidative phosphorylation (i.e., deplete ATP). At clinically relevant doses, salicylates cause cells to release micromolar concentrations of adenosine, which serves as an endogenous ligand for at least four different types of well-characterized receptors. Previously, we have shown that adenosine mediates the antiinflammatory effects of other potent and widely used antiinflammatory agents, methotrexate and sulfasalazine, both in vitro and in vivo. To determine in vivo whether clinically relevant levels of salicylate act via adenosine, via NFkappaB, or via the "inflammatory" cyclooxygenase COX-2, we studied acute inflammation in the generic murine air-pouch model by using wild-type mice and mice rendered deficient in either COX-2 or p105, the precursor of p50, one of the components of the multimeric transcription factor NFkappaB. Here, we show that the antiinflammatory effects of aspirin and sodium salicylate, but not glucocorticoids, are largely mediated by the antiinflammatory autacoid adenosine independently of inhibition of prostaglandin synthesis by COX-1 or COX-2 or of the presence of p105. Indeed, both inflammation and the antiinflammatory effects of aspirin and sodium salicylate were independent of the levels of prostaglandins at the inflammatory site. These experiments also provide in vivo confirmation that the antiinflammatory effects of glucocorticoids depend, in part, on the p105 component of NFkappaB.

Antiinflammatory action of salicylates: aspirin is not a prodrug for salicylate against rat carrageenin pleurisy

A current hypothesis postulates that the antiinflammatory effect of aspirin (acetylsalicylic acid) is mediated by its metabolite salicylic acid through inhibition of PGE 2 synthesis. We tested this hypothesis in rats with carrageenin-induced pleurisy. Aspirin or salicylate, given orally, reduced exudation and cell migration into the pleural cavity, aspirin being more potent than salicylate. The antiinflammatory effect of aspirin cannot be explained only in terms of salicylate formation. Doses of aspirin and salicylate that inhibit inflammation by 50% result in salicylate levels in the exudate of 70±12 and 323±17 μg/ml, respectively. At a significant antiinflammatory dose (100 mg/kg), salicylate did not reduce the prostaglandin and thromboxane content of the exudate. This indicates that inhibition of cyclooxygenase is not a likely mechanism for the antiinflammatory effect of salicylate. Salicylate only reduced the amount of 6-keto-PGF 1α in the exudate at higher doses (200 mg/kg), while aspirin at an equally antiinflammatory dose (50 mg/kg) reduced the content of 6-keto-PGF 1α, TXB 2, PGD 2 but not of PGE 2 in the exudate. It therefore seems unlikely that an inhibition of PGE 2 synthesis is the common mechanism by which aspirin and salicylate exert their antiinflammatory effects. These results do not supported the hypothesis that aspirin is a prodrug for salicylate but rather indicate that both compounds may exert their antiinflammatory effects partly by different mechanisms.