Contribution Of Cyclooxygenase Research Articles

Reduced basal macrovascular and microvascular cerebral blood flow in young adults with metabolic syndrome: potential mechanisms.

Ninety-million Americans suffer metabolic syndrome (MetSyn), increasing the risk of diabetes and poor brain outcomes, including neuropathology linked to lower cerebral blood flow (CBF), predominantly in anterior regions. We tested the hypothesis that total and regional CBF is lower in MetSyn more so in the anterior brain and explored three potential mechanisms. Thirty-four controls (25 ± 5 yr) and 19 MetSyn (30 ± 9 yr), with no history of cardiovascular disease/medications, underwent four-dimensional flow magnetic resonance imaging (MRI) to quantify macrovascular CBF, whereas arterial spin labeling quantified brain perfusion in a subset (n = 38/53). Contributions of cyclooxygenase (COX; n = 14), nitric oxide synthase (NOS, n = 17), or endothelin receptor A signaling (n = 13) were tested with indomethacin, NG-monomethyl-L-arginine (L-NMMA), and Ambrisentan, respectively. Total CBF was 20 ± 16% lower in MetSyn (725 ± 116 vs. 582 ± 119 mL/min, P < 0.001). Anterior and posterior brain regions were 17 ± 18% and 30 ± 24% lower in MetSyn; reductions were not different between regions (P = 0.112). Global perfusion was 16 ± 14% lower in MetSyn (44 ± 7 vs. 36 ± 5 mL/100 g/min, P = 0.002) and regionally in frontal, occipital, parietal, and temporal lobes (range 15-22%). The decrease in CBF with L-NMMA (P = 0.004) was not different between groups (P = 0.244, n = 14, 3), and Ambrisentan had no effect on either group (P = 0.165, n = 9, 4). Interestingly, indomethacin reduced CBF more in Controls in the anterior brain (P = 0.041), but CBF decrease in posterior was not different between groups (P = 0.151, n = 8, 6). These data indicate that adults with MetSyn exhibit substantially reduced brain perfusion without regional differences. Moreover, this reduction is not due to loss of NOS or gain of ET-1 signaling but rather a loss of COX vasodilation.NEW & NOTEWORTHY We tested the impact of insulin resistance (IR) on resting cerebral blood flow (CBF) in adults with metabolic syndrome (MetSyn). Using MRI and research pharmaceuticals to study the role of NOS, ET-1, or COX signaling, we found that adults with MetSyn exhibit substantially lower CBF that is not explained by changes in NOS or ET-1 signaling. Interestingly, adults with MetSyn show a loss of COX-mediated vasodilation in the anterior but not posterior circulation.

Preserved β-adrenergic-mediated vasodilation in skeletal muscle of young adults with obesity despite shifts in cyclooxygenase and nitric oxide synthase.

Central adiposity is associated with greater sympathetic support of blood pressure. β-adrenergic receptors (β-AR) buffer sympathetically mediated vasoconstriction and β-AR-mediated vasodilation is attenuated in preclinical models of obesity. With this information, we hypothesized β-AR vasodilation would be lower in obese compared with normal weight adults. Because β-AR vasodilation in normal weight adults is limited by cyclooxygenase (COX) restraint of nitric oxide synthase (NOS), we further explored the contributions of COX and NOS to β-AR vasodilation in this cohort. Forearm blood flow (FBF, Doppler ultrasound) and mean arterial blood pressure (MAP, brachial arterial catheter) were measured and forearm vascular conductance (FVC) was calculated (FVC = FBF/MAP). The rise in FVC from baseline (ΔFVC) was quantified during graded brachial artery infusion of isoproterenol (Iso, 1-12 ng/100 g/min) in normal weight (n = 36) and adults with obesity (n = 22) (18-40 yr old). In a subset of participants, Iso-mediated vasodilation was examined before and during inhibition of NOS [NG-monomethyl-l-arginine (l-NMMA)], COX (ketorolac), and NOS + COX (l-NMMA + ketorolac). Iso-mediated increases in FVC did not differ between groups (P = 0.57). l-NMMA attenuated Iso-mediated ΔFVC in normal weight (P = 0.03) but not adults with obesity (P = 0.27). In normal weight adults, ketorolac increased Iso-mediated ΔFVC (P < 0.01) and this response was lost with concurrent l-NMMA (P = 0.67). In contrast, neither ketorolac (P = 0.81) nor ketorolac + l-NMMA (P = 0.40) altered Iso-mediated ΔFVC in adults with obesity. Despite shifts in COX and NOS, β-AR vasodilation is preserved in young adults with obesity. These data highlight the presence of a compensatory shift in microvascular control mechanisms in younger humans with obesity.NEW & NOTEWORTHY We examined β-adrenergic receptor-mediated vasodilation in skeletal muscle of humans with obesity and normal weight. Results show that despite shifts in the contribution of cyclooxygenase and nitric oxide synthase, β-adrenergic-mediated vasodilation is relatively preserved in young, otherwise healthy adults with obesity. These data highlight the presence of subclinical changes in microvascular control mechanisms early in the obesity process and suggest duration of obesity and/or the addition of primary aging may be necessary for overt dysfunction.

Hypercapnic Cerebral Vasodilation: Contribution of Cyclooxygenase and Reactive Oxygen Species in Healthy and Metabolic Syndrome Adults

Excess reactive oxygen species (ROS) limit cerebral vasodilation in animal models of metabolic syndrome (MetSyn). Cyclooxygenase (COX) may be a source of ROS, but data are lacking in humans. We hypothesized ROS limit hypercapnic cerebral vasodilation in human MetSyn, but COX is not the source. We measured middle cerebral artery velocity (MCAv) with transcranial Doppler ultrasound in 12 MetSyn adults (34±2 yr) and 12 healthy adults (28±1 yr) during baseline and hypercapnia (end‐tidal CO‐2 +10 mmHg). Hypercapnia was performed under three conditions: 1) control, 2) ROS inhibition (intravenous ascorbic acid infusion), and 3) combined ROS and COX inhibition (oral indomethacin). MCAv was normalized for MABP and expressed as cerebrovascular conductance index [CVCi = (MCAv ÷ MABP) * 100]. The change in CVCi from baseline (ΔCVCi) indicated hypercapnic cerebral vasodilation. Hypercapnia increased CVCi in both groups across all conditions (p&lt;0.05). ΔCVCi was similar between groups in control trials and was unaffected by ROS inhibition. Combined ROS‐COX inhibition greatly decreased hypercapnic ΔCVCi (p&lt;0.05) similarly in both groups (healthy: 70±7% vs. MetSyn 84±8%). The decrease in hypercapnic cerebral vasodilation with combined ROS‐COX inhibition was quantitatively greater than previous published results with COX inhibition alone (~50% in both groups). In summary, MetSyn does not decrease hypercapnic cerebral vasodilation. ROS alone are not obligatory or inhibitory for hypercapnic cerebral vasodilation. Rather, ROS interact with COX to account for the vast majority (&gt;70%) of hypercapnic cerebral vasodilation in healthy and MetSyn adults.Support or Funding InformationAHA PRE7390038

Comparison in young White European (WE) and South Asian (SA) men of endothelium‐dependent cutaneous vasodilator responses: contribution of cyclooxygenase (COX) products

It is established that cardiovascular disease is more prevalent in South Asians (SA) than White Europeans (WE). The prevalence of diabetes central obesity and metabolic syndrome is particularly high in SAs, disorders that are associated with endothelial dysfunction. It is not known whether early markers of endothelial dysfunction can be detected even in young healthy SAs. Thus, we have compared responses evoked in recreationally‐active WE and SA men (18–25 years; n=10 in each case). SAs were 1st or 2nd generation residents in the UK with mother and father originating from India, Sri Lanka, Bangladesh or Pakistan; WEs were UK residents with WE parents. By using laser Doppler fluximetry, we monitored changes in cutaneous red cell flux (RCF) evoked in the cutaneous circulation of the forearm by iontophoresis of the endothelium‐dependent dilator acetylcholine (ACh, 8 × 20s pulses: 7 at 100 μA, 8th at 200 μA, at 60s intervals) and by release of arterial occlusion for 3 min (reactive hyperaemia). Responses were tested before and after aspirin (600mg p.o.) to assess the role of COX products. Mean arterial blood pressure (ABP) was continuously monitored by photoplethysmography using a finger cuff. Resting ABP was similar in WEs and SAs (124±1.8/70±1.7 vs 116.6±2.0/65.4±1.6 mmHg) and did not change during the protocol. Baseline RCF was also similar in WEs and SAs: 19.7±1.9 vs 12.3±0.9 perfusion units (PU), respectively. Further, ACh evoked similar dilator responses in WEs and SA, maximum RCF reaching 192.2±5.5 and 182.83 ± 5.20 perfusion units (PU) respectively. Aspirin had no net effect on ACh‐induced dilatation in either group (WEs: 182.6±4.5 and SAs: 193.0± 7.7 PU) indicating any influence of COX dilator and vasoconstrictor products was balanced in both WEs and SAs. By contrast, before aspirin, reactive hyperaemia was substantially larger in WEs than SA, peak RCF being 92.9±2.5 vs 74.2±3.1*PU, *: P&lt;0.01 RMANOVA). Further, aspirin attenuated reactive hyperaemia in WEs, peak RCF being only 75.1 ± 2.6§PU: §: P&lt;0.001 vs control response, but enhanced reactive hyperaemia in SAs, peak RCF reaching 84.7±2.7§PU. These results suggest that in young SA men, who have no overt signs of cardiovascular disease and are normotensive, there are already signs of endothelial dysfunction. Agonist‐evoked endothelium‐dependent dilatation is apparently normal in SAs with no net contribution from COX dilator or vasoconstrictor products, suggesting that nitric oxide and/or Endothelium‐dependent hyperpolarising factor are the main contributors in both ethnicities. However, reactive hyperaemia, which is induced by the combination of shear‐stress and metabolic stimuli, is blunted in young SAs relative to WEs and this is attributable to a predominating influence of vasoconstrictor COX products in SAs, but vasodilator COX products in WEs.Support or Funding InformationAlexander S. Onassis Public Benefit Foundation

Effects in young men of isometric handgrip training (IHG) on endothelium‐dependent vasodilator responses in the contralateral arm: changes in the contribution of cyclooxygenase (COX) products

Previous studies have shown that IHG and rhythmic handgrip training can reduce arterial blood pressure (ABP), especially in hypertensive subjects. The mechanisms underlying these effects are unclear, but it has been proposed that IHG training achieves its effects mainly by decreasing sympathetic activity. However, in hypertensive patients, IHG decreases plasma markers of oxidative stress. Thus, we tested the hypothesis in young normotensive men, that IHG improves endothelial function remotely, in the non‐trained arm. In 10 recreationally‐active men (18–25 years), we used laser Doppler fluximetry on the non‐dominant forearm to record changes in cutaneous red cell flux (RCF) evoked by iontophoresis of acetylcholine (ACh, 8 × 20s pulses: 7 at 100 μA, 8th at 200 μA, at 60s intervals), and following release of arterial occlusion for 3 min (reactive hyperaemia) before and after IHG training of the dominant forearm. IHG training comprised 4×3 min contractions at 30% Maximum voluntary contraction (MVC) at 5 min intervals, 4 days/week for 4 weeks. Before and after IHG training, we tested the contribution of COX products to dilator responses. IHG training did not affect resting ABP: 124±1.8/70±1.7 vs 125±1.8/72±1.6 mmHg. As expected, MVC was increased in the trained arm (29.0±1.3 vs 33.5±1.5Kg: P&lt;0.05, paired t‐test), but not in the contralateral arm (26±0.9 vs 27.1±2.6Kg). Before training, ACh‐induced dilator responses were unaltered by COX inhibition with aspirin (600mg p.o.): maximum RCF 192.2±5.5 vs 182.6±4.7 PU respectively), suggesting any contribution of COX dilator and constrictor products was balanced. By contrast, aspirin attenuated peak reactive hyperaemia from 92.9±2.5 to 75.07± 2.58PU (P&lt;0.05 : RMANOVA) indicating a contribution of COX dilator products. After IHG training, neither the magnitude of ACh‐induced dilatation, nor reactive hyperaemia was changed, but aspirin now augmented the ACh response: maximum RCF 192.6±4.1 increased to 227.5±5.2PU (P&lt;0.001), but had no effect on reactive hyperaemia (92.1±2.3 vs 91.8±3.6PU). These results suggest that in young normotensive men, IHG training of one arm has no effect on ABP and no net effect on the magnitude of endothelial‐dependent dilatation remotely, but does change the balance of influence of vasoconstrictor and dilator COX products. We propose that during IHG training, the contribution of COX dilator products to endothelium‐dependent, agonist‐evoked dilatation and reactive hyperaemia is attenuated and replaced with the influence of another dilator such as nitric oxide, leaving vasoconstrictor COX products limiting even greater agonist‐induced dilatation.Support or Funding InformationAlexander S. Onassis Public Benefit Foundation

Skin blood flow responses to locally applied acetylcholine in Caucasian and African descent individuals with and without cyclooxygenase inhibition

Individuals of African descent (AFD) are more susceptible to non-freezing cold injury (NFCI) than Caucasians (CAU) [1]. This may be a consequence of lower skin blood flow during local cold exposure and subsequent rewarming in AFD [2], possibly due to a difference in endothelium function as acetylcholine (ACh)-induced vasodilatation is smaller in AFD than CAU on the non-glabrous finger and toe skin sites [3]. It is known that prostaglandins produced by the enzyme cyclooxygenase (COX) mediate part of the ACh-induced vasodilator response [4] however in hypertensive individuals, COX inhibition results in augmented vasodilatation in response to ACh [5] demonstrating that COX can also promote vasoconstriction. Whether COX products are involved in the attenuated vasodilator response to ACh in healthy AFD [3] is not known. Therefore, the aim of the present study was to investigate the contribution of COX in both CAU and AFD to local application of ACh in foot and finger skin sites which are susceptible to NFCI.

Contributions of cyclooxygenase (COX) and NO synthase (NOS) pathways to endothelium‐dependent dilatation in the finger of women

We tested the roles of COX and NOS in finger vasodilatation evoked by iontophoresis of acetylcholine (ACh), using laser Doppler fluximetry. In 12 women in the low oestrogen (E2) phase of the menstrual cycle, aspirin (600mg p.o) decreased baseline finger red cell flux (RCF) from 55.0±7.8 to 30.6±5.5* perfusion units (pu; *: P&lt;0.05), and the ACh‐evoked response from +296.8±23.9 to +251.4±24.4* pu. In the high E2 phase, COX inhibition decreased baseline from 68.0 ± 13.8 to 38.4 ± 8.1*, but had no effect on the ACh response (259.5±27.4 vs 251.2±23.3 pu). On different days, NOS inhibition with L‐NAME had no effect on baseline RCF in the low, or high E2 phase. In the low E2 phase, the ACh response was unchanged (+228.26±25.8 vs 225.6±21.3pu), but aspirin then decreased the response further to 175.9±17.6*pu. In the high E2 phase, L‐NAME increased the ACh response from +198.1±23.7 to +229.2±27.4*pu; COX inhibition restored it to +202.8±27.8pu. We propose that in the finger, NOS generates both NO and O2− and thereby, ONOO− which inhibits PGI2 synthase. E2 facilitates NOS and PGI2 synthase such that when E2 is high, PGI2 contributes to endothelium‐dependent finger dilatation only after NOS inhibition.

Cyclooxygenases and lipoxygenases in cancer

Cancer initiation and progression are multistep events that require cell proliferation, migration, extravasation to the blood or lymphatic vessels, arrest to the metastatic site, and ultimately secondary growth. Tumor cell functions at both primary or secondary sites are controlled by many different factors, including growth factors and their receptors, chemokines, nuclear receptors, cell-cell interactions, cell-matrix interactions, as well as oxygenated metabolites of arachidonic acid. The observation that cyclooxygenases and lipoxygenases and their arachidonic acid-derived eicosanoid products (prostanoids and HETEs) are expressed and produced by tumor cells, together with the finding that these enzymes can regulate cell growth, survival, migration, and invasion, has prompted investigators to analyze the roles of these enzymes in cancer progression. In this review, we focus on the contribution of cyclooxygenase- and lipoxygenase-derived eicosanoids to tumor cell function in vitro and in vivo and discuss hope and tribulations of targeting these enzymes for cancer prevention and treatment.

Critical role of COX‐1 in prostacyclin production by human endothelial cells under modification of hydroperoxide tone

We aimed at evaluating the relative contribution of cyclooxygenase (COX) -1 and COX-2 to the synthesis of prostacyclin in endothelial cells under static conditions in the presence or absence of exogenous arachidonic acid and/or altered intracellular redox balance. Selective inhibitors of either COX-1 (SC560 and FR122047) or COX-2 (SC236) concentration dependently (1-300 nM) reduced basal and interleukin (IL) -1beta-induced prostacyclin production in human umbilical vein endothelial cells by 70% or more; compound selectivity was confirmed using a whole-blood assay (IC(50) COX-1/COX-2: 13 nM/930 nM for SC-560; 9 microM/457 nM for SC-236). The observed concomitant formation of isoprostane appeared to be associated with COX enzyme activity, while formation of COX-1/COX-2 heterodimers was detected by immunoprecipitation. In the presence of arachidonic acid and 12-hydroperoxy-eicosatetraenoic acid, either exogenous or provided by platelet activation, or after glutathione depletion, COX-1 inhibition but not COX-2 inhibition concentration dependently decreased prostacyclin production. Both isoforms appear to contribute to basal prostacyclin production by endothelial cells, with COX-2 providing the hydroperoxide tone required for COX-1 activity. Conversely, in the case of intracellular glutathione depletion or enhanced availability of arachidonic acid and hydroperoxides, selective COX-2 inhibition did not significantly affect the production of endothelial prostacyclin. These findings contribute to a better understanding of the effects of cyclooxygenase inhibitors on prostacyclin production.

Comparison of Vascular Reactivity Profiles in the Superior Mesenteric Artery and Aorta of Normal and Insulin Resistant Wistar Rats: Role of Cyclooxygenase

Regulation of vascular tone in the superior mesenteric artery (SMA) is an important contributor to elevating blood pressure secondary to insulin resistance. Although narrower than the aorta, it is debatable whether the SMA is a conduit or resistance vessel. In fructose-fed rats, an animal model of the metabolic syndrome, the contribution of cyclooxygenase (COX) isoforms to vascular reactivity in both aorta and SMA is unclear. We evaluated and compared the effects of COX-1 and 2 on (PE) phenylephrine-evoked contraction in the aorta and SMA of 9-week fructose-fed male rats. Following induction of insulin resistance and increased systolic blood pressure, isolated aorta and SMA rings were incubated with a selective COX-2 inhibitor NS-398 (10−6M) and non-selective inhibitor indomethacin (10−5M). Responses to PE (10−9 – 10−4M) were obtained prior to and after treatment. We also studied the changes in relaxation to ACh in SMA in the presence of indomethacin. Contraction to PE was reduced in both the aorta and SMA of fructose-fed rats in presence of either NS-398 or indomethacin as compared to untreated rings. Conversely, inhibition of COX also improved endothelium- dependent relaxation in the SMA of fructose-fed rats suggesting a proconstrictor role for COX-2-catalyzed prostanoids. In conclusion our results point to a conduit role for the SMA in vasoconstriction, which is similar to that observed in the aorta.

Evidence for chemicals sensitizing discharge from skeletal muscle afferents supporting cardiorespiratory reflexes during simulated exercise

the chemical metabolites in skeletal muscle that sensitize the activity of small-diameter afferents and support increases in cardiorespiratory function during exercise have been the subject of much investigation with a variety of methods. The chemicals that change within muscle with exercise have

Cellular distribution and contribution of cyclooxygenase (COX)-2 to diabetogenesis in NOD mouse

Unlike most other mammalian cells, beta-cells of Langerhans constitutively express cyclooxygenase (COX)-2 rather than COX-1. COX-2 is also constitutively expressed in type 1 diabetes (T1D) patients' periphery blood monocytes and macrophage. To understand the role of COX-2 in the beta-cell, we investigated COX-2 expression in beta-cells and islet infiltrates of NOD and BALB/c mice using fluorescence immunohistochemistry and cytochemical confocal microscopy and Western blotting. Immunostaining showed that COX-2 is expressed in islet-infiltrating macrophages, and that the expression of insulin and COX-2 disappeared concomitantly from the beta-cells when NOD mice progressed toward overt diabetes. Also cultured INS-1E cells coexpressed insulin and COX-2 but clearly in different subcellular compartments. Treatment with celecoxib increased insulin release from these cells in a dose-dependent manner in glucose concentrations ranging from 5 to 17 mM. Excessive COX-2 expression by the islet-infiltrating macrophages may contribute to the beta-cell death during insulitis. The effects of celecoxib on INS-1E cells suggest that PGE(2) and other downstream products of COX-2 may contribute to the regulation of insulin release from the beta-cells.

Cyclooxygenase and Alzheimer's disease: implications for preventive initiatives to slow the progression of clinical dementia

Industry and academia are devoting a tremendous amount of resources to the testing of anti-inflammatory drugs for the treatment of Alzheimer's disease (AD). This trend is the result of the growing consensus supporting the inflammatory hypothesis of AD. If anti-inflammatory strategies succeed in slowing the rate of disease progression, the impact on patients and families could be enormous. However, given the large number of candidates in the pool of anti-inflammatory drugs and given their widely divergent activities, it is essential to use methods which optimizes drug selection and study design. Pilot studies of anti-inflammatory regimens are useful in determining tolerability. However, these studies have limited value in estimating effective size since disease-modification, rather than symptomatic improvement, is the ultimate goal. Better understanding of the influence of inflammatory activity and the specific mechanisms which play an early role in the progression of the disease, will improve the likelihood of successfully identifying an effective anti-inflammatory treatment strategy. This review outlines directions in research that address possible contributions of cyclooxygenase (COX)-2, COX-1 and other inflammatory mediators to AD neurodegeneration. Finally, this article addresses potential interventions designed to control segments of classical inflammatory cascades in the brain in which cyclooxygenase is highly implicated. These considerations are critical to understand the role of cyclooxygenase in the clinical progression of AD.

Association of enhanced cyclooxygenase-2 expression with possible local immunosuppression in human colorectal carcinomas.

Prostaglandin (PG) E2 has an influence on antitumor lymphocyte reactions and causes local immunosuppression at tumor sites. The contribution of cyclooxygenase (COX), a key enzyme in PGE2 synthesis, to this effect is still unclear. We examined if cyclooxygenase (COX)-2 is involved in local immunosuppression in human colon carcinoma cell lines and in clinical tumor specimens. PGE2 concentrations were measured in culture media from a highly COX-2-expressing human colon carcinoma cell line (CE-1) and other cell lines. Lymphocyte proliferation in response to a mitogen was used to evaluate immunosuppression in tumor cell-lymphocyte cocultures with and without selective COX-2 inhibitor NS-398. We also evaluated expression of COX-2 mRNA in surgical specimens of colorectal carcinoma by reverse transcription polymerase chain reaction (RT-PCR) and COX-2 protein by immunohistochemistry, correlating COX-2 expression with clinicopathologic features. CE-1 cells produced large amounts of PGE2, which was significantly inhibited by NS-398. The proliferation index of lymphocytes cocultured with CE-1 cells was significantly less than that of control lymphocytes; again, this effect was inhibited by NS-398. While human colorectal carcinoma tissue expressed more COX-2 mRNA and protein than nonneoplastic tissue, no significant correlation was found between COX-2 levels and clinicopathologic features. Overexpression of COX-2 in colon cancer may cause local immunosuppression, and COX-2 inhibitors might be therapeutically useful against these tumors.

Platelet-activating factor-induced vasoconstriction in rat isolated, perfused hearts: Contribution of cyclo-oxygenase and lipoxygenase arachidonic acid metabolites

The mechanism of the coronary vasoconstrictor action of platelet-activating factor (PAF) has been investigated in rat isolated, perfused hearts. PAF elicited an increase in coronary perfusion pressure which was attenuated by indomethacin- or diethylcarbamazine- pretreatment, whereas FPL55712 had a marked inhibitory effect. Accompanying the coronary vasoconstrictor response to PAF was an increase in the release of PGE 2, PGF 2α, 6-keto-PGF 1α and TxB 2 and the appearance of biologically-active concentrations of LTB 4 and LTC 4 in the cardiac effluent. Indomethacin-pretreatment prevented the increase in release of the measured cyclo-oxygenase metabolites without significantly altering the generation of either LTB 4 or LTC 4. Diethylcarbamazine markedly inhibited the PAF-induced release of both cyclo-oxygenase and lipoxygenase products. These findings suggest a causal role for vasoconstrictor arachidonic acid metabolites in the acute cardiac effects of PAF with the quantitatively most important contribution to the vasoconstriction made by LTC 4.

The contribution of cyclooxygenase and lipoxygenase products to acute inflammation in the rat.

The contribution of cyclooxygenase and lipoxygenase products to acute inflammation in the rat.