Platelet function: aggregation by PAF or sequestration in lung is not modified during immediate or late allergen-induced bronchospasm in man

Among the mediators involved in the pathophysiologic mechanisms that underly the reactions of the acute and delayed phases of bronchospasm induced by allergens in man, platelet-activating factor (PAF) could play an important role, in particular by its effects on platelets. In animals, inhalation or injection of PAF causes a platelet-dependent bronchoconstriction that is blocked by prior administration of an antiplatelet antiserum and accompanied by platelet accumulation in the pulmonary vessels. In man, inhalation of PAF causes a bronchospasm and induces a bronchial hyperreactivity. Abnormalities of platelet aggregation and the secretion into plasma of platelet factor 4 and beta-thromboglobulin have been described in patients with asthma during induced bronchospasm. Platelet functions have been studied in 15 patients with asthma before and after allergen bronchial provocation tests. There was no difference between platelet counts, plasma concentrations of platelet factor 4 and beta-thromboglobulin, and platelet aggregation induced by several agonists (adrenaline, arachidonic acid, or PAF) before and immediately after the allergen bronchial provocation test. There was no platelet pulmonary sequestration as studied with 111Indium-labeled platelets during 24 hours after the antigen challenge, and the life span of circulating platelets was normal. Our results do not support an important direct role for PAF in the pathophysiology of asthma. It is still possible that the current methodology is too insensitive to detect amounts of PAF in the circulation or that PAF is acting locally.     

Edematogenic Activity of Scorpion Venoms from the Buthidae Family and the Role of Platelet-Activating Factor and Nitric Oxide in Paw Edema Induced by <Emphasis Type="Italic">Tityus</Emphasis> Venoms

We compared the edematogenic activity of venoms of scorpions from the Buthidae family, Tityus bahiensis (Tbv), Tityus serrulatus (Tsv) and Rhopalurus rochai (Rrv). Three doses (20, 40 and 80 μg/kg sc) of each venom were administrated in hind paw of mice and edema was measured from 5 min to 24 h. Tbv and Tsv both induced edema of rapid onset (135% of increase at 15 min); Rrv induced only a mild edema (40% of increase). We then investigated the involvement of platelet-activating factor (PAF) and endogenous nitric oxide (NO) in Tbv and Tsv-induced paw edema. Pretreatment of mice with a PAF antagonist (WEB-2170) inhibited Tsv but not Tbv-induced edema. Pretreatment with a non selective inhibitor of NO-synthases (l-NAME) inhibited or increased the edema depending on the dose and the time the edema was measured. In conclusion, the venoms from Tityus are stronger inducers of edema than the venom from the Rhopalurus scorpion. The venoms of Tityus species are similar in potency and time-course edema development. PAF is involved in the edema induced only by Tsv.     

Evidence for platelet-activating factor as a late-phase mediator of chronic pancreatitis in the rat.

The role of platelet-activating factor (PAF) as a mediator of pancreatic inflammation was examined in the rat pancreatic duct ligation model of obstructive pancreatitis. Pancreatic generation of PAF, as measured by bioassay (ie, platelet [3H]serotonin secretion), was determined at various times after induction of inflammation. Tissue levels of PAF in the normal pancreas averaged 600 +/- 49 pg/g, but PAF was not detectable during the initial 24 hours of pancreatitis, a time when the inflammatory reaction would be considered acute, that is, during the period of maximal serum amylase release and the development of interstitial edema. However a substantial increase in pancreatic PAF levels (12 times control levels) was observed 7 to 14 days after duct ligation during the late-phase response interval similar to the situation characteristic of chronic pancreatitis in which parenchymal atrophy, fibrosis, and pancreatic insufficiency evolve. One week after duct ligation when PAF levels peaked, an evaluation was made of the effects of PAF antagonists (BN52021 and WEB2170) on pancreatic lesions using Evan's blue extravasation, pancreatic myeloperoxidase (MPO) activity, and acid phosphatase activity in peritoneal lavage fluid. BN52021 or WEB2170 treatment was shown to reduce pancreatic damage and inflammation significantly. Long-term in vivo administration of exogenous PAF (20 micrograms/kg/hr for 7 days) exhibited a reduction of [3H]thymidine uptake into and amylase release from pancreatic acini in vitro. Our observations 1) that pancreatic PAF levels increased significantly during the chronic phase of obstructive pancreatitis induced by duct ligation; 2) that inhibition of the action of PAF, through specific receptor antagonism, caused an attenuation of pancreatic lesions; and 3) that chronic administration of PAF resulted in decreased pancreatic regeneration and exocrine function are consistent with a pivotal role for PAF as a late-phase inflammatory mediator in chronic pancreatitis in rats.     

Platelet activating factor potentiates rat paw oedema induced by different phlogogen agents

Carrageenin oedema is enhanced by the simultaneous injection in the rat paw of platelet activating factor (PAF). The enhancement of carrageenin oedema is observed throughout the time course of the experiments. This enhancement is also present when the oedema-producing agent is dextran, cellulose sulphate, histamine, 5-hydroxytryptamine, bradykinin or prostaglandin E₂. Both verapamil and BN 52021 abolished the enhancement induced by PAF without modifying significantly carrageenin oedema. In essential fatty acid deficient (EFAD) rats depleted of kininogen and amines, carrageenin oedema is not modified by PAF. These findings suggest that PAF interacts with other inflammatory mediators regulating the formation of oedema induced by irritants injected locally.     

Aggregating and prostanoid-releasing effects of platelet-activating factor and leukotrienes on human polymorphonuclear leukocytes and platelets

Aggregating and prostanoid-releasing properties of the inflammatory mediators, platelet-activating factor (PAF) and leukotrienes B4, C4 and D4 were studied in human polymorphonuclear leukocytes (PMNL) and in human platelet-rich plasma. Leukotriene B4 (LTB4) and PAF both induced a reversible aggregation of human PMNL with concomitant stimulation of PGE2 formation, whereas LTC4 had no effect on human PMNL. Arachidonic acid (AA) caused an irreversible aggregation of PMNL which was accompanied by formation of both PGE2 and TXB2. Inhibition of TXB2 synthesis by indomethacin or by OKY-1581, a thromboxane synthetase inhibitor, had no effect on the PMNL aggregation induced by LTB4, PAF or AA. Leukotrienes B4, C4 and D4 caused neither aggregation nor TXB2 release in human platelet-rich plasma. PAF, on the other hand, induced a dose-dependent, reversible platelet aggregation which was not accompanied by TXB2 formation nor inhibited by OKY-1581. The present study indicates that in addition to inducing PMNL aggregation, LTB4 is capable of releasing arachidonate metabolites from human PMNL but not from human platelets. Also the responses of PMNL and platelets to PAF seem to differ as the PAF-induced PMNL aggregation was accompanied by increased prostanoid formation whereas the PAF-induced reversible platelet aggregation was obviously independent from arachidonate metabolism.     

Comparison of antiinflammatory and antiallergic drugs in the melittin- and D49 PLA2-induced mouse paw edema models

Melittin (MLT) (10 g/paw) and D49 (0.4 g/paw) were injected into the hind paw of male CD-1 mice and elicited 70–80% of maximal paw edema responses at 60 and 30 min after injection, respectively. D49 paw edema was significantly inhibited by anti-histamine/serotonin agents, a PAF antagonist, a PLA₂ inhibitor, and some but not all 5-LO and CO inhibitors, indicating that this edema is produced by several classes of inflammatory mediators with mast cell degranulation apparently playing a major role. In contrast, MLT paw edema was not inhibited effectively using the same pharmacological agents except theophylline, suggesting it was elicited via a different sequence of inflammatory events. In summary, D49 and MLT paw edema models were found to be ineffective models to identify experimental PLA₂ compounds in our laboratory.     

血小板活化因子的支气管收缩作用及其机理研究

本文研究了血小板活化因子对豚鼠在体和离体支气管平滑肌的收缩作用，同时对ＰＡＦ的这一作用机制进行了讨论。结果：１．ＰＡＦ静脉和雾化吸入均迅速引起支气管收缩，并伴有外周循环血小板数减少。２．单纯ＰＡＦ对离体支气管平滑肌条的收缩作用微弱，当加入洗涤血小板后其收缩作用明显增强。３．血栓素Ａ２受体拮抗剂（ＡＡ－２４１４）明显抑制了ＰＡＦ加血小板而引起的支气管平滑肌收缩。提示ＰＡＦ对支气管平滑肌可有直接作用，     

Experimental acute pancreatitis induced by platelet activating factor in rabbits.

This study indicates that a single injection of platelet activating factor (PAF, 50-500 ng) into the superior pancreaticoduodenal artery of rabbits induces dose-dependent morphologic alterations of pancreatic tissue and increases serum amylase levels, both consistent with the development of an acute pancreatitis. The main histologic findings observed by light microscopy 24-72 hours after the injection of PAF were edema, polymorphonuclear neutrophil infiltration, cell vacuolization, and acinar cell necrosis. Fat cell necrosis was present in 30% of animals. By electron microscopy an increase of the number of zymogen granules in the apical region of acinar cells was observed 3 hours after PAF challenge. At 24-72 hours, many acinar cells showed vacuoles containing myelinlike figures, zymogen granules, and cellular debris. Pancreatic lesions developed in the area supplied by the artery injected with PAF and they were completely antagonized by the pretreatment of rabbits with CV 3988, a specific antagonist of PAF. In addition, the significant protective effect of atropine suggests a potential role for cholinergic mechanisms in the pancreatic alterations induced by PAF.     

Effect of selected antiinflammatory agents and other drugs on zymosan,arachidonic acid,PAF and carrageenan induced paw edema in the mouse

Zymosan, carrageenan, arachidonic acid and platelet activating factor (PAF) were used to induce inflammation (edema) in the paws of mice. Antiinflammatory drugs (e.g., BW755C and indomethacin) as well as cyproheptadine (mediator antagonist), theophylline (phosphodiesterase inhibitor) and guanabenz ( adrenoceptor agonist) showed the greatest efficacy in the carrageenan and zymosan models. Nonsteroidal antiinflammatory (NSAIDs) agents showed greater activity in the arachidonic acid (AA) paw edema model than the dual 5-lipoxygenase (LO)/cyclooxygenase (CO) inhibitors. The PAF model was insensitive to NSAIDs but showed some activity with drugs possessing inhibitory 5-LO activity (e.g., phenidone, BW755C) and the mediator antagonist, cyproheptadine. Suramin, a complement inhibitor, as expected, was active only against zymosan-induced edema. In conclusion, the inhibitory activities of dual 5-LO/CO inhibitors and NSAIDs were not different in the zymosan, carrageenan and AA edema models in the mouse; however, some selectivity for 5-LO inhibitors was observed in the PAF model.     

Characteristic features of actinomycin D-induced paw inflammation of the rat.

Features of paw edema induced by subplantar injection of actinomycin D (act D) were investigated in rats. The paw edema was produced as early as the 1st day and reached a maximal level on the 3rd or the 4th day. Thereafter, it began to subside progressively and was considerably reduced by the 16th day following act D (20 μgm) injection. A direct dose response relationship between the amount of act D injected and the intensity of the paw edema was obtained. No difference in β-glucuronidase and acid phosphatase activity was found between saline and act D-injected paws on the 2nd day. This was followed by an increase in the activity of both enzymes on the 4th, 8th, and 16th days after injection. The histamine content of the saline and act D-injected paws remained unchanged during the early phase of inflammation. A marked increase in the histamine content was noted during the late phase in the drug-injected paw. The effects of act D treatment on capillary permeability to Evans blue dye (EBD) and the edema formation of the paw revealed that a maximal increase in vascular permeability to EBD occurred on the 1st day and was maintained until the 8th day. In contrast to permeability, the paw edema on the 1st day was minimal and increased progressively until the 3rd or 4th day. Thereafter, both the permeability and the paw edema began to diminish and were considerably reduced on the 16th day. Aspirin and hydrocortisone treatment were ineffective in suppressing the act D-induced paw inflammation. Indomethacin produced a somewhat dose-related anti-inflammatory effect against the inflammation caused by this drug.     

Use of cetirizine to investigate non-H1 effects of second-generation antihistamines.

In addition to their increased potency as H1 blockers and their nonsedating effects, the second-generation antihistamines have other unusual and potentially beneficial properties. Evidence is accumulating from several laboratories that at least one of these agents under investigation, cetirizine, may be effective in inhibiting the late reaction. The Johns Hopkins group showed that during the cutaneous late phase response (LPR), histamine release was not altered by cetirizine, 20 mg, pretreatment. The most dramatic effect of cetirizine was attenuation of inflammatory cell migration into the chamber. Eosinophils, neutrophils, and basophils were reduced by about 75% during hours 6 to 8. It can be concluded that cetirizine influences the LPR by causing a reduction in the inflammatory cell infiltrate. Cetirizine, 10 mg, orally once a day also induced a significant decrease in the wheal and flare skin reactions caused by pollen, histamine, and compound 48/80. Cetirizine inhibited eosinophil recruitment and platelet-activating factor (PAF) in skin chambers 24 hours after pollen challenge. We and others have studied the mechanisms of this effect. The release of eosinophil peroxidase induced by PAF and formyl-methionyleucyl/phenylalanine was not attenuated by cetirizine. At therapeutic concentrations, however, cetirizine has a potent inhibitory action in vitro on eosinophil chemotaxis induced either by formyl-methionyleucyl/phenylalanine or PAF and also on IgE-dependent stimulation of platelets. In a separate study in patients with chronic urticaria, cetirizine markedly reduced both the immediate wheal and flare induced by PAF and the delayed reaction at six hours. These results suggest that cetirizine acts on eosinophil migration to inhibit the late reaction.     

The effects of some benzoic acid derivatives on polymorphonuclear leukocyte accumulation in vivo

Previous studies, aimed at establishing a relationship between the inhibition of prostaglandin (PG) biosynthesis and the suppression of carrageenin-induced rat paw edema, indicated that, in a series of acetylsalicylic acid (ASA)-like compounds, there is not a good correlation between ability to inhibit platelet PG biosynthesis and anti-inflammatory activity. Some of the compounds tested had good anti-edema properties compared to ASA, but did not inhibit platelet lysate conversion of 14C-arachidonic acid (AA) to PGs. The effects of these compounds on polymorphonuclear (PMN) leukocyte accumulation in urethane-anesthetized rats were examined to extend the pharmacological profile of these agents in a search for other mechanisms of anti-inflammatory activity. 3-Methylphthalide (3-MP), an inhibitor of rat paw edema, suppressed PMN leukocyte accumulation although it is a poor inhibitor of PG cyclo-oxygenase activity. 3-Propionyloxybenzoic acid (3-PBA), an agent which increases primary platelet aggregation and arterial PGI2 production, caused increases in edema formation but decreases in PMN leukocyte accumulation. 2-Propionyloxybenzoic acid (2-PBA), which is similar to ASA in many effects, resulted in a trend towards decreased PMN leukocyte accumulation, while ASA did not. 2-Acetylbenzoic acid (ABA), an agent with anti-edema properties similar to ASA in the rat paw model but without any effect on PG biosynthesis, also caused a trend towards inhibition of PMN leukocyte accumulation. In addition to drug effects on prostaglandin biosythesis, this study indicates that drug effects on PMN leukocyte accumulation is an important determinant of anti-inflammatory potential.     

Inhibition of platelet activation by quinones isolated from Auxemma oncocalyx Taub

The present work explored the anti-platelet effect produced by the quinone fractions (17.8, 35.7 and 71.4 microg/ml) isolated from the heartwood of Auxemma oncocalyx Taub. Our results show that the quinone fraction (QF) is a reversible and concentration-dependent inhibitor of human platelet aggregation induced by ADP, arachidonic acid (AA), collagen and thrombin. Besides, the QF effect was significantly potentiated after its association with aspirin or imidazole, and in this case, the AA-induced platelet aggregation was completely blocked. The addition of QF to L-arginine caused a small but significant increase in the percentage of platelet inhibition (13%) only when compared to QF alone. Finally, the addition of QF to pentoxifylline, a known phosphodiesterase inhibitor, resulted in significant potentiation (43% inhibition) of the antiplatelet effects seen with QF (9.7%) or PTX (10%) alone. Although QF presented an antiplatelet effect, it caused a significant decrease in bleeding time, manifested 3 h after oral (100 or 200 mg/Kg) or 1 and 3 h after intraperitonial (30 mg/Kg) administration. In conclusion. QF possibly acts through a combined cyclo-oxygenase and TxA2 synthase inhibition. Besides, QF also increases platelets cAMP levels which also contributes to its anti-aggregatory effects.     

Anti-inflammatory pharmacology and mechanism of the orally active capsaicin analogs,NE-19550 and NE-28345

We have evaluated the properties of a new class of anti-inflammatory agents derived from capsaicin, using the analogs NE-19550 (N-vanillyloleamide) and NE-28345 (N-oleyl-homovanillamide) as examples. This class displayed an atypical profile in the assays utilized, including 1) anti-edema and antileukocyte migration activity in the rat carrageenan pleurisy assay without suppression of pleural prostanoid synthesis, 2) blockade of human platelet aggregation induced by arachidonate or PAF but not that induced by the PGH₂ analog U-46619, without equivalent inhibitionin vitro of mammalian cyclooxygenase or thromboxane synthetase preparations, 3) greater potency and efficacy in the rat implanted sponge assay than in the adjuvant arthritis assay, without inhibition of LTB₄ or 15-HETE synthesisin vitro, 4) stronger topical activity in the mouse croton oil inflamed ear assay than the guinea pig UV erythema assay, and 5) oral activity in the rat carrageenan paw edema assay and mouse phenylquinone abdominal constriction rest combined with failure to induce gastric erosion in rats at therapeutic doses. We conclude that NE-19550 and NE-28345 do not act like conventional NSAIDs via suppression of arachidonic acid metabolism.     

Effect of dexamethasone associated with serum therapy on treatment of Bothrops jararaca venom-induced paw edema in mice

Objective and design: The present study investigates the supposed advantage of using an association of anti-inflammatory drugs and serum therapy to treat mouse paw edema induced by injection of Bothrops jararaca snake venom (BjV). Material and methods: Edema was induced by injecting BjV (2 μg) into the footpad of male Swiss mice (20–25 g) and measured by plethysmography. Groups of mice were treated 15, 30 or 45 min after BjV injection with Bothrops antivenom or anti-inflammatory drugs (dexamethasone, indomethacin or zileuton), or with the association of antivenom and each one of these drugs. Results: Antivenom, dexamethasone and indomethacin were effective in reducing the paw edema when used up to 30 min after BjV injection. Zileuton had the same effect, but only if used up to 15 min after BjV injection. The association of antivenom and dexamethasone showed the greatest inhibitory effect when used up to 45 min after BjV injection. At this time, antivenom or anti-inflammatory drugs administered alone were ineffective. Conclusion: Results suggest that dexamethasone combination with serum therapy can be beneficial for treatment of inflammatory edema caused by B. jararaca envenomation. Received 5 June 2006; returned for revision 7 July 2006; returned for final revision 22 November 2006; accepted by M. Katori 17 May 2007     

Analysis of the inflammatory response in the rat paw caused by the venom of <Emphasis Type="Italic">Apis melifera</Emphasis> bee

OBJECTIVE: This study examines the pro-inflammatory action caused by subcutaneous (s.c.) injection of the bee venom (BV) Apis melifera in the rat paw. METHODS: Male Wistar rats were used. The venom of Apis melifera was injected s.c. into the rat paw and the oedema formation and the activity of myeleperoxidase (MPO) were measured. RESULTS: Subcutaneous injection of BV caused dose-and time-dependent paw oedema (ED50 of 1.5 microg/paw) with peak at 30 min. The MPO activity increased about 1.6, 4.2 and 8.9 folds at 0.5, 4 and 6 h after s.c. injection of BV. The mast cell degranulating drug 48/80, pyrilamine or metysergide, inhibited BV-mediated oedema formation (88, 62 and 96%, respectively). Likewise, L-NAME, the NK1 antagonist FK 888, the B1 des-Arg9-[Leu8]-BK or B2 kinin antagonist Hoe 140 also antagonised the paw oedema induced by BV (60, 59, 49, and 49%, respectively). SR48968 and SR14280, respectively NK2 and NK3 antagonists and also indomethacin, inhibited by 31, 29 and 22%, respectively BV-induced oedema formation. In contrast, the PAF antagonist WEB 2086 or valeryl salycilate, did not affect the BV-induced paw oedema. The levels of MPO were inhibited by compound 48/80, cyproheptadine, Hoe 140, or by des-Arg9[Leu8]-BK (85, 61, 59, and 53%, respectively) measured 6 h after. CONCLUSION: These results indicate that the BV from Apis melifera causes a marked dose-and time-dependent oedema formation in the rat paw, an effect that is accompanied by intense leukocyte migration. The pro-inflammatory response induced by BV is mediated by several mechanisms, namely the release of histamine and/or serotonin from mast cells, activation of H1 histamine receptor, production of nitric oxide, the involvement of kinins through the activation of B1 and B2 receptors, and also tachykinins acting at NK1 receptor or and to a lesser extent at NK2 and NK3 receptors.     

The anti-inflammatory effects of 2 Hz electroacupuncture with different intensities on acute carrageenan-induced inflammation in the rat paw

The aim of this study was to investigate the anti-inflammatory effects of low frequency electroacupuncture (EA) with different intensities in carrageenan-injected rat paw. Bilateral 2 Hz EA stimulation with 0.5, 1 and 3 mA were delivered at those acupoints corresponding to Zusanli and Sanyinjiao in man via needles for 30 min. We first examined the degrees of edema and hyperalgesia using measurements of paw swelling and hot plate latency over 180 min, at 30 min intervals, after the carrageenan injection. The edema and thermal sensitivities of the hind paw induced by a carrageenan-injection were strongly inhibited by EA stimulation, especially at low intensity. At 3 h after carrageenan-injection, we investigated whether the effects of a 2 Hz EA on a carrageenan-induced edema and hyperalgesia are associated with peripheral cyclooxygenase (COX) mRNA induction and prostaglandin E2 (PGE2) synthesis. Although the induction of COX-2 mRNA was inhibited by 2 Hz EA at various intensities, there was no significant change. However, the synthesis of PGE2 induced by a carrageenan injection was significantly attenuated in rat paw with low intensity EA treatment. The data indicate that low frequency EA treatment with relatively low intensity might be a useful therapy for mitigation of inflammatory edema and hyperalgesia through the regulation of COX-2 expression and PGE2 production in a model of peripheral inflammation in rats.     

rhPLD2可降低豚鼠慢性哮喘模型血液中PAF的含量

目的：研究人重组磷脂酶D2（rhPLD2）变构体的生物学功能。方法：采用由鸡卵白蛋白（Ovalbumin，OVA）诱导的豚鼠慢性哮喘模型，通过血小板聚集法以观察rhPLD2对哮喘中PAF的作用。结果：rhPLD2可显著降低豚鼠慢性哮喘模型血清中的PAF含量；与NS组相比较P〈0．01。结论：rhPLD2在体内具有一定的抗哮喘炎症的生物学功能。     

Human recombinant platelet phospholipase A2 exacerbates poly-l-arginine induced rat paw edema

In this study by using the human recombinant non-pancreatic-secreted platelet PLA₂ (r-hnps-PLA₂) and rabbit polyclonal antibodies directed against either the human (group II) or the porcine enzyme (group I), we have shown a possible involvement of platelet PLA₂ in poly-l-arginine (25 kDa)-induced rat paw edema. Local treatment of rats with the anti-platelet-PLA₂ antibody (anti-hnps-PLA₂) but not with anti-porcine-PLA₂ antibody (anti-porc-PLA₂) significantly reduced the edema induced by a maximal dose of poly-l-arginine (1 mg/paw). Furthermore when r-hnps-PLA₂ (1–10g) was injected together with a subliminal dose of poly-l-arginine (50g/paw), a dose-dependent increase in both edema and protein leakage was observed. This effect was selectively inhibited by the anti-hnps-PLA₂ (10–100g/paw) but not anti-porc-PLA₂ (10–100 g paw). Thus, platelets seem to be involved in both vascular and cellular components of the inflammatory response by contributing, most likely in the early phase, to the edema formation through secretion of PLA₂.     

Pharmacologic modulation of D-49 phospholipase A2-induced paw edema in the mouse

Paw edema was produced in CD-1 mice by the injection of 0.3 g of snake venom PLA₂ (A.p. piscivorus D-49) into the hind paw. Edema peaked at 10 min, remained elevated until 60 min, and then declined slowly. The PLA₂ inhibitors, luffariellolide and aristolochic acid, reduced the edema but only when coinjected with the PLA₂. The histamine/serotonin antagonists were the most effective drug class against PLA₂-induced paw edema. The PAF antagonists, CV-6202 (iv) and kadsurenone (coinjected) reduced the PLA₂-induced edema, whereas high doses of the corticosteroids, dexamethasone and hydrocortisone, were also effective. NSAIDs only partially inhibited the paw edema. The LO/CO inhibitors yielded varying activities, with only BW755C and NDGA inhibiting the edema. These results suggest that PLA₂ induces paw edema in the mouse via the action of several classes of inflammatory mediators.