Cyclooxygenase-derived Products Research Articles

Sub-chronic lead exposure produces β1-adrenoceptor downregulation decreasing arterial pressure reactivity in rats

Lead is considered a causative factor for hypertension and other cardiovascular diseases. AimsTo investigate the effects of sub-chronic lead exposure on blood pressure reactivity and cardiac β1-adrenoceptor activity and to evaluate whether the effects found in vitro are similar to those found in vivo. Main methodsMale Wistar rats were randomly distributed into two groups: control rats (Ct) and rats administered drinking water containing 100ppm lead (Pb) for 30days. Key findingsBlood pressure in the Pb rats increased starting from the first week of treatment until the end of the study [systolic blood pressure, Ct: 122±4 vs. Pb: 143±3mmHg; diastolic blood pressure, Ct: 63±4 vs. Pb: 84±4mmHg]. The heart rate was also increased (Ct: 299±11 vs. Pb: 365±11bpm), but the pressure reactivity to phenylephrine was decreased. Losartan and hexamethonium exhibited a greater reduction in blood pressure of Pb rats than in the Ct rats. Isoproterenol increased the left ventricular systolic and end-diastolic pressure, and heart rate only in Ct rats, suggesting that lead induced β1-adrenoceptor downregulation. Indomethacin reduced the blood pressure and heart rate in the Pb rats, suggesting the involvement of cyclooxygenase-derived products (which are associated with reduced nitric oxide bioavailability) in this process. SignificanceThese findings offer further evidence that the effects of sub-chronic lead exposure in vitro can be reproduced in vivo—even at low concentrations—thus triggering mechanisms for the development of hypertension. Therefore, lead should be considered an environmental risk factor for cardiovascular disease.

Selective venous vasodilator properties of the analgesic metamizole (dipyrone) in a human ex vivo model-implications for postoperative pain management.

Metamizole (dipyrone) is a first-line, non-opioid analgesic used for postoperative pain management. Clinical data and animal experiments indicate a possible vasodilator action of this drug. We investigated the effects of metamizole on human artery and vein tone in an ex vivo model to assess potential contributions to venous pooling. Excess segments of bypass grafts were harvested during coronary artery bypass grafting procedures. Tensions were measured in an organ bath for 120min after adding metamizole to the preconstricted vessels. Contribution of endothelium was assessed in endothelium-denuded vessels, and indometacin was used to identify cyclooxygenase-mediated effects. Internal mammary arteries (n=6) constricted after addition of 1, 3, and 10μM metamizole and remained constricted at the lower doses. Transient constrictions also occurred in saphenous veins (n=20), but veins relaxed below solvent controls after 20min at all concentrations. Endothelium removal (n=12) and cyclooxygenase inhibition (n=12) suppressed the vasoconstrictor effect but not the vasodilator effect. Metamizole and its metabolites display counteracting effects on blood vessel tone ex vivo. The vasoconstrictor effect is mediated by cyclooxygenase-derived products. The net effect is site-specific, resulting in a selective venous vasodilator action. This may exacerbate unwanted venous pooling during postoperative pain therapy.

Formaldehyde inhalation reduces respiratory mechanics in a rat model with allergic lung inflammation by altering the nitric oxide/cyclooxygenase-derived products relationship

Bronchial hyperresponsiveness is a hallmark of asthma and many factors modulate bronchoconstriction episodes. A potential correlation of formaldehyde (FA) inhalation and asthma has been observed; however, the exact role of FA remains controversial. We investigated the effects of FA inhalation on Ovalbumin (OVA) sensitisation using a parameter of respiratory mechanics. The involvement of nitric oxide (NO) and cyclooxygenase-derived products were also evaluated. The rats were submitted, or not, to FA inhalation (1%, 90 min/day, 3 days) and were OVA-sensitised and challenged 14 days later. Our data showed that previous FA exposure in allergic rats reduced bronchial responsiveness, respiratory resistance (Rrs) and elastance (Ers) to methacholine. FA exposure in allergic rats also increased the iNOS gene expression and reduced COX-1. L-NAME treatment exacerbated the bronchial hyporesponsiveness and did not modify the Ers and Rrs, while Indomethacin partially reversed all of the parameters studied. The L-NAME and Indomethacin treatments reduced leukotriene B₄ levels while they increased thromboxane B₂ and prostaglandin E₂. In conclusion, FA exposure prior to OVA sensitisation reduces the respiratory mechanics and the interaction of NO and PGE₂ may be representing a compensatory mechanism in order to protect the lung from bronchoconstriction effects.

Endothelial dysfunction in cardiovascular and endocrine-metabolic diseases: an update

The endothelium plays a vital role in maintaining circulatory homeostasis by the release of relaxing and contracting factors. Any change in this balance may result in a process known as endothelial dysfunction that leads to impaired control of vascular tone and contributes to the pathogenesis of some cardiovascular and endocrine/metabolic diseases. Reduced endothelium-derived nitric oxide (NO) bioavailability and increased production of thromboxane A2, prostaglandin H2 and superoxide anion in conductance and resistance arteries are commonly associated with endothelial dysfunction in hypertensive, diabetic and obese animals, resulting in reduced endothelium-dependent vasodilatation and in increased vasoconstrictor responses. In addition, recent studies have demonstrated the role of enhanced overactivation of β-adrenergic receptors inducing vascular cytokine production and endothelial NO synthase (eNOS) uncoupling that seem to be the mechanisms underlying endothelial dysfunction in hypertension, heart failure and in endocrine-metabolic disorders. However, some adaptive mechanisms can occur in the initial stages of hypertension, such as increased NO production by eNOS. The present review focuses on the role of NO bioavailability, eNOS uncoupling, cyclooxygenase-derived products and pro-inflammatory factors on the endothelial dysfunction that occurs in hypertension, sympathetic hyperactivity, diabetes mellitus, and obesity. These are cardiovascular and endocrine-metabolic diseases of high incidence and mortality around the world, especially in developing countries and endothelial dysfunction contributes to triggering, maintenance and worsening of these pathological situations.

Altered responsiveness of small uterine arteries in women with idiopathic menorrhagia

This study was undertaken to study vascular reactivity of small myometrial arteries in women with idiopathic menorrhagia. Small myometrial arteries were isolated from 6 patients with idiopathic menorrhagia and 4 controls. The contractile responses to thromboxane mimetic (U46619) and endothelin-1 were assessed before and after incubation with N(w)-nitro-L arginine methyl ester alone or in combination with indomethacin (Indo). Endothelium-dependent dilation to bradykinin and basal tension were compared before and after incubation with N(w)-nitro-L arginine methyl ester alone, or with N(w)-nitro-L arginine methyl ester in combination with indomethacin. Constriction to endothelin-1 was enhanced in idiopathic menorrhagia arteries (P < .05). Idiopathic menorrhagia arteries demonstrated enhanced basal tension after incubation with N(w)-nitro-L arginine methyl ester, which was further exaggerated by indomethacin. NOS inhibition had no effect on basal tension in controls, but basal tension was enhanced after inhibition of cyclooxygenase-derived products (P < .05). Bradykinin-mediated dilation was significantly increased in idiopathic menorrhagia (P < .05). The presence of functional alterations in small myometrial arteries could contribute to idiopathic menorrhagia.

Nitroflurbiprofen, a Nitric Oxide-Releasing Cyclooxygenase Inhibitor, Improves Cirrhotic Portal Hypertension in Rats

We studied whether administration of nitroflurbiprofen (HCT-1026), a cyclooxygenase inhibitor with nitric oxide (NO)-donating properties, modulates the increased intrahepatic vascular tone in portal hypertensive cirrhotic rats. In vivo hemodynamic measurements (n = 8/condition) and evaluation of the increased intrahepatic resistance by in situ perfusion (n = 5/condition) were performed in rats with thioacetamide-induced cirrhosis that received either nitroflurbiprofen (45 mg/kg), flurbiprofen (30 mg/kg, equimolar concentration to nitroflurbiprofen), or vehicle by intraperitoneal injection 24 hours and 1 hour prior to the measurements. Additionally, we evaluated the effect of acute administration of both drugs (250 micromol/L) on the intrahepatic vascular tone in the in situ perfused cirrhotic rat liver (endothelial dysfunction and hyperresponsiveness to methoxamine) and on hepatic stellate cell contraction in vitro. Typical systemic adverse effects of nonsteroidal anti-inflammatory drugs, such as gastrointestinal ulceration, renal insufficiency, and hepatotoxicity, were actively explored. In vivo, nitroflurbiprofen and flurbiprofen equally decreased portal pressure (8 +/- 0.8 and 8.4 +/- 0.1 mm Hg, respectively, vs 11.8 +/- 0.6 mm Hg) and reduced the total intrahepatic vascular resistance. Systemic hypotension was not aggravated in the different treatment groups (P = .291). In the perfused cirrhotic liver, both drugs improved endothelial dysfunction and hyperresponsiveness. This was associated with a decreased hepatic thromboxane A(2)-production and an increased intrahepatic nitrate/nitrite level. In vitro, nitroflurbiprofen, more than flurbiprofen, decreased hepatic stellate cells contraction. Flurbiprofen-treated rats showed severe gastrointestinal ulcerations (bleeding in 3/8 rats) and nefrotoxicity, which was not observed in nitroflurbiprofen-treated cirrhotic rats. Treatment with nitroflurbiprofen, an NO-releasing cyclooxygenase inhibitor, improves portal hypertension without major adverse effects in thioacetamide-induced cirrhotic rats by attenuating intrahepatic vascular resistance, endothelial dysfunction, and hepatic hyperreactivity to vasoconstrictors.

Modulation of ACTH-induced cortisol release by polyunsaturated fatty acids in interrenal cells from gilthead seabream, Sparus aurata

Highly unsaturated fatty acids are essential components of cellular membranes of vertebrates and can modulate physiological processes, including membrane transport, receptor function and enzymatic activities. In gilthead sea bream, dietary deficiencies of essential fatty acids of marine fish raise the basal cortisol levels and alter the pattern of cortisol release after stress. The aim of the present study was to clarify the effect of different essential fatty acids on adrenocorticotropic hormone (ACTH)-induced cortisol production and release in fish, through in vitro studies of sea bream interrenal cells maintained in superfusion and incubated with different types of fatty acids and eicosanoid production inhibitors. Results showed the first evidence of the effect of certain fatty acids on cortisol production by ACTH-stimulated interrenal cells in fish. Both arachidonic acid (ARA) and particularly eicosapentaenoic acid (EPA) promoted cortisol production in sea bream interrenal cells. Moreover, incubation with indometacin (INDO) reduced the increased cortisol production induced by EPA and ARA, suggesting mediation by their cyclooxygenase-derived products. Docosahexaenoic acid stimulated cortisol production to a lesser extent than that caused by EPA or ARA, but the inhibitory effect of INDO was not as marked as it was for the other fatty acids. In contrast, supplementation with dihomogammalinolenic acid reduced cortisol production, denoting the inhibitor effect of this fatty acid in cortisol secretion.

Functional assessment of vascular reactivity after chronic intermittent hypoxia in the rat

We recently developed a model of chronic intermittent hypoxia (CIH) (FiO2 5%, 8 h/day, 35 days) in the rat that was associated with an increased infarction in isolated heart. The aim of the present study was to characterize its functional consequences on vasoreactivity. Aorta and carotid artery were studied using organ bath technique while mesenteric vascular bed was perfused. In the three vascular beds, relaxation to acetylcholine was similar in CIH and control normoxic (NX) rats. Contractions to noradrenaline and angiotensin II were similar between CIH and NX rats. In contrast, contraction to endothelin-1 was increased by 17% (P < 0.05) in carotid artery from CIH rats. Indomethacin pre-treatment reduced by 24% (P < 0.001) contraction to endothelin-1 in carotid artery from CIH rats only. These data suggested that 35-day CIH-exposure induced no change in endothelial function of aorta, carotid artery and mesenteric bed. In contrast, CIH-exposure induced an increased contractile response to endothelin-1 in carotid artery, presumably owing to the release of constrictor cyclooxygenase-derived products.

2-Arachidonoyl glycerol induces contraction of isolated rat aorta: role of cyclooxygenase-derived products.

Endocannabinoids have been shown to play a role in the regulation of vascular tone. The effects of 2-arachidonoyl glycerol (2-AG) on induced-tone were examined in rat aortic rings in vitro. Aortic rings from Wistar Kyoto (WKY) rats were suspended in organ chambers for recording isometric tension development in response to 2-AG. The production of TXA2 in response to 2-AG was also assessed by enzyme immunoassay. In endothelium-intact rings pre-contracted to PGF(2alpha), 2-AG (10 nM-30 microM) induced a biphasic effect: a weak relaxation from 10 nM to 0.1 microM, which turned into a concentration-dependent contraction from 3 to 30 microM. Endothelium-denudation did not change 2-AG-mediated vascular effects. 2-AG-induced contraction was unaffected by both the cannabinoid CB1 receptor antagonist SR141716A (3 microM) and the CB2 receptor antagonist SR144528 (1 microM). In contrast, the anandamine transport inhibitor (AM404, 100 microM) and the amino hydrolase inhibitor (PMSF, 30 microM) attenuated (P<0.05) the contractile response evoked by 2-AG in endothelium-intact and rubbed aortic rings. In addition, the cyclooxygenase inhibitor (indomethacin, 10 microM) and the thromboxane A2 (TXA2) receptor (TP receptor) antagonist GR32191 (0.3 microM) totally abolished the contraction elicited by 2-AG in endothelium-intact and rubbed aortic rings. Challenge of isolated aortic rings with 2-AG (10 microM) evoked a significant increase in TXA2 level (measured as TXB2 level) in endothelium-intact and rubbed aortic rings. These data suggested that the contraction elicited by 2-AG resulted from the vascular smooth muscle cell uptake and conversion of 2-AG to constrictor prostanoid TXA2, which in turn caused vasoconstriction through the stimulation of TP receptor.

Effects of estrogen on the vascular system.

The cardiovascular protective actions of estrogen are partially mediated by a direct effect on the vessel wall. Estrogen is active both on vascular smooth muscle and endothelial cells where functionally competent estrogen receptors have been identified. Estrogen administration promotes vasodilation in humans and in experimental animals, in part by stimulating prostacyclin and nitric oxide synthesis, as well as by decreasing the production of vasoconstrictor agents such as cyclooxygenase-derived products, reactive oxygen species, angiotensin II, and endothelin-1. In vitro, estrogen exerts a direct inhibitory effect on smooth muscle by activating potassium efflux and by inhibiting calcium influx. In addition, estrogen inhibits vascular smooth muscle cell proliferation. In vivo, 17beta-estradiol prevents neointimal thickening after balloon injury and also ameliorates the lesions occurring in atherosclerotic conditions. As is the case for other steroids, the effect of estrogen on the vessel wall has a rapid non-genomic component involving membrane phenomena, such as alteration of membrane ionic permeability and activation of membrane-bound enzymes, as well as the classical genomic effect involving estrogen receptor activation and gene expression.

Cyclooxygenase-derived products modulate the increased intrahepatic resistance of cirrhotic rat livers

In cirrhotic livers, increased resistance to portal flow, in part due to an exaggerated response to vasoconstrictors, is the primary factor in the pathophysiology of portal hypertension. Our aim was to evaluate the response of the intrahepatic circulation of cirrhotic rat livers to the α 1-adrenergic vasoconstrictor methoxamine and the mechanisms involved in its regulation. A portal perfusion pressure dose-response curve to methoxamine was performed in control and cirrhotic rat livers preincubated with vehicle, the nitric oxide synthase blocker N G -nitro- L-arginine ( L-NNA), indomethacin cyclooxygenase (COX) inhibitor, L-NNA + indomethacin, or the thromboxane (TX) A 2 receptor blocker SQ 29,548. TXA 2 production, COX-1 and COX-2 mRNA expression, and immunostaining for TXA 2 synthase were evaluated. Cirrhotic livers exhibited a hyperresponse to methoxamine associated with overexpression of COX-2 and TXA 2 synthase as well as with increased production of TXA 2. The hyperresponse to methoxamine of cirrhotic livers disappeared by COX inhibition with indomethacin but not after NO inhibition. SQ 29,548 also corrected the hyperresponse of cirrhotic livers to methoxamine. In conclusion, COX-derived prostanoids, mainly TXA 2, play a major role in regulating the response of cirrhotic livers to methoxamine. (H EPATOLOGY 2003;37:172-181.)

Cyclooxygenase-derived products, rather than nitric oxide, are endothelium-derived relaxing factor(s) in the ventral aorta of carp ( Cyprinus carpio)

In some fish blood vessels, the existence of a NO (nitric oxide) system has been reported. We examined the possibility that this NO system acts as an endothelium-derived relaxing factor (EDRF) in carp aorta using the carp aorta alone and in a combined carp–rat aorta donor-detector system. Use of the typical NO stimulating agent in mammal acetylcholine (ACh) only induced constriction of the carp aorta. This response was not modified by denudation or by NO synthesis inhibition with N-nitro- l-arginine methyl ester. Neither the indirect NO stimulating agents bradykinin and histamine nor the direct NO releasers sodium nitroprusside (SNP) and SIN-1 induced vasorelaxation. Both SNP and ACh elevated the cGMP concentration in rat aorta, but not in carp aorta. In the aorta combination set-up, where carp served as a NO donor and rat aorta served as a NO detector, no relaxation of the rat aorta was observed. The calcium ionophore A23187, a known EDRF producer in mammals, induced relaxation of carp aorta through an endothelium- and cyclooxygenase-dependent mechanism. These results indicate that carp aorta does not produce NO as an EDRF nor does it respond to exogenously supplied NO. The major EDRF in carp is apparently a product(s) of cyclooxygenase metabolism.

Effect of neuropeptide Y on bradykinin-induced release of prostacyclin and thromboxane from guinea pig perfused lung

We have previously reported that neuropeptide Y (NPY) inhibits responses induced by various agonists (noradrenaline, vasoactive intestinal peptide, substance P,5-hydroxytryptamine) in isolated guinea pig trachea. Although the underlying mechanisms have not been fully characterized, it was found that the NPY-evoked inhibition was specifically expressed with agents for which locally released prostaglandins (PGs) are important determinants for their myotropic activity. In the present study, we have extended these findings by examining whether NPY was capable of regulating the release of prostacyclin and thromboxane A2 induced by bradykinin (BK) from naive and ovalbumin-sensitized guinea pig perfused lungs. Our results showed that infusion of NPY (0.24 microM) through the lung significantly inhibited the release of 6-keto-PGF1 alpha (> 30%) and thromboxane B2 (50%) induced by intraarterial administration of BK (3 micrograms) from untreated and ovalbumin-sensitized guinea pig perfused lung. However, the inhibitory effect of NPY was lost in the immunological production of prostaglandins. These results suggest that NPY may act as a regulatory agent of the release of cyclooxygenase-derived products by possibly acting on events preceding phospholipase A2 activation.

Interleukin-6 production by macrophages from BALB/c mice with a chronic infection of lactic dehydrogenase virus.

The production of interleukin-6 (IL-6), which is known as a B cell differentiation factor, by peritoneal macrophages from mice with a chronic lactic dehydrogenase virus (LDV) infection was compared with that from uninfected mice. The same amounts of IL-6 were detected in the culture supernatant of macrophages from LDV-infected mice as those from uninfected mice. Furthermore IL-6 production of macrophages from LDV-infected and uninfected mice was not affected by the addition of indomethacin. These results suggested that many immunological alterations seen in LDV-infected mice may not be due to, at least in part, altered IL-6 production ability of macrophages and the IL-6 production may not be affected by cyclooxygenase-derived products.

Cyclooxygenase products mediate the cutaneous vasodilation induced by endothelin-1 in humans

Intradermal injection of endothelin-1 (ET-1) causes vasoconstriction (pallor) at the injection site, surrounded by a larger area of vasodilation (flare) in humans. Some of the vasomotor responses to ET-1 are thought to be mediated by prostaglandins. In the present study, we investigated the involvement of cyclooxygenase-derived products of arachidonic acid metabolism on the cutaneous vasomotor responses to ET-1. Ten normal subjects (25–44 years) were studied after treatment with either indomethacin (50 mg t.i.d.) or placebo according to a double blind cross-over design. Five doses of ET-1 (5·10 −5 to 5·10 −1 pmol) were injected intradermally 2 h after the last dose of indomethacin or placebo. Pallor and flare areas measured by planimetry 15 min after the injection were analyzed to evaluate cutaneous vasomotor responses to ET-1. ET-1 induced dose-dependent pallor and flare responses that were significant at the dose of 5·10 −3 pmol or greater. Indomethacin did not affect the ET-1-induced pallor but significantly shifted to the right the flare dose-response curve to ET-1. The inhibition of the flare response to 5·10 −1 pmol ET-1 was 58.9 ± 8.5%. These results indicate that the cutaneous vasodilation induced by intradermal injection of ET-1 is mediated by the release of vasodilating cyclooxygenase products.

In vivo effects of interferon-γ and indomethacin on murine alveolar macrophage activity

This study determined the effects of treatment with recombinant interferon-γ (rIFN-γ) and the cyclooxygenase inhibitor, indomethacin (INDO), on alveolar macrophage (AM) immune function in AKR/J mice. Bactericidal activity, interleukin 1 (IL1) synthesis and antigen presentation by AM were enhanced at 24 hr after a single intravenous injection with 5 × 10 4 U of rIFN-γ. Concomitant treatment with 2 mg INDO/kg given subcutaneously did not further enhance the effects of a single injection of rIFN-γ, even though the prostaglandin E 2 (PGE 2) concentrations in lung airways were reduced by 50%. These results suggest that the stimulatory effects of rIFN-γ on AM are not altered by blocking potentially immunosuppressive cyclooxygenase metabolites such as PGE 2 with INDO. Mice given three consecutive daily intravenous injections of 5 × 10 4 U of rIFN-γ had suppressed AM bactericidal activity and IL1 synthesis, while PGE 2 concentrations in the lungs were increased. Concomitant treatment with INDO prevented suppression of these AM functions and elevation of PGE 2 concentrations in the lungs. Therefore, it appears that INDO can prevent suppression of AM activity induced by multiple injections of rIFN-γ and this effect may be by blockage of PGE 2 synthesis or other cyclooxygenase-derived products.

Essential fatty acids and immune response

The implication that essential fatty acids (EFA) can affect immune response was based on the observation that EFA deficiency can accentuate or improve symptoms of certain autoimmune diseases in animals, and that supplementation of linoleic acid to animals reversed such effects. Furthermore, treatment of animals with cyclooxygenase inhibitors abrogated the effect of linoleic acid. Administration of cyclooxygenase inhibitors to animals enhanced both cell-mediated and humoral immune responses. In vitro studies have shown that prostaglandin E (PGE) group inhibits both T and B lymphocyte functions; it is suggested that effects of EFA on immune response are, in part, mediated through eicosanoids. Growing evidence now suggests that the PGE group of prostaglandins can serve as a negative feedback modulator of immune response. However, in vitro effects of other cyclooxygenase-derived products, such as PGI2 and thromboxane A2 (TXA2) have not been well established, perhaps because of their instability in aqueous media. Unlike the PGE group, some of lipoxygenase-derived products of arachidonic acid have shown immunostimulatory effects, as assessed by lymphokine production in vitro. Whether such effects can be seen in vivo remains to be determined. Some lipoxygenase-derived products with strong chemotactic action may indirectly influence immune response by modulating the population of antigen-presenting macrophages in tissues. Thus, the net effect of eicosanoids synthesized in macrophages on modulating immune response may depend on relative amounts of cyclooxygenase-derived products as compared with lipoxygenase-derived products. Macrophages are the major source of eicosanoids among immunocompetent cells. The profile of eicosanoids, produced in vitro by macrophages, varies with type of stimuli and anatomical sites. It can also be affected by the fatty acid composition of tissue lipids, which in turn can be modified by the composition of dietary EFA. Whether manipulating dietary EFA can modulate immune response in normal humans and animals needs to be determined.

The role of cyclooxygenase and lipoxygenase mediators in oxidant-induced lung injury.

Infusion of the oxidant lipid peroxide tert-butyl hydroperoxide (t-bu-OOH) causes pulmonary vasoconstriction and increases vascular permeability in isolated perfused rabbit lungs. We have previously shown that t-bu-OOH stimulates arachidonic acid metabolism, increasing the synthesis of the cyclooxygenase products. The current experiments were designed to determine the role that cyclooxygenase- and lipoxygenase-derived mediators play in the lung injury caused by t-bu-OOH. In the present experiments, we found that t-bu-OOH not only increased the synthesis of the cyclooxygenase-derived products thromboxane and prostacyclin but also increased the synthesis of the lipoxygenase-derived products leukotrienes B4, C4, D4, and E4. To determine the role that these arachidonic acid metabolites play in the increase in pressure and vascular permeability caused by t-bu-OOH, we studied the effect that inhibitors of arachidonic acid metabolism or a leukotriene receptor blocker had on the pulmonary edema. We compared an uninjured control group with 4 groups of lungs given t-bu-OOH: a t-bu-OOH control group; a group pretreated with the cyclooxygenase inhibitor indomethacin (14 microM); a group pretreated with an analogue of arachidonic acid, 5-, 8-, 11-, 14-eicosatetraynoic acid (ETYA) (100 microM), that inhibits both the cyclooxygenase and lipoxygenase pathways; and a group pretreated with the leukotriene receptor antagonist FPL 55712 (38 microM). To produce lung injury, t-bu-OOH (300 microM) was infused throughout the first minute of 4 successive 10-min periods.(ABSTRACT TRUNCATED AT 250 WORDS)

Recognition and Treatment of Endotoxemia

Endotoxemia occurs secondary to several diseases that disrupt the mucosal barrier to bacteria or their toxins. The effects of endotoxemia are varied and are mediated by a wide variety of proinflammatory substances. Although evidence certainly exists to incriminate the cyclooxygenase-derived products of arachidonic acid in the early responses to endotoxemia, various other mediators must also be considered. Treatment presently involves fluid replacement, correction of acid-base abnormalities, augmentation of cardiovascular function, and inhibition of cyclooxygenase activity.

Dietary Linolenic Acid and Longer-Chain n-3 Fatty Acids: Comparison of Effects on Arachidonic Acid Metabolism in Rats

Rats were fed graded amounts of purified 18:3n-3 or fish oil concentrate in the presence of a constant amount of 18:2n-6 to evaluate the ability of 18:3n-3 compared with longer-chain n-3 fatty acids to inhibit 20:4n-6 metabolism in platelets and lungs. Dietary 18:3n-3 at a ratio of 0.28 (n-3 to n-6 fatty acids) suppressed levels of 20:4n-6 in lung and plasma phospholipids and the capacity of the tissues to synthesize cyclooxygenase-derived products in a dose-dependent fashion. At similar ratios of n-3 to n-6 dietary fatty acids, longer-chain n-3 fatty acids, which are abundant in fish oil, appear to be more effective than 18:3n-3 in suppressing 20:4n-6 levels and the capacity of the tissues to synthesize cyclooxygenase-derived products. Much greater amounts of 12-hydroxyeicosapentaenoic acid (12-HEPE) and 5-HEPE than of 12-hydroxyeicosatetraenoic acid (12-HETE) and 5-HETE appeared to be formed in tissues of the group receiving the highest amount of fish oil. These results suggest that ingestion of fish oil leads to increased formation of lipoxygenase-derived products of longer-chain n-3 fatty acids.