Leukotriene E4 induces airflow obstruction and mast cell activation through the cysteinyl leukotriene type 1 receptor.

BACKGROUND: Leukotriene (LT) E4 is the final active metabolite among the cysteinyl leukotrienes (CysLTs). Animal studies have identified a distinct LTE4 receptor, suggesting that current cysteinyl leukotriene type 1 (CysLT1) receptor antagonists can provide incomplete inhibition of CysLT responses. OBJECTIVE: We tested this hypothesis by assessing the influence of the CysLT1 antagonist montelukast on responses induced by means of inhalation of LTE4 in asthmatic patients. METHODS: Fourteen patients with mild intermittent asthma and 2 patients with aspirin-exacerbated respiratory disease received 20 mg of montelukast twice daily and placebo for 5 to 7 days in a randomized, double-blind, crossover study (NCT01841164). The PD20 value was determined at the end of each treatment period based on an increasing dose challenge. Measurements included lipid mediators in urine and sputum cells 4 hours after LTE4 challenge. RESULTS: Montelukast completely blocked LTE4-induced bronchoconstriction. Despite tolerating an at least 10 times higher dose of LTE4 after montelukast, there was no difference in the percentage of eosinophils in sputum. Urinary excretion of all major lipid mediators increased after LTE4 inhalation. Montelukast blocked release of the mast cell product prostaglandin (PG) D2, as well as release of PGF2α and thromboxane (Tx) A2, but not increased excretion of PGE2 and its metabolites or isoprostanes. CONCLUSION: LTE4 induces airflow obstruction and mast cell activation through the CysLT1 receptor.

Inhibition of eicosanoid signaling leads to increased lipid peroxidation in a host/parasitoid system.

We posed the hypothesis that inhibition of eicosanoid biosynthesis leads to increased lipid peroxidation in insects. Here we report that rearing the greater wax moth, Galleria mellonella, on media supplemented with selected inhibitors of eicosanoid biosynthesis throughout the larval, pupal and adult life led to major alterations in selected oxidative and antioxidative parameters of wax moth and its ectoparasitoid, Bracon hebetor. The highest dietary dexamethasone (Dex), esculetin (Esc) and phenidone (Phe) led to increased malondialdehyde (MDA) levels and to elevated catalase (CAT) and glutathione-S-transferase (GST) activities in all developmental stages of host larvae. Dietary Phe resulted in increased MDA levels, and CAT activity in G. mellonella adults by about 4-fold and about 2-fold, respectively. The Phe effect on GST activity in all stages of the wax moth was expressed in a dose-dependent manner, increased to 140nmol/mg protein/min in larvae. MDA levels were increased by over 30-fold in adult wasps reared on Dex- and Esc-treated hosts. CAT and GST activities were increased in adult parasitoids reared on Esc-and Phe-treated hosts. GST activity of Dex-treated parasitoid larvae increased from about 4 to over 30nmol/mg protein/min. Dietary Phe led to increased GST activity, by about 25-fold, in adult wasps. These data indicate that chronic inhibition of eicosanoid biosynthesis leads to increased oxidative stress, strongly supporting our hypothesis. The significance of this work lies in understanding the roles of eicosanoids in insect biology. Aside from other well-known eicosanoids actions, we propose that eicosanoids mediate reductions in oxidative stress.

Structural analogs of pulmonary surfactant phosphatidylglycerol inhibit toll-like receptor 2 and 4 signaling.

The pulmonary surfactant phospholipid, 1-palmitoyl-2-oleoylphosphatidylglycerol (POPG), potently inhibits toll-like receptor (TLR)2 and TLR4 signaling from the cell surface of macrophages. Analogs of POPG that vary in polar head group length, hydroxylation, and alkyl branching were synthesized using a phospholipase D-catalyzed transphosphatidylation reaction and a 1-palmitoyl-2-oleoyl phosphatidylcholine substrate. Lipid analogs with C3 and C4 alkyl head group length (POP-propanol and POP-butanol) are less effective than POPG as TLR2 and TLR4 antagonists. However, adding a hydroxyl group at the alkyl chain 3- or 4-position (POP-propanediols or POP-butanediols) greatly increased their inhibitory effects against TLR2 and TLR4. POP-2',2'-dimethylpropanediol is a weak inhibitor of TLR2 and TLR4 activation that results in arachidonic acid release, but an effective inhibitor of TLR4 activation that results in TNF-α production. Addition of an amino group at the alkyl-2 position (POP-2'-aminopropanediol) completely abolished the antagonism of TLRs 2 and 4. Multiple analogs strongly bind to the TLR4 coreceptors, cluster of differentiation 14 (CD14) and myeloid differentiation 2, but competition for di[3-deoxy-D-manno-octulosonyl]-lipid A binding to CD14 is the best predictor of biological activity at the cellular level. Collectively, these findings identify new compounds for antagonizing TLR2 and TLR4 activation and define structural properties of POPG analogs for discriminating between two TLR systems.

Importancia biológica de las grasas en la alimentación humana / Fats and human nutrition: biological importance

Fundamentos: las grasas constituyen un grupo heterogéneo y complejo de sustancias con un gran aporte energético. Independientemente de su aporte energético a la dieta tienen una serie de funciones biológicas de gran importancia así como un papel preventivo o paliativo en el desarrollo y evolución de algunas patologías.Métodos: se realiza una búsqueda bibliográfica en MEDLINE (PubMed; enero de 1996-diciembre de 2002) y en la Biblioteca Cochrane, utilizando como palabras clave (palabra de texto y/o término incluido en el tesauro): nutrición y grasas, enfermedades cardiovasculares, lípidos complejos, lípidos simples, nutrición en etapas de la vida, dieta mediterránea, cáncer, diabetes). Además de la búsqueda computarizada se realiza una búsqueda manual entre las referencias de los estudios seleccionados y de las últimas revisiones. Resultados: las grasas ingeridas con la dieta proporcionan un aporte energético al organismo. En etapas de la vida que engloban desde la infancia hacia la vejez las grasas participan en numerosos procesos necesarios para un adecuado desarrollo de estas etapas. Por último, indicar que algunos tipos de grasas ingeridas tienen un efecto protector en el sistema cardiovascular y en algunos casos mejoran algunas patologías tales como diabetes y procesos neoplásicos.Conclusiones: son necesarios más estudios sobre los efectos de los diferentes tipos de grasas de la alimentación en el organismo, ya que las grasas son un grupo de compuestos heterogéneos y de gran complejidad. Modificar los hábitos de vida es difícil y se asocia con riesgos de carencias y desequilibrios nutricionales, existen nuevas alternativas de enriquecimiento de alimentos con algunos nutrientes (esteroles vegetales, ácidos grasos n-3.) que pueden ayudar a conseguir beneficios terapéuticos y preventivos sobre la salud (AU)

Papel del factor de activación plaquetaria, los eicosanoides y la bradicinina en la terapia adyuvante de la sepsis / Role of platelet-activating factor, eicosanoids and bradykinin in adjuvant therapy for sepsis

Con el término autocoide se define un grupo de pequeñas moléculas liberadas por diversos tipos celulares y que actúan como hormonass autocrinas y paracrinas. La mayoría de estas moléculas se liberan como parte de la respuesta inflamatoria y están implicadas en la patogénesis de la sepsis y el choque séptico. Entre los autocoides se encuentran los eicosanoides, el factor de activación plaquetaria (PAF) y los mediadores peptídicos bradicinina y calidina. En numerosos modelos animales la administración de fármacos que bloquean la síntesis o los receptores de los autocoides ha mejorado las condiciones de sepsis o shock séptico; no obstante, los resultados son contradictorios cuando se habla de ensayos clínicos (AU)

Endocannabinoids in the central nervous system--an overview.

Many aspects of the physiology and pharmacology of anandamide (arachidonoyl ethanol amide), the first endogenous cannabinoid ligand ("endocannabinoid") isolated from pig brain, have been studied since its discovery in 1992. Ethanol amides from other fatty acids have also been identified as endocannabinoids with similar in vivo and in vitro pharmacological properties. 2-Arachidonoyl glycerol and noladin ether (2-arachidonyl glyceryl ether), isolated in 1995 and 2001, respectively, so far, display pharmacological properties in the central nervous system, similar to those of anandamide. The endocannabinoids are widely distributed in brain, they are synthesized and released upon neuronal stimulation, undergo reuptake and are hydrolyzed intracellularly by fatty acid amide hydrolase (FAAH). For therapeutic purposes, inhibitors of FAAH may provide more specific cannabinoid activities than direct agonists, and several such molecules have already been developed. Pharmacological effects of the endocannabinoids are very similar, yet not identical, to those of the plant-derived and synthetic cannabinoid receptor ligands. In addition to pharmacokinetic explanations, direct or indirect interactions with other receptors have been considered to explain some of these differences, including activities at serotonin and GABA receptors. Binding affinities for other receptors such as the vanilloid receptor, have to be taken into account in order to fully understand endocannabinoid physiology. Moreover, possible interactions with receptors for the lysophosphatidic acids deserve attention in future studies. Endocannabinoids have been implicated in a variety of physiological functions. The areas of central activities include pain reduction, motor regulation, learning/memory, and reward. Finally, the role of the endocannabinoid system in appetite stimulation in the adult organism, and perhaps more importantly, its critical involvement in milk ingestion and survival of the newborn, may not only further our understanding of the physiology of food intake and growth, but may also find therapeutic applications in wasting disease and infant's "failure to thrive".

El papel de los ácidos grasos n-3: estudios clínicos / No disponible

No disponible

Respuesta inflamatoria sistémica: fisiopatología y mediadores / Systemic inflammatory response: pathophysiology and mediators

Introducción. Se efectúa una revisión de las características y significado de la respuesta inflamatoria. Se describen las reacciones programadas que se desencadenan cuando la respuesta inflamatoria se generaliza y se analizan los mecanismos de puesta en marcha y finalización del proceso. Material. Revisión bibliográfica de los estudios recogidos en Medline. Resumen de la revisión. Tras la agresión se desencadena una serie de respuestas orgánicas programadas que tienden a limitar el cuadro inflamatorio. La pérdida del control local induce una respuesta inflamatoria generalizada, rápida y ampliada, controlada humoral y celularmente (complemento, cininas, coagulación y cascada fibrinolítica) y desencadenada por la activación conjunta de fagocitos y células endoteliales. Si esta respuesta inflamatoria no es adecuadamente modulada, se origina un síndrome inflamatorio sistémico, que puede alterar el metabolismo intermediario y el funcionalismo de los diferentes órganos. Se describe el complejo entramado de los mediadores de la inflamación, así como sus relaciones con la respuesta neuroendocrina y con la respuesta de fase aguda. Se pasa revista a los mecanismos que ponen en marcha la respuesta inflamatoria y a los sistemas orgánicos establecidos para su modulación o contrarregulación. Se concluye en la necesidad de sistematizar el estudio de las diferentes respuestas a la inflamación, con fines pronósticos y terapéuticos (AU)

[Lipid emulsions and pulmonary function]. / Emulsiones lipídicas y función pulmonar.

A review is made of possible adverse effects of lipid emulsions on the respiratory function, based on the use and acceptance thereof as part of the non-protein caloric supply of the total parenteral nutrition of critical patients from the first hypotheses of the role played by the subsequent lipemia, to the most recent which lend great importance to the eicosanoids generated by the fatty acids supplied by the lipid emulsions. It is also verified whether the observed effects are similar both in healthy as well as in damaged lungs. Another variable to keep in mind, is the rate of administration of the lipid emulsions, which, related to the clearance thereof, could have different actions. Finally, and due to the fatty acid pattern of the lipid emulsion being different than that of the chylomicron, it is evaluated whether the actions of these emulsions may vary as a function of the quantity and quality of the fatty acids supplied.

[Nutrition as adjuvant therapy in chronic polyarthritis]. / Ernährung als adjuvante Therapie bei chronischer Polyarthritis.

In the literature many casual observations report an arthritogenic effect of individual nutrients. The discovery of eicosanoids derived from arachidonic acid (AA) as most relevant mediators of joint inflammation allowed to elaborate the basis for a dietary therapy of rheumatoid arthritis. With an average intake of 18 g/d linoleic acid in western societies, linoleic acid is not converted to AA, and plasma levels of AA depend on its dietary intake with meat or meat products. The amount of AA ingested with the diet correlates with the formation of proinflammatory eicosanoids. Additionally, AA levels can be lowered by the ingestion of fish oil fatty acids. In our experiment, we aimed to combine the effect of low AA intake with the known anti-inflammatory effect of fish oil fatty acids. Our results demonstrate that vegetarians have lower AA percentages in erythrocyte lipids compared to the control group. The lower AA levels in plasma lipids coincided with higher percentages of fish oil fatty acids after supplementation, resulting in lower formation of mediators of inflammation. Moreover, the vegetarian group experienced a more pronounced decrease of AA in erythrocyte lipids after supplementation with fish oil fatty acids. These effects are supposed to contribute to the more favorable clinical course and laboratory findings in patients with rheumatoid arthritis on a vegetarian diet.