ABSTRACT
Bacterial endotoxin produces sepsis associated with alterations in body temperature (fever or hypothermia). The intraperitoneal administration of bacterial endotoxin, lipopolysaccharide (LPS; 50 microg/mouse) led to a decrease in colonic temperature starting 1 hr after the injection. The hypothermic effect was accompanied by a significant increase in hypothalamic leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) levels. 5-lipoxygenase inhibitor, zileuton (200 and 400 mg/kg, po) administered 30 min before LPS challenge significantly prevented hypothermia. However, non-selective cyclooxygenase inhibitor, indomethacin (10, 20 mg/kg, po) did not reverse the hypothermic response. Further, pretreatment of mice with zileuton prevented LPS-stimulated increase in hypothalamic LTB4 levels and caused a relatively small increase in PGE2 levels. Indomethacin had no effect on LTB4 levels but it reduced PGE2 levels. These results suggest a possible involvement of leukotrienes in LPS-induced hypothermia and the potential protective role of 5-lipoxygenase inhibitors in endotoxemia.
Subject(s)
Animals , Arachidonate 5-Lipoxygenase/antagonists & inhibitors , Colon/drug effects , Dinoprostone/metabolism , Female , Hydroxyurea/analogs & derivatives , Hypothalamus/drug effects , Hypothermia/drug therapy , Hypothermia, Induced , Indomethacin/pharmacology , Leukotriene B4/metabolism , Leukotrienes/physiology , Lipopolysaccharides/pharmacology , Lipoxygenase Inhibitors/pharmacology , Male , MiceABSTRACT
Mast cells (MC) are important in the numerous physiological processes of homeostasis and disease. Most notably, MC are critical effectors in the development and exacerbation of allergic disorders. Nitric oxide (NO) is a diatomic radical produced by nitric oxide synthase (NOS), and has pluripotent cell signaling and cytotoxic properties. NO can influence many MC functions. Recent evidence shows the source of this NO can be from the mast cell itself. Governing the production of this endogenous NO, through alterations in the expression of tetrahydrobiopterin (BH4), a NOS cofactor, has stabilizing effects on MC degranulation. Furthermore, NO regulates the synthesis and secretion of de novo generated mediators, including leukotrienes and chemokines. These novel observations add to the growing body of knowledge surrounding the role of NO in the MC.
Subject(s)
Animals , Humans , Male , Mice , Rats , Mast Cells/physiology , Nitric Oxide/physiology , Biopterin/analogs & derivatives , Biopterin/metabolism , Cells, Cultured , Cell Degranulation/physiology , Chemokines/physiology , Leukotrienes/physiology , Mast Cells/enzymology , Nitric Oxide Synthase/metabolism , Nitric Oxide/metabolism , Phenotype , Rats, Sprague-DawleyABSTRACT
Se revisan los conocimientos bioquímicos y farmacológicos de los leucotrienos, incluyendo los procesos enzimáticos y celulares que participan en su síntesis. Los efectos biológicos mediados a través de diversos receptores, como los cyste-leucotrienos, tienen una participación primordial en la fisiopatología del asma. Los inhibidores de la 5-lipooxigenasa, los antagonistas de los receptores cystenil-leucotrienos son, en general, tres nuevos modulares de uso clínico. En grandes estudios multicéntricos se ha revisado su efecto en diversos modelos clínicos de asma, como la inducida por alergenos, ejercicio aspirina. Las conclusiones orientan a que su farmacología y la experiencia clínica que se tiene, los agrupa como un nuevo recurso terapéutico para el tratamiento del asma
Subject(s)
Humans , Asthma/drug therapy , Asthma/physiopathology , Bronchial Spasm/etiology , Leukotriene B4 , Leukotrienes/antagonists & inhibitors , Leukotrienes/physiologySubject(s)
Inflammation/physiopathology , Blood Platelets/cytology , Capillary Permeability/drug effects , Biological Factors/analysis , Free Radicals/therapeutic use , Histamine/therapeutic use , Leukotrienes/physiology , Macrophages/cytology , Mast Cells/cytology , Nitric Oxide/therapeutic use , Phagocytosis/physiologyABSTRACT
En este artículo revisamos los avances en el entendimiento de la fisopatología del asma, especialmente el papel de la inflamación y su asociación con lo leucotrienos. Revisamos los medicamentos antagonistas del receptor e inhibidores de la síntesis, utilizados en asma asociado a ejercicio, alergenos y reto con aspirina. Estudios clínicos con antagonistas de los leucotrienos han confirmado el papel central de los leucotrienos en la fisiopatología de el asma; sugiriendo la importancia de estos agentes en el tratamiento del asma
Subject(s)
Asthma/physiopathology , Leukotriene C4 , Leukotrienes/adverse effects , Leukotrienes/antagonists & inhibitors , Leukotrienes/immunology , Leukotrienes/physiology , Receptors, Leukotriene/antagonists & inhibitorsABSTRACT
En la respuesta inflamatoria local a la cirugía intervienen diversas substancias tales como histamina, kalikreínas, prostaglandinas, leucotrienos, complemento, interleucinas, factor de necrosis tumoral, factor derivado de plaquetas y radicales de oxígeno, que modulan la formación de edema. Migración de leucocitos y reparación tisular necesarios para existencia de condiciones microambientales satisfactorias para la nutrición, crecimiento y regeneración tisulares
Subject(s)
Amino Acids, Peptides, and Proteins , Tissue Preservation , Granulocyte-Macrophage Colony-Stimulating Factor/physiology , Immunologic Factors/metabolism , Inflammation/etiology , Leukotrienes/physiology , Neurosecretory Systems/physiology , Prostaglandins/physiology , Proteins/biosynthesisABSTRACT
Os autores promovem ampla revisäo dos conceitos acerca dos leucotrienos, caracterizando os seus fundamentos bioquímicos e envolvimento no mecanismo fisiopatológico de enfermidades inflamatórias diversas, discutindo as perspectivas de sua abordagem terapêutica na prática médica.