Disease relevance of leukotriene D4

• We found leukotriene C4 and leukotriene D4 in the lung lavage fluids of all five newborns who had the clinical diagnosis of persistent pulmonary hypertension and who required ventilatory assistance [1].
• Leukotriene D4 (LTD4), a component of slow reacting substance of anaphylaxis (SRS-A)1, produces marked hypotension in laboratory animals2,3, implicating it as a potential mediator of anaphylactic shock [2].
• LTD4 hypotension was also reversed by intracerebroventricular (i.c.v.) administration of TRH at a dose that had no effect when given systemically [2].
• Antagonism of endogenous LTD4 actions, however, was associated with prevention of the NTS-induced fall in SNGFR because of the abrogation of the fall in Kf which characterizes this form of experimental glomerulonephritis [3].
• Thus, in the autologous phase of PHN, LTD4 mediates glomerular hemodynamic abnormalities and a hemodynamic component of the accompanying proteinuria [4].

Psychiatry related information on leukotriene D4

• In guinea-pig tracheal mucosa, there was an indication of an increase in the amount of mucus and disorientation of cilia were seen by SEM after immersion in LTD4 [5].
• LTC4 and LTD4 induced a dose-related decrease in total intestinal blood flow, mucosal blood flow and in oxygen consumption, and an increase in intestinal motor activity [6].

High impact information on leukotriene D4

• Inhibition of exercise-induced bronchoconstriction by MK-571, a potent leukotriene D4-receptor antagonist [7].
• Inhibition of exercise-induced bronchoconstriction by MK-571, a potent leukotriene D4-receptor antagonist [8].
• However, SRSs isolated from both immunological and non-immunological reactions have been identified as a combination of two related lipid substances--leukotriene C4 (LTC) and leukotriene D4 (LTD); thus it is now possible to use pure SRSs (leukotrienes) in pharmacological studies of airway smooth muscle [9].
• Intravenous FPL 55712 completely abolished the coronary vasoconstriction of leukotriene D4, but a significant reduction of regional wall shortening persisted [10].
• Leukotriene D4 (2 c 10(-9) mole), injected into the left circumflex coronary artery of anesthetized sheep, produced profound coronary vasoconstriction and impaired regional ventricular wall motion [10].

Chemical compound and disease context of leukotriene D4

• Alteration of leukotriene D4 hypotension by thyrotropin releasing hormone [2].
• The lipoxygenase inhibitor nordihydro-guaiaretic acid and the LTD4 antagonist ICI 198,615 inhibited ACh-induced contraction of esophagitis but not of normal ESO [11].
• In the LES, LTD4 activates a calmodulin-dependent pathway through pertussis toxin-insensitive Gq proteins and phosphatidylinositol-specific phospholipase C. The intracellular pathways activated by LTD4 in the esophagus and the LES are similar to those activated by acetylcholine and other agonists [12].
• Effects of LTD4 were suppressed by the CysLT1 receptor antagonist MK-571 and reduced by pertussis toxin [13].
• In addition, the leukotriene metabolite pattern in bile was profoundly altered and was characterized in hypoxia by a 75% to 80% decrease of both leukotriene C4 and polar metabolites, representing omega-oxidation products, whereas the appearance of leukotriene D4 in bile was not affected [14].

Biological context of leukotriene D4

• The purpose of this study was to investigate the importance of LTD4 as a mediator of exercise-induced bronchoconstriction [8].
• In contrast, LTD4 was substantially less inhibitory (IC50 greater than 40 microM), and LTE4 and LTB4 had no effect on the enzyme, indicating that the mixed type product inhibition observed was specific for sulfidopeptide leukotrienes bearing the GSH moiety [15].
• Expression of the leukotriene D4 receptor CysLT1, COX-2, and other cell survival factors in colorectal adenocarcinomas [16].
• The signal transduction system of the leukotriene D4 receptor [17].
• Affinities of stereoisomers and related compounds for the leukotriene D4 binding sites closely paralleled their contractile activities in guinea pig lung parenchymal strips [18].

Anatomical context of leukotriene D4

• These results demonstrate that the peptido-leukotrienes derived from eicosapentaenoic acid (LTC5 and LTD5) are on the order of five times less potent than the leukotrienes derived from arachidonic acid (LTC4 and LTD4), in terms of increasing the susceptibility of the gastric mucosa to damage and reducing gastric blood flow [19].
• When displacement of LXA4 binding with pINF114-transfected CHO cells was tested with other eicosanoids, including LXB4, leukotriene D4 (LTD4), LTB4, or prostaglandin E2, only LTD4 competed with LXA4, giving a Ki of 80 nM [20].
• The observed highly localized protective action of the LTD4 antagonist on the glomerular capillary points to a possibly major functional role for intraglomerularly released LTD4, likely originating from infiltrating leukocytes, in the pathophysiology of this form of glomerulonephritis [3].
• The synthesis of LTD4 likely occurs directly from macrophages or from macrophage-derived LTA4, through LTC4 synthase in glomerular cells [4].
• In hepatocytes prepared from untreated rats, this concentration of intracellular LTD4 neither raised intracellular Ca2+ nor activated the conductance [21].

Associations of leukotriene D4 with other chemical compounds

• Here we report the remarkable contractile activity of both LTC4 and LTD4 on isolated human bronchi, which further emphasizes the possibility that leukotrienes are potent mediators of bronchoconstriction in man [22].
• Intra-arterial infusion of leukotriene C4 (LTC4) and LTD4 (0.1-3 micrograms/kg/min for 5 min) produced dose-dependent increases in gastric mucosal damage induced by topically applied 20% ethanol, as assessed macroscopically, by changes in transmucosal potential difference and by measurement of efflux of protein into the gastric lumen [19].
• The inhibition of lymphocyte proliferation by either hydrocortisone or by the 5-lipoxygenase inhibitor was totally reversed by LTB4 but not by leukotriene C4 or leukotriene D4 [23].
• Stimulation by leukotriene D4 of increases in the cytosolic concentration of calcium in dimethylsulfoxide-differentiated HL-60 cells [24].
• The lipoxygenase inhibitor nordihydroguaiaretic acid, the specific leukotriene D4 (LTD4) receptor antagonist MK-571, and the 5-lipoxygenase activating protein inhibitor MK-886 all significantly inhibited the conductance [21].

Gene context of leukotriene D4

• We demonstrated previously that leukotriene D4 (LTD4) regulates proliferation of intestinal epithelial cells through a CysLT receptor by protein kinase C (PKC)epsilon-dependent stimulation of the mitogen-activated protein kinase ERK1/2 [25].
• LTD4-mediated CREB activation was not affected by expression of kinase-dead p90RSK but was abolished by transfection with the regulatory domain of PKCalpha (a specific dominant-inhibitor of PKCalpha) [25].
• Similar treatment of cells transfected with K-p90RSK resulted in cell cycle arrest in the G0/G1 phase, consistent with a role of p90RSK in LTD4-induced proliferation [25].
• CysLT1 receptor upregulation by TGF-beta and IL-13 is associated with bronchial smooth muscle cell proliferation in response to LTD4 [26].
• Following reexposure to IL-3, a rapid time-dependent biosynthesis of leukotriene D4 (LTD4) is induced by M-07e cells [27].

Analytical, diagnostic and therapeutic context of leukotriene D4

• The biliary production rate of endogenous LTD4 increased from 0.3 +/- 0.1 to 6.2 +/- 1.8 pmol x min-1 x kg-1 (p less than 0.001) during anaphylactic shock induced by intravenous injection of OVA (0.2 mg/kg) into sensitized guinea pigs [28].
• Preservation of the glomerular capillary ultrafiltration coefficient during rat nephrotoxic serum nephritis by a specific leukotriene D4 receptor antagonist [3].
• Micropuncture measurements were performed in euvolemic Munich-Wistar rats 2 h after i.v. administration of 0.8 ml of rabbit serum (group 1, n = 6), 0.8 ml of rabbit anti-rat glomerular basement membrane antibody in the absence (group 2, n = 8), or presence (group 3, n = 7) of the new highly specific LTD4 receptor antagonist SK&F 104353 [3].
• LTC4 and LTD4 were also found in bronchoalveolar lavage fluid from one of the three atopic subjects challenged with antigen before lavage, and in a single patient who underwent lavage after admission with severe acute asthma [29].
• Peptidoleukotrienes (LTC4 and LTD4) were quantitated after reverse-phase high-performance liquid chromatography coupled with radioimmunoassay [30].

References