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No description available.

A review of the discovery, biological activity and chemical synthesis of the leukotrienes is presented, together with the latest developments in their structural modification to produce useful antagonists. Strategies are presented for the preparation of chiral leukotriene derivatives in which the characteristic triene unit is replaced by various aromatic groups and include: (i) The preparation and attempted separation of the racemic diastereomers of methyl S-hydroxy-6-(2-methoxycarbonyl- 2-amino-ethylthio > -6-phenylhexanoate; (ii) A chemical synthesis involving the Sharpless asymmetricepoxidation of (El-ethyl 4-hydroxy-6-phenylhex-S-enoate to (El-ethyl S( R).6(S)-epoxy-6-phenyl-4(S)-hydroxyhexanoate followed by selective de-oxygenation studies on the corresponding racemic epoxy alcohol to give (E}-ethyIS.6-epoxy-6-phenyl-hexanoate; iii An enzymic route utilizing the porcine pancreatic lipase catalysed hydrolysis of a number of racemic 3-alkyl-3-butanoyloxy- 1.2-epoxides to the corresponding chiral epoxy alcohols with various degrees of selectivity. one of the most useful being the completely enantioselective hydrolysis of the less polar diastereomer of· (E)-3-butanoyloxy-I.2-epoxy-I-phenylhexane. The more polar diastereomer was preferentially hydrolysed to l( R),2(S)-epoxy-I-phenylhexan-3-( R)-ol, as verified by Sharpless epoxidation of (E)-I-phenylhex-I-en-3-01.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 4 uppsatser.

Myocardial infarction (MI) is primarily caused by blockade of the coronary circulation, resulting in ischemic insult. The only available remedy is reperfusion, which induces oxidative stress and activates inflammatory responses at the site of injury. Cysteinyl leukotrienes (cysLTs) are potent pro-inflammatory mediators that exert their effects through two classical receptors: cysLT receptor 1 (CysLT1R) and cysLT receptor 2 (CysLT2R), the latter of which is prevalent in the heart and circulatory system and has been implicated in cardiovascular disease. However, although endothelial CysLT2R overexpression exacerbates MI damage and induces vascular hyperpermeability, understanding of CysLT2R activation-induced mechanisms is poor, as isolating CysLT2R-specific effects has proven difficult due to a lack of appropriate pharmacological agents. We investigate herein the role of CysLT2R activation in myocardial ischemia/reperfusion injury. We have characterized a novel CysLT2R-selective antagonist BayCysLT2 in both in vitro and in vivo systems, and establish that CysLT2R-selective antagonism attenuates exacerbated MI injury, adhesion molecule gene regulation, and myocardial neutrophil presence observed in CysLT2R overexpressing (EC) mice. We also examined effects of CysLT2R antagonism in long-term cardiac remodeling post-myocardial infarction, and found that blockade of CysLT2R post-reperfusion, regardless of whether CysLT2R is overexpressed or not, elicits a mild pathological cardiac hypertrophic response despite mitigating infarction damage to the apical ventricular wall. Finally, we created a novel mouse model (EC/KO) that expresses CysLT2R predominantly in vascular endothelium in order to identify tissue-specific mechanisms of CysLT2R activation. Surprisingly, MI injury was attenuated in EC/KO mice, indicating that both endothelial and non-endothelial CysLT2R expression subsets have roles in mediating infarction injury. Indeed, EC/KO mice demonstrated hyperpermeability in cremaster venules only when leukotrienes are applied, in contrast to EC mice. In addition, endothelial CysLT2R activation facilitates leukocyte transmigration, whereas non-endothelial CysLT2Rs regulate basal rolling leukocyte flux in microvasculature. Although much work remains to be done, the characterization of a CysLT2R-selective antagonist provides a vital tool for CysLT2R research moving forward, and our investigation of CysLT2R activation reveal the existence of a complicated and multi-faceted pathway resulting in activation of pro-inflammatory mechanisms. / Thesis (Ph.D, Physiology) -- Queen's University, 2013-09-26 10:29:03.466

Diss. (sammanfattning) Stockholm : Karol. inst., 2001. / Härtill 5 uppsatser.

Human neutrophil 5-lipoxygenase (5-LOX) oxidizes arachidonic acid (AA) to 5S-hydro(pero)xy-6E,8Z,11Z,14Z-eicosatetraenoic acid (5-H(p)ETE) and leukotriene (LT)A4, which is further converted to the chemoattractant LTB4. These cells contain also the heme enzyme myeloperoxidase (MPO) producing several potent oxidants such as hypochlorous acid (HOCl). Previously, it was shown that MPO-metabolites influence 5-LOX product formation. Here, we addressed the question, whether a simultaneous activation of MPO and 5-LOX in neutrophils results in comparable changes of 5-LOX activity. Human neutrophils were stimulated with H2O2 or phorbol 12-myristate 13-acetate (PMA) for MPO activation and subsequently treated with calcium ionophore A23187 inducing 5-LOX product formation on endogenous AA. Special attention was drawn to neutrophil vitality, formation of MPO-derived metabolites and redox status. The pre-stimulation with H2O2 resulted in a concentration-dependent increase in the ratio of 5-HETE to the sum of LTB4 + 6-trans-LTB4 in consequence of MPO activation. Thereby no impairment of cell vitality and only a slightly reduction of total glutathione level was observed. An influence of MPO on 5-LOX product formation could be suggested using an MPO inhibitor. In contrast, the pre-stimulation with PMA resulted in different changes of 5-LOX product formation leading to a reduced amount of 5-HETE unaffected by MPO inhibition. Furthermore, impaired cell vitality and diminished redox status was detected after PMA stimulation. Nevertheless, a MPO-induced diminution of LTB4 was obvious. Further work is necessary to define the type of 5-LOX modification and investigate the effect of physiological MPO activators.

Atopic asthma is a complex disease process that has a significant social, personal and economic burden across all ages. Leukotriene-receptors are involved in the cascade of inflammation that may result in symptoms of atopy and asthma. Two leukotriene receptors have been identified in the lung. The cysteinyl leukotriene receptor 1 and cysteinyl leukotriene receptor 2 genes (i.e., CYSLTR1 and CYSLTR2) have been sequenced, and a number of single nucleotide polymorphisms (SNPs) within these genes have been identified.The purpose of this study was to: (1) Determine the relationship between CYSLTR1 genotypes, CYSLTR2 genotype, atopy, elevated IgE level, and eosinophilia, (2) Determine the relationship between CYSLTR1 genotypes, CYSLTR2 genotype, asthma, and atopic asthma, and (3) Determine the degree of interaction between CYSLTR2 genetic variation and gender in atopic asthma.Nested within two sub-studies of the Tucson Epidemiological Study of Airway Obstructive Disease (TESAOD) study, a prospective longitudinal cohort, 853 individuals were entered into this study. Study criteria included Non-Hispanic white adults, who consented to genetic testing in the two sub-studies. Tagging SNPs of the CYSLTR1 and CYSLTR2 genes were genotyped. Serum IgE status and eosinophilia were obtained from existing dataset. Questionnaires collected in the parent study were used to obtain demographic and clinical data.SNP rs321006 in the CYSLTR1 gene was associated with atopy among Non-Hispanic white women. Assuming a recessive model, among female Non-Hispanic white adults, the odds of having rs321073 CC genotype was 5.82 times higher among those with atopic asthma than those without atopic asthma. No gene by gender interaction was found between SNP of interest in CYSLTR2 and atopic asthma. Genetic association of SNPs rs321006 with atopy and rs321073 with atopic asthma are novel findings to date.Implications for nurses, clinicians, and scientists include better understanding of associations of these genetic variations with asthma, atopy, and atopic asthma that can generate further inquiry into other mechanisms of atopic asthma. These novel genetic associations with atopy and atopic asthma may have the potential for personalized medicine that might afford patients with appropriate treatment based on their genotype.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 4 uppsatser.

Lic.-avh. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 2 uppsatser.