1,720,984 research outputs found
FLAP inhibitors for the treatment of inflammatory diseases
No full textLeukotrienes are lipid inflammatory mediators that are implicated in asthma, COPD, arthritis, cardiovascular disease and cancer. Leukotriene synthesis requires 5-lipoxygenase activating protein (FLAP), which acts as a scaffolding protein for the assembly of other enzymes involved in the leukotriene synthetic pathway occurring at the nuclear envelope of leukocytes. By blocking the formation of both leukotriene B4 and the cysteinyl leukotrienes (ie, LTC4 , LTD4 and LTE4), FLAP inhibitors act as broad-spectrum leukotriene-modifier drugs that may have a wide range of therapeutic applications. FLAP inhibitors such as MK-886, MK-0591 and veliflapon (BAY-X-1005, DG-031) demonstrated promise in clinical trials with patients with inflammatory diseases in the mid 1990 s, but, unlike the 'lukast' class of cysteinyl-leukotriene receptor antagonists, these compounds were not brought to market. The elucidation of the 3D structure of FLAP has enabled novel compound development, and several FLAP inhibitors including 2190914 (AM-103) and GSK-2190915 (both under development by GlaxoSmithKline plc) have entered phase II trials for the treatment of inflammatory disease, including asthma
Variation in preparation for gastroscopy: lessons towards safer and better outcomes
No full textOBJECTIVE:To identify the methods employed within the UK practice prior to diagnostic gastroscopy and compare with published guidelines for patients undergoing general anaesthesia.DESIGN:National Health Service (NHS) endoscopy units were invited to take part in a structured telephone survey to determine the length of time patients are kept nil-by-mouth (NBM) for food and fluids prior to gastroscopy, and whether a preprocedure mucolytic drink was used.METHODS:212 NHS Trusts providing endoscopy services were identified from the Joint Advisory Group on GI Endoscopy. Trusts were excluded if they were children's hospitals (n=5).RESULTS:207 NHS Trusts were telephoned. 193 completed the survey (93%), 11 Trusts declined and there was no response from 3 Trusts. 13 separate policies regarding NBM timings were identified. 51 Trusts (21%) used the timings ratified by Surgical and Anaesthetic Societies (6 h NBM for food, 2 h for clear fluid). 135 Trusts (70%) used a policy which starved patients in excess of the standard surgical guidelines. No Trust used a mucolytic drink prior to gastroscopy.CONCLUSIONS:The survey revealed large variation in NHS Trust's policies regarding the times patients were starved prior to gastroscopy. Results of surgical studies demonstrate increased risk of significant pulmonary aspiration with increased fluid-starvation periods, 68% of NHS endoscopy policy would be deemed excessive by surgical practice. There is no routine use of a mucolytic drink to improve mucosal visualisation in the UK practice
Leukotrienes in the sputum and urine of cystic fibrosis children
No full text1. Leukotrienes (LTs) are potent pro‐inflammatory mediators with actions relevant to the pathophysiology of cystic fibrosis (CF), including increased mucus production, bronchoconstriction, leucocyte chemotaxis, and increased vascular permeability. We have therefore investigated the potential role of LTs in children with CF. Leukotriene E4 levels were assessed in the urine of 30 normal (N) children (aged 1.3‐12.7 years) and 30 CF children (1.6‐14.3 years). Sputum from 13 of the CF children was analysed from LTB4, LTC4, LTD4, and LTE4. LTs were separated by reversed‐phase h.p.l.c. and quantitated by radioimmunoassay. 2. Urinary LTE4 levels were log normally distributed, with geometric mean values (95% confidence intervals) of N: 88.4 (71.3‐ 111) pmol mmol‐1 creatinine (n = 30), and CF: 112 (70.6‐177) pmol mmol‐ 1 creatinine (n = 30; P greater than 0.05). Of the CF subjects, 33% had urinary LTE4 levels above 200 pmol mmol‐1 creatinine, compared with 3.3% of the N children. 3. In sputum, mean (+/‐ s.e. mean) LT concentrations were (pmol g‐1), LTB4: 44.3 +/‐ 10.8, LTC4: 4.9 +/‐ 1.3, LTD4: 1.8 +/‐ 0.9, and LTE4: 67.7 +/‐ 18.9 (n = 13). 4. Urinary LTE4 levels correlated significantly with sputum LTE4 levels (r = 0.673, P = 0.012), and with sputum levels of total cysteinyl‐LTs (r = 0.660, P = 0.014). 5. In conclusion, total cysteinyl‐LT content in sputum is 10‐ fold higher than previously reported, consisting primarily (91%) of LTE4. The high levels of LTE4 and LTB4 in sputum suggest involvement of LTs in the pathophysiology of CF. Urinary LTE4 levels may prove useful as a marker for cysteinyl‐LT production in sputum. 1990 The British Pharmacological Society</p
Human bronchial fibroblasts express the 5-lipoxygenase pathway.
No full textBACKGROUND: Fibroblasts are implicated in sub-epithelial fibrosis in remodeled asthmatic airways and contribute to airway inflammation by releasing cytokines and other mediators. Fibroblast activity is influenced by members of the leukotriene family of bronchoconstrictor and inflammatory mediators, but it is not known whether human bronchial fibroblasts can synthesize leukotrienes. METHODS: The expression of leukotriene biosynthetic enzymes and receptors was investigated in primary fibroblasts from the bronchi of normal and asthmatic adult subjects using RT-PCR, Western blotting, immunocytochemistry and flow cytometry. RESULTS: These techniques revealed that human bronchial fibroblasts from both subject groups constitutively express 5-lipoxygenase, its activating protein FLAP, the terminal enzymes leukotriene A4 hydrolase and leukotriene C4 synthase, and receptors for leukotriene B4 (BLT1) and cysteinyl-leukotrienes (CysLT1). Human bronchial fibroblasts generated immunoreactive leukotriene B4 and cysteinyl-leukotrienes spontaneously and in increased amounts after calcium-dependent activation. Flow cytometry showed that human bronchial fibroblasts transformed to a myofibroblast-like phenotype by culture with transforming growth factor-beta1 expressed 320-400% more immunofluorescence for leukotriene C4 synthase and CysLT1 receptors, with 60-80% reductions in leukotriene A4 hydrolase and BLT1 receptors. CONCLUSION: These results indicate that human bronchial fibroblasts may not only respond to exogenous leukotrienes but also generate leukotrienes implicated in narrowing, inflammation and remodeling of the asthmatic airway
Persistent increase in plasma and urinary leukotrienes after acute asthma
No full textLeukotrienes may mediate bronchoconstriction in asthma. Cysteinyl leukotriene production rises in vivo after allergen challenge, but few reports describe leukotriene concentrations in clinical asthma or in children. Using high performance liquid chromatography/radioimmunoassay, plasma and urinary leukotrienes in asthmatic children (aged 5-10 years) were measured during an acute exacerbation (peak expiratory flow (PEF) <65%, n=10) and one month later (PEF 74-169%, n=9), and in non-atopic normal children (aged 1.3-13.2 years). In the asthmatics, geometric mean (95% confidence interval) plasma leukotriene B4 (LTB4) was 746 pg/ml (398 to 1403) acutely and 1026 pg/ml (662 to 1593) in remission, compared with 369 pg/ml (167 to 728) in the normal children (n=14). Plasma cysteinyl leukotrienes were low or undetectable, but urinary leukotriene E4 (LTE4) was higher in the asthmatics during an acute episode (210 pmol/mmol creatinine, 101 to 454) and at follow up (179 pmol/mmol, 110 to 293), compared with the normal children (98 pmol/mmol, 81 to 118, n=41). This persistent increase in plasma LTB4 and urinary LTE4 concentrations one month after a severe asthmatic episode suggests leukotriene production is related to chronic inflammation rather than to acute bronchoconstriction.</p
Reduction in leukotriene B4 generation by bronchoalveolar lavage cells in asthma.
No full textBackground: leukotrienes are inflammatory mediators implicated in the pathogenesis of asthma. The capacity of inflammatory cells within the airways to generate leukotrienes may be altered in asthma. This hypothesis was tested using bronchoalveolar lavage (BAL) to sample cells within the airways from atopic asthmatic and normal subjects, and by measuring their capacity to generate leukotriene B4 (LTB4) and leukotriene C4 (LTC4) in response to A23187, a potent stimulus of leukotriene generation.Methods: bronchoalveolar lavage was performed in 12 mild asymptomatic atopic asthmatic patients and 12 normal subjects. Mixed BAL cell aliquots (approximately 80% alveolar macrophages) were incubated with 0-20 μM A23187 for 10 minutes and with 4 μM A23187 for 0-30 minutes, and leukotrienes were measured by radioimmunoassay and high performance liquid chromatography. Results: mixed BAL cells from asthmatic subjects generated less LTB4 than cells from normal subjects in dose response and time course experiments (area under the curve 81.5 (0.0-228.5) ng·min 10-6 cells in asthmatic subjects and 197.9 (13.9-935.6) ng·min 10-6 cells in normal subjects. There were no differences in LTC4 generation between BAL cells from asthmatic and normal subjects. Conclusions: generation of LTB4 by BAL cells from atopic asthmatic subjects in response to A23187 was reduced. As the alveolar macrophage is the major source of LTB4 in BAL cells, these results probably reflect reduced generation of LTB4 by alveolar macrophages from asthmatic patients. This may be a consequence of monocyte migration into the lung, or altered alveolar macrophage function in asthma, or both.</p
Promoter polymorphism influences the effect of dexamethasone on transcriptional activation of the LTC4 synthase gene
No full textThe molecular mechanisms of corticosteroid action in asthma are gradually being elucidated. The LTC4S gene encodes for LTC(4) synthase, the terminal enzyme in the generation of cysteinyl-leukotrienes (cys-LTs), which are key mediators in the pathogenesis of asthma. We have identified a novel promoter polymorphism in LTC4S at position -1072 (G/A) and a -444 (A/C) polymorphism has previously been reported. We hypothesised that the LTC4S gene promoter may be a potential site of regulation by corticosteroids and that genetic polymorphism may determine their effects at this locus. Using in vitro transfection of promoter-reporter constructs, dexamethasone was shown to increase transcription of LTC4S by more than 50% for the -1072G/-444A, A-C and G-C haplotype constructs (P&<0.02), but to have no effect on the A-A haplotype (P=0.27). These data identify an interesting phenomenon that requires validation in a human study examining ex vivo production of LTC(4) in cells from genotyped asthmatic and nonasthmatic subjects. The 9% of the Caucasian asthmatic population with the A-A haplotype may have genetically predetermined lower cys-LT levels in the presence of corticosteroids compared to other patients. These findings have potential implications in the evaluation of combined corticosteroid and antileukotriene therapy in asthma
MK886 reduces cerebral amyloid angiopathy severity in the TgCRND8 mouse model of Alzheimer’s disease
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