Leukotrienes Are Dispensable for Vaginal Neutrophil Recruitment as Part of the Immunopathological Response During Experimental Vulvovaginal Candidiasis.

Recruitment of polymorphonuclear neutrophils (PMNs) into the vaginal lumen is the hallmark of an acute immunopathologic inflammatory response during vulvovaginal candidiasis (VVC) caused by Recurrent VVC (RVVC) remains a chronic health burden in affected women worldwide despite the use of antifungal therapy. Based on the role leukotrienes (LTs) play in promoting inflammation, leukotriene receptor antagonists (LTRAs) targeted for LTB (etalocib) or LTC, LTD and LTE (zafirlukast or montelukast) have been shown to reduce inflammation of epithelial tissues. An open-label pilot study using long-term regimens of zafirlukast in women with RVVC indicated the potential for some relief from recurrent episodes.

Effects of celecoxib augmentation of antidepressant or anxiolytic treatment on affective symptoms and inflammatory markers in patients with anxiety disorders: exploratory study.

Prolonged stress has been associated with elevated levels of circulating proinflammatory cytokines. Cyclo-oxygenase-2 inhibitors such as celecoxib exert anti-inflammatory effects and may enhance the response to antidepressant drug treatment in patients with depressive disorders, but their effect on anxiety symptoms in patients with anxiety disorders is uncertain. Patients with a primary diagnosis of an anxiety disorder, with stabilised symptoms, underwent either 6 weeks of celecoxib augmentation of continued treatment (n = 18) or continued 'treatment as usual' (n = 9).

Resolvin E1, resolvin D1 and resolvin D2 inhibit constriction of rat thoracic aorta and human pulmonary artery induced by the thromboxane mimetic U46619.

Background And Purpose: The ω-6 fatty acid-derived lipid mediators such as prostanoids, thromboxane and leukotrienes have well-established roles in regulating both inflammation and smooth muscle contractility. Resolvins are derived from ω-3 fatty acids and have important roles in promoting the resolution of inflammation, but their activity on smooth muscle contractility is unknown. We investigated whether resolvin E1 (RvE1), resolvin D1 (RvD1) and resolvin D2 (RvD2) can modulate contractions of isolated segments of rat thoracic aorta (RTA) or human pulmonary artery (HPA) induced by the α -adrenoceptor agonist phenylephrine or the stable thromboxane A mimetic U46619.

MK886 reduces cerebral amyloid angiopathy severity in TgCRND8 mice.

Background: Deposition of amyloid-β (Aβ) in blood vessel walls as cerebral amyloid angiopathy (CAA) is observed in the majority of Alzheimer's disease (AD) brains. Inhibition of the 5-lipoxygenase (5-LOX) pathway has recently been suggested to play a role in reducing parenchymal Aβ deposition. However, products of the 5-LOX pathway also activate the peroxisome proliferator-activated receptor (PPAR) family, which promotes clearance of Aβ from the brain.

Activity of the leukotriene pathway in Barrett's metaplasia and oesophageal adenocarcinoma.

Objective: Leukotriene (LT) B(4) is a lipid inflammatory mediator implicated in tumorigenesis in animal models of Barrett's oesophagitis, but little is known about the cysteinyl-leukotrienes (LTC(4), LTD(4), LTE(4)), which have distinct inflammatory and tumorigenic actions in other tissues. We recently showed that the terminal enzymes for the synthesis of both LT families are highly expressed in human oesophageal adenocarcinoma (OA) tissues. This study therefore examined the capacity of Barrett's metaplasia (BM) and OA tissues to synthesise LTs in vitro.

Increased expression of the 5-lipoxygenase pathway and its cellular localization in Barrett's adenocarcinoma.

Aims: Up-regulation of the 5-lipoxygenase (5-LOX) leukotriene pathway is evident in numerous tumour types, and has been linked to the promotion of cancer cell growth. The aim of this study was to evaluate the immunohistochemical expression of 5-LOX pathway proteins in oesophageal adenocarcinoma and its premalignant lesion, Barrett's metaplasia.

Methods And Results: Tissue samples were collected at endoscopy from 16 patients with Barrett's metaplasia and from seven with oesophageal adenocarcinoma; five proximal squamous oesophagus samples were used as controls.

Interleukin-13, but not indomethacin, increases cysteinyl-leukotriene synthesis in human lung macrophages.

Aspirin-exacerbated respiratory disease (AERD) is associated with constitutively elevated synthesis of bronchoconstrictor cysteinyl-leukotrienes, associated with increased expression of leukotriene (LT)C(4) synthase and Th2 cytokines and airway eosinophilia. We examined whether interleukin-13 can increase LTC(4) synthase gene transcription and cysteinyl-leukotriene synthesis in macrophages isolated from resected human lung tissue and whether an NSAID (indomethacin) can trigger further cysteinyl-leukotriene synthesis in these cells. Overnight culture of human lung macrophages with IL-13 (10 ng/mL) increased spontaneous and ionophore-stimulated production of cysteinyl-leukotrienes by 42% (P = 0.

FLAP inhibitors for the treatment of inflammatory diseases.

Leukotrienes 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.

CysLTR1 promoter polymorphism and requirement for leukotriene receptor antagonist in aspirin-intolerant asthma patients.

Objectives: Leukotriene receptor antagonists (LTRA), such as montelukast, have been used as a first-line treatment for patients with aspirin-intolerant asthma (AIA). This study evaluated associations between the clinical requirement for LTRA and genetic polymorphisms of the ALOX5, LTC4S, COX-2, CysLTR1 and TBXA2R genes in the arachidonic acid cascade in the long-term management of 89 AIA patients from a Korean population.

Methods: Asthma control status was monitored for 1 year with maintenance medications of inhaled corticosteroid and oral LTRA, and AIA patients were classified into three groups according to the mean montelukast dose required per month to maintain asthma control for 1 year: group I (> or = 200 mg montelukast/month; n = 37), group II (5-150 mg/month; n = 25) and group III (< 5 mg/month; n = 27).

Colonic expression of leukotriene-pathway enzymes in inflammatory bowel diseases.

Background: Leukotrienes derived from the 5-lipoxygenase pathway are proinflammatory lipid mediators that possibly play a role in inflammatory bowel diseases. The expression of 5-lipoxygenase pathway proteins has not previously been examined in colonic mucosa in inflammatory bowel disease.

Results: Quantitative immunohistochemical analyses showed that, compared to those of the control subjects (n = 9), colonic biopsies from patients with active inflammatory bowel disease (n = 17) had 3- to 7-fold higher mean counts of cells expressing 5-lipoxygenase (P = 0.

Cysteinyl leukotrienes synergize with growth factors to induce proliferation of human bronchial fibroblasts.

Background: Cysteinyl leukotrienes (cys-LTs) are potent asthma-related mediators that function through their G protein-coupled receptors, cys-LT receptor type 1 (CysLT1R) and cys-LT receptor type 2 (CysLT2R).

Objective: Because many G protein-coupled receptors transactivate the epidermal growth factor receptor (EGFR) through metalloprotease-mediated ligand shedding, we investigated the effects of cys-LTs on signal transduction and proliferation of bronchial fibroblasts.

Methods: Human bronchial fibroblasts were grown from biopsy specimens of healthy subjects.

Human bronchial fibroblasts express the 5-lipoxygenase pathway.

Background: 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.

Effects of cysteinyl leukotrienes and leukotriene receptor antagonists on markers of inflammation.

The understanding that asthma pathophysiology includes an inflammatory component has spurred the more aggressive use of anti-inflammatory therapies and created a need for effective tools to measure inflammation. Biomarkers of airway inflammation proposed are obtained by methods that are direct but highly invasive (bronchial biopsy, bronchoalveolar lavage), moderately direct, and less invasive (indirect sputum, exhaled air, breath condensate) or indirect and least invasive (blood, urine). Several studies described in this review have implicated the cysteinyl leukotrienes (CysLTs) as inflammatory mediators in a wide range of diseases, implying that their biological activities reach far beyond acute bronchoconstriction, the activity traditionally ascribed to them.

Cysteinyl leukotriene interactions with other mediators and with glucocorticosteroids during airway inflammation.

Unexpected aspects of the antiasthmatic efficacy of leukotriene modifiers and glucocorticosteroids have been observed. For both classes, the observed effects may be partially explainable on the basis of underrecognized interactions involving leukotrienes. This review examines the interactions between leukotrienes and other mediators of asthma.

Rhinovirus infection increases 5-lipoxygenase and cyclooxygenase-2 in bronchial biopsy specimens from nonatopic subjects.

Rhinovirus infections cause wheeze, cough, and bronchial hyperresponsiveness. To investigate the involvement of cysteinyl-leukotrienes and prostanoids in these symptoms, bronchial biopsy specimens from 9 normal subjects (nonatopic and with no history of chronic lung disease) were immunostained for 5-lipoxygenase (5-LO) and cyclooxygenase (COX) pathway enzymes 2 weeks before and 4 days after experimental infection with human rhinovirus serotype 16. 5-LO-positive cell counts increased 9-fold (from 0.