Lipoxin, leukotriene, and PDGF receptors cross-talk to regulate mesangial cell proliferation.
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The lipoxygenase-derived leukotrienes (LTs) are important proinflammatory lipid mediators. Lipoxins (LXs), more recently described lipoxygenase products, modulate many proinflammatory actions of LTs and have impressive proresolution properties. Mesangial cell (MC) proliferation is a central event in the pathogenesis of glomerulonephritis. LTD4-induced proliferation of mesangial cells is modulated by LXA4. Here, we demonstrate that LXA4 inhibits PDGF- and LTD4-stimulated proliferation through modulation of platelet-derived growth factor receptor beta (PDGFRbeta) activation. Specifically, we demonstrate that LTD4 transactivates the PDGFRbeta, a process associated with c-src recruitment and ras activation. We demonstrate expression of cysLT1 and cysLT2 receptors in MCs. LTD4-induced c-src activation was insensitive to pertussis toxin and the cysLT1 receptor antagonist Zafirlukast but was blocked by the nonselective antagonist Pobilukast. We show that LXA4 inhibits LTD4-stimulated activation of the PDGFRbeta and that LXA4 modulates PDGF-BB-stimulated tyrosine phosphorylation of the PDGFRb and subsequent mitogenic events. Furthermore, expression of recombinant LXA4 receptor (ALXR) in CHOK1 cells was associated with an attenuation of serum-stimulated proliferation. These data demonstrate that LXA4 receptor (ALXR) activation is accompanied by antimitogenic effects coupled with inactivation of growth factor receptors, highlighting the complex cross-talk between G protein-coupled receptors and receptor tyrosine kinases in an inflammatory milieu. These data elaborate on the profile of cell signaling events that underpin the anti-inflammatory and proresolution bioactions of LX. (+info)
Neuroprotective effect of ONO-1078, a leukotriene receptor antagonist, on focal cerebral ischemia in rats.
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AIM: To determine whether ONO-1078 (pranlukast), a potent leukotriene receptor antagonist, has neuroprotective effect on focal cerebral ischemia in the rat. METHODS: Focal cerebral ischemia was induced by 30 min of middle cerebral artery (MCA) occlusion and followed by 24 h reperfusion. ONO-1078 (0.003-1.0 mg/kg) or vehicle (saline 1 mL/kg) was ip injected 30 min before MCA occlusion and 2 h after reperfusion. The neurological score, infarct volume, neuron density (in cortex, hippocampus, and striatum), brain edema, and albumin exudation around the vessels were determined 24 h after reperfusion. RESULTS: ONO-1078 slightly improved the neurological deficiency, and dramatically decreased infarct volume and neuron loss which showed a bell shaped dose response effect with highest effect at doses of 0.01-0.3 mg/kg. Enlargement of the ischemic hemisphere and albumin exudation were inhibited at doses of 0.01-1.0 mg/kg. CONCLUSION: ONO-1078 has the protective effect on focal cerebral ischemia in rats, which is partially attributed to the inhibition of brain edema. This may represent a novel approach to the treatment of acute cerebral ischemia with cysteinyl leukotriene receptor antagonists. (+info)
Pharmacological treatment of asthma today.
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The current concept of asthma therapy is based on a stepwise approach, depending on disease severity, and the aim is to reduce the symptoms that result from airway obstruction and inflammation, to prevent exacerbations and to maintain normal lung function. Beta2-adrenoceptor agonists and glucocorticoids are at present the most effective drugs for the treatment of airway obstruction and inflammation, with theophylline, leukotriene receptor antagonists and anticholinergics as second- or third-line therapy. There are, to date, no additional or newly developed drugs available that add substantially to the current strategies or even replace beta2-adrenoceptor agonists or glucocorticoids. New approaches in asthma therapy recommend drug combinations of inhaled steroids, primarily with long-acting beta2-adrenoceptor agonists, based on their improved efficacy and the potential for a steroid-sparing effect. Although existing drug entities are able to control the vast majority of patients with mild and moderate asthma, patients' (and doctors') adherence to guidelines and treatment strategies falls well short of the desired standards. Treatment choices, however, differ between countries and should take into account convenience to the patient and the occurrence of side-effects. Additionally, the cost of therapy and reimbursement policies also influences therapeutic strategies. (+info)
Differential peristaltic motor effects of prostanoid (DP, EP, IP, TP) and leukotriene receptor agonists in the guinea-pig isolated small intestine.
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1. Since the role of prostanoid receptors in intestinal peristalsis is largely unknown, the peristaltic motor effects of some prostaglandin (DP, EP, IP), thromboxane (TP) and leukotriene (LT) receptor agonists and antagonists were investigated. 2. Propulsive peristalsis in fluid-perfused segments from the guinea-pig small intestine was triggered by a rise of the intraluminal pressure and recorded via the intraluminal pressure changes associated with the peristaltic waves. Alterations of distension sensitivity were deduced from alterations of the peristaltic pressure threshold and modifications of peristaltic performance were reflected by modifications of the amplitude, maximal acceleration and residual baseline pressure of the peristaltic waves. 3. Four categories of peristaltic motor effects became apparent: a decrease in distension sensitivity and peristaltic performance as induced by the EP1/EP3 receptor agonist sulprostone and the TP receptor agonist U-46619 (1-1000 nM); a decrease in distension sensitivity without a major change in peristaltic performance as induced by PGD(2) (3-300 nM) and LTD(4) (10-100 nM); a decrease in peristaltic performance without a major change in distension sensitivity as induced by PGE(1), PGE(2) (1-1000 nM) and the EP1/IP receptor agonist iloprost (1-100 nM); and a decrease in peristaltic performance associated with an increase in distension sensitivity as induced by the EP2 receptor agonist butaprost (1-1000 nM). The DP receptor agonist BW-245 C (1-1000 nM) was without effect. 4. The peristaltic motor action of sulprostone remained unchanged by the EP1 receptor antagonist SC-51089 (1 micro M) and the DP/EP1/EP2 receptor antagonist AH-6809 (30 micro M), whereas that of U-46619 and LTD(4) was prevented by the TP receptor antagonist SQ-29548 (10 micro M) and the cysteinyl-leukotriene(1) (cysLT(1)) receptor antagonist tomelukast (10 micro M), respectively. 5. These observations and their pharmacological analysis indicate that activation of EP2, EP3, IP, TP and cysLT(1) receptors, but not DP receptors, modulate intestinal peristalsis in a receptor-selective manner, whereas activation of EP1 seems to be without influence on propulsive peristalsis. In a wider perspective it appears as if the effect of prostanoid receptor agonists to induce diarrhoea is due to their prosecretory but not peristaltic motor action. (+info)
Dose reduction of inhaled corticosteroids under concomitant medication with montelukast in patients with asthma.
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The present study aimed at comparing the effects of a dose reduction of inhaled corticosteroids on lung function, indirect measures of airway inflammation and clinical scores during treatment with a leucotriene receptor antagonist. In 50 patients (mean forced expiratory volume in one second (FEV1) 94% predicted), steroid doses (800 microg beclomethasone dipropionate) were first reduced to 50% and then to 25%, for 6 weeks each. One group received a placebo and the other group received montelukast (10 mg). The first reduction did not cause significant effects. During the second, FEV1 and peak expiratory flow decreased in both groups (p<0.001). Daytime symptoms were not altered with placebo but were reduced by montelukast (p<0.05). Night-time symptoms were slightly elevated with placebo (p<0.05) but not montelukast, as well as the use of supplemental salbutamol. Changes in provocative concentration of methacholine causing a 20% fall in FEV1 (PC20), sputum eosinophils and exhaled nitric oxide were mostly nonsignificant for both placebo and montelukast. These data demonstrate that a 75% reduction in the dose of steroid given to patients with asthma led to a deterioration in lung function not prevented by montelukast, whereas changes in clinical state seemed to favour montelukast treatment. It therefore appears that potential effects of montelukast, in the presence of low-dose steroids, could not be attributed to single indices of lung function or airway inflammation. (+info)
Lipoxin A(4) (LXA(4)) and its stable analogs downregulate chemokine secretion in polarized epithelia. This anti-inflammatory effect has been suggested to be mediated by the LXA(4) receptor (LXA(4)R), a G protein-coupled receptor. To determine whether LXA(4)R is expressed on the apical, basolateral, or both poles of intestinal epithelia, an NH(2)-terminal c-myc epitope tag was added to the human LXA(4)R cDNA and recombinant retroviruses were used to transduce polarized epithelial cells. In polarized T84 intestinal epithelial cells, c-myc-LXA(4)R was preferentially expressed on the basolateral surface as indicated by cell surface-selective biotinylation and confocal microscopy. Furthermore, expression of c-myc-LXA(4)R and a truncation mutant lacking the cytoplasmic terminus was primarily confined to the lateral subdomain. We also observed that the expression of myc-LXA(4) conferred enhanced downregulation of IL-8 expression in response to LXA(4) analog and that blockade of the CysLT1 receptor by montelukast did not prevent this response to LXA(4) analog. Thus LXA(4) generated in or near the paracellular space via neutrophil-epithelial interactions can rapidly act on epithelial LXA(4)R to downregulate epithelial promotion of intestinal inflammation. (+info)
Pharmacological evidence for a novel cysteinyl-leukotriene receptor subtype in human pulmonary artery smooth muscle.
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1. To characterize the cysteinyl-leukotriene receptors (CysLT receptors) in isolated human pulmonary arteries, ring preparations were contracted with leukotriene C(4) (LTC(4)) and leukotriene D(4) (LTD(4)) in either the absence or presence of the selective CysLT(1) receptor antagonists, ICI 198615, MK 571 or the dual CysLT(1)/CysLT(2) receptor antagonist, BAY u9773. 2. Since the contractions induced by the cysteinyl-leukotrienes (cysLTs) in intact preparations failed to attain a plateau response over the concentration range studied, the endothelium was removed and the tissue treated continuously with indomethacin (Rubbed+INDO). In these latter preparations, the pEC(50) for LTC(4) and LTD(4) were not significantly different (7.61+/-0.07, n=20 and 7.96+/-0.09, n=22, respectively). However, the LTC(4) and LTD(4) contractions were markedly potentiated when compared with data from intact tissues. 3. Leukotriene E(4) (LTE(4)) did not contract human isolated pulmonary arterial preparations. In addition, treatment of preparations with LTE(4) (1 microM; 30 min) did not modify either the LTC(4) or LTD(4) contractions. 4. Treatment of preparations with the S-conjugated glutathione (S-hexyl-GSH; 100 microM, 30 min), an inhibitor of the metabolism of LTC(4) to LTD(4), did not modify LTC(4) contractions. 5. The pEC(50) values for LTC(4) were significantly reduced by treatment of the preparations with either ICI 198615, MK 571 or BAY u9773 and the pK(B) values were: 7.20, 7.02 and 6.26, respectively. In contrast, these antagonists did not modify the LTD(4) pEC(50) values. 6. These findings suggest the presence of two CysLT receptors on human pulmonary arterial vascular smooth muscle. A CysLT(1) receptor with a low affinity for CysLT(1) antagonists and a novel CysLT receptor subtype, both responsible for vasoconstriction. Activation of this latter receptor by LTC(4) and LTD(4) induced a contractile response which was resistant to the selective CysLT(1) antagonists (ICI 198615 and MK 571) as well as the non-selective (CysLT(1)/CysLT(2)) antagonist, BAY u9773. (+info)
Eosinophilic oesophagitis: a novel treatment using Montelukast.
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BACKGROUND: Eosinophilic oesophagitis is a rarely diagnosed condition involving eosinophil infiltration of the oesophageal mucosa and creating significant symptoms of dysphagia. Failure to diagnose this disorder relates to reluctance to biopsy an apparently normal oesophagus. This is essential for histological diagnosis. To date, treatment success has been achieved only with corticosteroids. We describe here the use of an eosinophil stabilising agent Montelukast for the symptomatic relief of these patients. PATIENTS AND METHODS: Twelve patients have been identified with this condition in our unit since 1995, after thorough investigation of their dysphagia. We commenced eight of these patients on the leukotriene receptor antagonist Montelukast to symptomatically improve their swallowing while avoiding the use of long term corticosteroids. RESULTS: Many of these patients had been previously misdiagnosed, and therefore inappropriately and unsuccessfully treated for an extensive period prior to referral to our unit. All patients were unresponsive to acid suppression therapy alone but showed improvement in their swallowing on Montelukast. Six of eight reported complete subjective improvement, five patients remaining completely asymptomatic on a maintenance regimen. CONCLUSIONS: Eosinophilic oesophagitis is a disease that is often misdiagnosed due to lack of awareness and reluctance of clinicians to biopsy an apparently normal oesophagus in dysphagic patients, and therefore obtain a histological diagnosis. Investigation of these patients adds further evidence to this condition being a separate pathological state from gastro-oesophageal reflux and eosinophilic enteritis. Montelukast has been found to be of significant help in the symptomatic control of these patients while avoiding long term corticosteroids use. (+info)