Role of leukotrienes in asthma pathophysiology

Bisgaard, Hans

doi:10.1002/1099-0496(200008)30:2<166::aid-ppul15>3.0.co;2-l

Cited by 59 publications

(44 citation statements)

References 111 publications

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“…[41] receiving placebo; 35 of 81 (43%) pediatric patients receiving Moreover, Bisgaard [15] provided evidence that inhaled LTD4 amelubant 75mg experienced pulmonary exacerbation compared causes a dose-dependent reduction in flow measures of small with 26 of 74 (35%) pediatric patients receiving placebo.…”

Section: Safety and Tolerabilitymentioning

confidence: 99%

“…suggesting that cysLTRAs and corticosteroids affect different Moreover, the mean values for the plasma elimination half-life, targets. [15] Another advantage of cysLTRA treatment in CF should elimination rate constant, AUC, and maximum plasma concentrabe an amelioration of symptoms following viral infections (see tion for the control individuals were 2.37 ± 0.38 hours, 0.30 ± 0.05 section 2.1.3). [60] Moreover, impaired mucus transport is a hours -1 , 2680 ± 693.6 ng • min/mL, and 448.9 ± 165.3 ng/mL; and pathophysiologic feature of CF and there is evidence that cysLTs 2.97 ± 1.21 hours, 0.28 ± 0.13 hrs -1 , 3976.1 ± 2073.4 ng • min/ decrease the activity of human respiratory cilia.…”

Section: Eosinophilic Inflammationmentioning

confidence: 99%

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Leukotriene Receptor Antagonists in Children with Cystic Fibrosis Lung Disease

Schmitt‐Grohé

Zielen

2005

Pediatric Drugs

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Cystic fibrosis (CF) lung disease is characterized by chronic endobronchial infection resulting in progressive pulmonary destruction; this is a major cause of mortality and morbidity. Neutrophils are the primary effector cells responsible for the progressive deterioration of lung function. Peptido-leukotriene B4 antagonists, new anti-inflammatory agents that block the neutrophil-dominated inflammation, could have had the potential for long-term use. A trial on the pharmacokinetics of amelubant administered orally as a single dose of up to 75 mg in pediatric patients with CF and 300 mg in adults, and as a repeated dose of 75 mg and 150 mg, respectively, once daily for 15 days provided evidence that amelubant metabolism in adult and pediatric patients with CF is similar to that in healthy adults. In another study using the same dosage regimen, amelubant appeared to be safe and well tolerated. Safety measures included physical examination, vital signs, spirometry, oximetry, ECG, and clinical laboratory testing. However, a randomized, double-blind, placebo-controlled, multinational, phase II trial (Boehringer Ingelheim 543.45) was conducted to investigate the clinical efficacy of 24 weeks of treatment with amelubant in patients with CF with mild-to-moderate lung disease. Two doses of amelubant (75 and 150 mg) were tested in adult patients (> or = 18 years) and one dose of amelubant (75mg) was tested in pediatric (6-17 years) patients. The trial was terminated early due to a statistically significant increase in the risk of pulmonary-related, serious adverse events in adults receiving amelubant. Cysteinyl leukotrienes, eosinophilic inflammation, and viral infections also contribute to progressive pulmonary destruction in CF. Cysteinyl leukotrienes are potential targets for cysteinyl leukotriene receptor antagonist use. A study on the pharmacokinetics of montelukast in children with CF provided evidence that the dose of montelukast and the administration interval does not need to be modified if the goal is to mimic the serum concentrations used to treat asthma. In a randomized, double-blind, crossover, placebo-controlled study, 16 children with mild CF (median age 9.5 years; vital capacity [VC] >70%) were treated with montelukast (5 to < or =14 years; 5 mg; >14 years; 10 mg) or placebo as a once-daily tablet for 21 days. There was a significant (p < or = 0.02) reduction in serum eosinophil cationic protein levels and eosinophils (p < or = 0.027) with montelukast. However, neither lung function tests (VC, forced expiratory volume in 1 second [FEV1], maximum expiratory flow at 25% of forced VC), nor clinical symptom scores changed significantly. In another study, 26 patients aged 6-18 years with moderate CF (VC between 40% and 69% predicted) received montelukast or placebo for 8 weeks in a 20-week, randomized, double-blind, crossover, placebo-controlled trial. After treatment with montelukast there was a significant improvement in FEV1, peak expiratory flow, and forced expiratory flow between 25% and 75%, and a significa...

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Section: Safety and Tolerabilitymentioning

confidence: 99%

Section: Eosinophilic Inflammationmentioning

confidence: 99%

Leukotriene Receptor Antagonists in Children with Cystic Fibrosis Lung Disease

Schmitt‐Grohé

Zielen

2005

Pediatric Drugs

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“…18,19 Previous studies have demonstrated the effectiveness of these medications for reducing the occurrence of EIB. 20,21 However, other studies have demonstrated that there are some limitations of pharmacologic therapy, such as potential side effects, the effectiveness of each medication, the frequency of administration, the duration of action, bad taste, and tolerance level. [21][22][23][24] Non-pharmacologic management includes physical conditioning, incorporating a warm-up before and a cool-down period after exercise, nasal breathing, avoidance of cold weather or environmental allergens, and using a face mask or other aid to warm and humidify inhaled air.…”

Section: Introductionmentioning

confidence: 99%

The Role of Pro-inflammatory and Anti-inflammatory Adipokines on Exercise-Induced Bronchospasm in Obese Adolescents Undergoing Treatment

Silva¹,

Mello²,

Cheik

et al. 2012

Respir Care

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BACKGROUND: Recent studies have demonstrated a greater prevalence in exercise-induced bronchospasm (EIB) in obese adolescents. However, the role of pro-/anti-inflammatory adipokines and the repercussions of obesity treatment on EIB need to be explored further. Therefore, the objective of this study was to evaluate the role of pro-/anti-inflammatory adipokines on EIB in obese adolescents evaluated after long-term interdisciplinary therapy. METHODS: Thirty-five post-pubertal obese adolescents, including 20 non-EIB (body mass index [BMI] 36 ؎ 5 kg/m 2 ) and 15 EIB (BMI 36 ؎ 5 kg/m 2 ), were enrolled in this study. Body composition was measured by plethysmography, using the BOD POD body composition system, and visceral fat was analyzed by ultrasound. Serum levels of adiponectin and leptin were analyzed. EIB and lung function were evaluated according to the American Thoracic Society criteria. Patients were recruited to a 1-year interdisciplinary intervention of weight loss, consisting of medical, nutritional, exercise, and psychological components. RESULTS: Anthropometrics and lung function variables improved significantly after the therapy in both groups. Furthermore we observed a reduction in EIB occurrence in obese adolescents after treatment. There was an increase in adiponectin levels and a reduction in leptin levels after the therapy. In addition, a low FEV 1 value was a risk factor associated with EIB occurrence at baseline, and was correlated after treatment with changes in anthropometric and maximal O 2 consumption values as well as the adipokines profile. CONCLUSIONS: In the present study it was demonstrated that 1 year of interdisciplinary therapy decreased EIB frequency in obese adolescents, paralleled by an increase in lung function and improvement in pro-/anti-inflammatory adipokines.

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“…Cysteinyl leukotrienes (CysLTs) play an important role in the pathogenesis of airway inflammation and remodeling in asthma (Drazen, 1998;Bisgaard, 2000;Henderson et al, 2002). The biological effects of CysLTs are mediated by at least two G protein-coupled receptors (GPCRs), namely cysteinyl leukotrienes receptor 1 (CysLT 1 R) and receptor 2, and the CysLT 1 R is known to be involved in most of the biological effects in the lung (Nicosia et al, 1999;Dahlén, 2000).…”

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confidence: 99%

Cysteinyl Leukotriene-1 Receptor Activation in a Human Bronchial Epithelial Cell Line Leads to Signal Transducer and Activator of Transcription 1-Mediated Eosinophil Adhesion

Profita

Sala

Bonanno

et al. 2008

J Pharmacol Exp Ther

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We studied the effect of leukotriene D 4 (LTD 4 ) on a human bronchial epithelial cell line (16HBE) overexpressing the cysteinyl leukotriene (CysLT) 1 receptor (HBECysLT 1 R), looking at the associated signal transduction mechanisms as well as at effects on inflammatory cell adhesion. The results obtained showed that LTD 4 increases the phosphorylation of extracellular signal-regulated protein kinase (ERK) 1/2 and of the signal transducer and activator of transcription 1 (STAT-1) in serine 727 (STAT-1Ser727), resulting in increased eosinophil adhesion to HBECysLT 1 R, associated with enhanced surface expression of intercellular adhesion molecule (ICAM) 1. Pretreatment with a CysLT 1 R-selective antagonist or with a selective inhibitor of protein kinase C (PKC) or with a selective inhibitor of the mitogen-activated protein kinase kinase (MEK) successfully suppressed both LTD 4 -induced STAT-1Ser727 phosphorylation and the associated increase in eosinophil adhesion. The use of the MEK inhibitor and of the selective CysLT 1 R antagonist in electrophoretic mobility shift assay experiments showed that LTD 4 promotes the nuclear translocation of STAT-1 through the activation of ERK1/2 pathway. The key role of STAT-1 in leukotriene D 4 transduction signaling was confirmed by RNA interference experiments, where silencing of STAT-1 expression abolished the effect of leukotriene D 4 on eosinophil adhesion. In conclusion, for the first time, we provide evidence of the involvement of STAT-1 in the signal transduction mechanism of the CysLT 1 receptor; phosphorylation of STAT-1, through PKC and ERK1/2 activation, causes enhanced ICAM-1 surface expression and eosinophil adhesion. Effective CysLT 1 R antagonism may therefore contribute to the control of the chronic inflammatory condition that characterizes human airways in asthma.Cysteinyl leukotrienes (CysLTs) play an important role in the pathogenesis of airway inflammation and remodeling in asthma (Drazen, 1998;Bisgaard, 2000;Henderson et al., 2002). The biological effects of CysLTs are mediated by at least two G protein-coupled receptors (GPCRs), namely cysteinyl leukotrienes receptor 1 (CysLT 1 R) and receptor 2, and the CysLT 1 R is known to be involved in most of the biological effects in the lung (Nicosia et al., 1999;Dahlén, 2000). CysLT 1 R is expressed in smooth muscle cells and lung macrophages (Lynch et al., 1999) and is widely distributed in human eosinophils, monocytes, and neutrophils (Figueroa et al., 2001;Mita et al., 2001); little is known about the expression and the responses of CysLT 1 R in the airway epithelium, but recent evidence showed that LTC 4 may elicit transformThis study was supported in part by the European Community VIth Framework Program (Grant LSHM CT 2004 005033; to A.S.)

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Role of leukotrienes in asthma pathophysiology

Cited by 59 publications

References 111 publications

Leukotriene Receptor Antagonists in Children with Cystic Fibrosis Lung Disease

Leukotriene Receptor Antagonists in Children with Cystic Fibrosis Lung Disease

The Role of Pro-inflammatory and Anti-inflammatory Adipokines on Exercise-Induced Bronchospasm in Obese Adolescents Undergoing Treatment

Cysteinyl Leukotriene-1 Receptor Activation in a Human Bronchial Epithelial Cell Line Leads to Signal Transducer and Activator of Transcription 1-Mediated Eosinophil Adhesion

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