The Cysteinyl Leukotriene (CysLT) Pathway in Allergic Rhinitis

The cysteinyl leukotrienes (CysLTs), leukotriene C₄(LTC₄), leukotriene D₄(LTD₄) and leukotriene E₄(LTE₄) are released in response to specific allergen in nasal secretions from patients with active allergic rhinitis. The symptoms and inflammation of allergic rhinitis can be induced by inhalation of CysLTs. Inflammatory cells from patients with allergic rhinitis express both the synthetic and signaling proteins for the CysLT pathway. CysLTs activate cell migration, in particular eosinophils, endothelial or epithelial cell adhesion and release of cytokines and other oxidative inflammatory mediators. Cytokines may also activate the release of CysLTs from eosinophils and other myeloid cells and also enhance the expression of the CysLT₁ receptor creating an inflammatory amplification cycle. Systemic CysLT₁ receptor antagonists can reduce the inflammation and symptoms of both allergic rhinitis and asthma.     

Low-level environmental tobacco smoke exposure and inflammatory biomarkers in children with asthma

Objective: The effects of low-level environmental tobacco smoke (ETS) exposure, on asthma control, lung function and inflammatory biomarkers in children with asthma have not been well studied. The objective of the study was to assess ETS exposure in school-age children with asthma whose parents either deny smoking or only smoke outside the home, and to assess the impact of low-level ETS exposure on asthma control, spirometry and inflammatory biomarkers. Methods: Forty patients age 8–18 years with well-controlled, mild-to-moderate persistent asthma treated with either inhaled corticosteroids (ICS) or montelukast were enrolled. Subjects completed an age-appropriate Asthma Control Test and a smoke exposure questionnaire, and exhaled nitric oxide (FeNO), spirometry, urinary cotinine and leukotriene E₄ (LTE₄) were measured. ETS-exposed and unexposed groups were compared. Results: Only one parent reported smoking in the home, yet 28 (70%) subjects had urinary cotinine levels ≥1?ng/ml, suggesting ETS exposure. Seven subjects (18%) had FeNO levels >25parts per billion, six of whom were in the ETS-exposed group. In the ICS-treated subjects, but not in the montelukast-treated subjects, ETS exposure was associated with higher urinary LTE₄, p?=?0.04, but had no effect on asthma control, forced expiratory volume in 1?s or FeNO. Conclusions: A majority of school-age children with persistent asthma may be exposed to ETS, as measured by urinary cotinine, even if their parents insist they don’t smoke in the home. Urinary LTE₄ was higher in the ETS-exposed children treated with ICS, but not in children treated with montelukast.     

Effect of a leukotriene receptor antagonist pranlukast hydrate,on airway inflammation airway hyperresponsiveness in patients with moderate to severe asthma

Asthma is characterized by chronic airway inflammation and the recruitment of inflammatory cells, typically eosinophils and lymphocytes, into the airway. Although several chemical mediators are released during the inflammatory process of asthma, evidence strongly suggests that the cysteinyl leukotrienes (LT), LTC₄, LTD₄, and LTE₄, play key roles in asthma. The short-term clinical efficacy of an LT receptor antagonist, pranlukast hydrate, in symptomatic patients with asthma who had already been treated with moderate to high doses of inhaled corticosteroids was therefore investigated. Treatment with pranlukast hydrate for 4 weeks significantly improved respiratory function and decreased asthma symptoms, the rescue use of inhaled β2-agonists, the number of peripheral blood eosinophils and serum levels of eosinophil cationic protein. Furthermore, airway inflammation, as evaluated by the percentage of eosinophils in induced sputum and airway responsiveness to histamine, decreased significantly after treatment. There were no significant changes in these parameters in control patients with asthma whose treatment was not changed over 4 weeks. These preliminary results suggest that pranlukast hydrate, an LT receptor antagonist, is an effective agent in the management of asthma in combination with moderate to high doses of inhaled corticosteroids.     

Effect of Suplatast Tosilate on Airway Hyperresponsiveness and Inflammation in Asthma Patients

Because eosinophilic airway inflammation is a characteristic of bronchial asthma, the treatment of such inflammation is important in the management of this disease. Suplatast tosilate is a novel anti-asthma drug that suppresses eosinophil proliferation and infiltration through selective inhibition of Th2 cytokine synthesis.

We investigated the effect of oral suplatast tosilate therapy in patients with mild and moderate asthma.

Twenty-eight asthma patients were randomized into two groups with or without suplatast tosilate treatment (100 mg t.i.d. for 28 days). We examined the blood eosinophil counts, eosinophilic cationic protein level, sputum eosinophil count, exhaled nitric oxide level, and airway responsiveness before and after treatment.

In patients treated with suplatast tosilate, the eosinophil count in the blood and sputum was significantly decreased after treatment, while there was no such change in the patients without suplatast treatment. The exhaled nitric oxide level and airway responsiveness (measured using an Astograph) were also decreased after treatment with suplatast tosilate, while there were no significant changes in patients without suplatast tosilate.

These results strongly suggest that oral administration of suplatast tosilate suppresses airway hyperresponsiveness in asthma patients by reducing eosinophilic inflammation in the airways.     

Enhanced Synthesis of Cysteinyl Leukotrienes in Juvenile Rheumatoid Arthritis

Objective. Endogenous synthesis of cysteinyl leukotrienes in juvenile rheumatoid arthritis (JRA) was investigated. Methods. Cysteinyl leukotriene synthesis was assessed by measuring the excretion of leukotriene E₄ (LTE₄) in urine by radioimmunoassay. The identity of urinary LTE₄ was investigated by gas chromatography—mass spectrometry (GC-MS), and 2,3-dinor-thromboxane B₂ was measured with GC-MS. Results. Excretion of LTE₄ into urine was significantly (P < 0.05) enhanced in children with JRA compared with that in healthy children (n = 10). Aspirin, in a dosage of 2.5 gm/day, had no effect on urinary LTE₄ levels, but it reduced urinary 2,3-dinorthromboxane B₂ levels by more than 85% in healthy adults. There was a positive correlation between LTE₄ excretion and the number of affected joints. Conclusion. This study demonstrates a markedly enhanced cysteinyl leukotriene synthesis and a positive correlation between LTE₄ excretion and the number of affected joints in children with JRA.     

Responsiveness to leukotriene D4 and methacholine for predicting efficacy of montelukast in asthma

A lower responsiveness to leukotriene D₄ (LTD₄) or higher LTD₄/[methacholine (MCh)] potency ratio might suggest preferable outcomes of short-term montelukast monotherapy in terms of airway inflammation and lung function in asthmatic patients.KEY WORDS : Asthma, leukotriene D₄ (LTD₄), leukotriene-responsive, leukotriene-unresponsive, methacholine (MCh), montelukast     

Effect of fluticasone on markers of inflammation and quality of life in steroid‐naive patients with mild asthma

Background and Aims: Patients with mild asthma may adapt to symptoms that may be neglected at a medical consultation. Despite active airway inflammation, indicating need for treatment symptoms may be poorly perceived and influence on quality of life. The aim was to find out if markers of asthma activity and quality of life are influenced by inhaled steroids in patients who regard themselves as free of symptoms. Methods: Seventy steroid‐free patients with mild asthma were treated with inhaled fluticasone (250 µg twice daily) or placebo for 3 months in a randomised, double‐blind, study. Spirometry with reversibility test, exhaled nitric oxide (NO), bronchial responsiveness to methacholine and eucapnic dry air hyperventilation and quality of life [(Asthma Quality of Life Questionnaire (AQLQ)] were assessed before and after treatment. Results: Fluticasone, but not placebo, decreased methacholine responsiveness. Bronchial responsiveness to dry air and exhaled NO levels was significantly lowered by fluticasone compared with placebo. Quality‐of‐life scores were high already before treatment and were not significantly altered by treatment. Conclusion: Treatment with an inhaled steroid in mild asthmatics altered bronchial responsiveness and exhaled NO levels but did not improve quality of life. In mild asthma, there is thus a space for improvement with regard to inflammatory parameters in patients who have only minor symptoms that are not influenced by treatment. In a long‐term perspective, the indication for treatment of surrogate markers remains, however, unclear. Please cite this paper as: Ehrs P‐O, Sundblad B‐M and Larsson K. Effect of fluticasone on markers of inflammation and quality of life in steroid‐naive patients with mild asthma. The Clinical Respiratory Journal 2009; DOI:10.1111/j.1752‐699X.2009.00145.x.     

Dipeptidase inhibitor and epithelial removal potentiate leukotriene D4-induced human tracheal smooth muscle contraction

We investigated the role of epithelium in smooth muscle contraction induced by leukotriene D₄ (LTD₄) in isolated human trachea. The contractile response to LTD₄ was potentiated by an inhibitor of dipeptidases l-cysteine and by removal of the epithelium. Both l-cysteine (3×10⁻³ M) and removal of the epithelium shifted the concentration-response curves to LTD₄, to lower concentrations by 0.7 and 0.6 log units, respectively. Incubation of cultured or isolated human tracheal epithelial cells with LTD₄ resulted in the formation of LTE₄, which was completely blocked by pretreatment with l-cysteine (3×10⁻³ M). The isolated and cultured human tracheal epithelial cells contained microsomal dipeptidase (MDP) activity. Immunohistochemical study indicated MDP protein was present in the epithelium and endothelial cells of submucosal microvessels in the human trachea. These results suggest that the epithelium modulates the contractile response to LTD₄ in human trachea by dipeptidases degrading LTD₄.     

Exhaled nitric oxide following leukotriene E(4) and methacholine inhalation in patients with asthma

Nitric oxide (NO) is a molecular gas that can be recovered in higher levels from the exhaled gas of subjects with asthma than from subjects without asthma. However, the precise mechanisms responsible of promoting increased fraction of expired nitric oxide (FE(NO)) in asthma are unknown. As leukotriene antagonism has been shown to reduce FE(NO) in patients with asthma, we hypothesized that leukotrienes mediate the increased FE(NO) encountered in this condition. Furthermore, because leukotriene antagonism stabilizes serum eosinophil markers during reductions in inhaled corticosteroid doses, and FE(NO) has been shown to correlate with sputum eosinophils in asthma, we reasoned that the effect of leukotrienes on FE(NO) might be mediated by eosinophils recruited to the airway by leukotrienes. To test this hypothesis, we performed methacholine and leukotriene (LT) E(4) bronchoprovocation challenges in 16 subjects with atopic asthma and measured FE(NO) and sputum differential counts before and after bronchoprovocation. We then compared FE(NO) in the seven subjects who developed increased sputum eosinophils following LTE(4) inhalation with values measured after methacholine inhalation in these seven subjects. Following LTE(4) inhalation, eosinophils rose from 4.01 +/- 0.89% pre-LTE(4) to 8.33 +/- 1.52% post-LTE(4). The mean change in sputum eosinophils from baseline after LTE(4) inhalation was larger than that after methacholine inhalation (+4.31 +/- 1.25% versus -1.14 +/- 0.93%). After LTE(4) inhalation, FE(NO) levels did not differ from prechallenge baseline or from levels following methacholine inhalation (ANOVA p > 0.05). These data indicate that neither LTE(4) nor recruitment of eosinophils into the airway by LTE(4) is a sufficient stimulus to acutely increase FE(NO) in subjects with asthma.     

Increased exhaled nitrite in children with allergic asthma is not related to nitric oxide formation

Introduction: Nitrite sampled from the upper airways could originate from inflammation‐induced nitric oxide (NO), as reports of elevated nitrite in exhaled breath condensate (EBC) from asthmatics suggest, but also through bacterial action in the pharyngo‐oral tract. Objectives: To correlate EBC nitrite and nitrate to exhaled NO (FENO, fraction of expired NO) and other markers of disease activity in children with allergic asthma and thereby further investigate their role and origin. Materials and methods: EBC was collected from 27 asthmatic subjects (ages 6–17 years, all immunoglobulin E‐positive for aeroallergens) and 21 age‐matched non‐atopic healthy controls for fluorometric analysis of nitrite and nitrate. These markers were compared with measurements of FENO, blood eosinophil count (EOS), methacholine reactivity (PD₂₀) and baseline spirometry. Results: EBC nitrite, in contrast to nitrate, was significantly increased (P < 0.01) in the asthmatic children. They also had increased levels of FENO (P < 0.001) and EOS (P < 0.001) along with decreased PD₂₀ (P < 0.001) and FEV1/FVC (P < 0.01). However, there was no correlation between EBC nitrite and FENO (r = 0.05) or any other marker of disease activity in the asthmatic children, whereas between the other markers correlations could be established. Conclusion: EBC nitrite is elevated in childhood asthma but the lack of correlation to FENO and other markers, together with simultaneously normal levels of nitrate, make its origin as a metabolite of inflammation‐induced NO questionable. Please cite this paper as: Zetterquist W, Marteus H, Hedlin G and Alving G. Increased exhaled nitrite in children with allergic asthma is not related to nitric oxide formation. The Clinical Respiratory Journal 2008; 2: 166–174.     

Airway hyper-responsiveness in young adults with asthma that remitted either during or before adolescence

Background and objective: More than 50% of patients with childhood asthma enter clinical remission by puberty, although 40–50% of these people will probably develop asthma symptoms during early adulthood. The mechanism of relapsing asthma in early adulthood remains unclear. This study determined the characteristics of young adults whose asthma remitted either during or before adolescence. Methods: A comparative study was performed on 24 students whose childhood asthma had gone into clinical remission by puberty (remission group), 25 atopic students with no history of asthma (atopy group) and 19 non‐atopic students without allergic diseases (control group). Examinations included spirometry, levels of serum‐specific IgE‐antibodies, airway responsiveness to methacholine, exhaled nitric oxide (eNO) and evidence of airway inflammation in induced sputum. Results: Airway responsiveness (P < 0.01), eosinophil counts in sputum (P < 0.05) and the prevalence of sensitization to Dermatophagoides forinae (P < 0.01) were significantly higher, and FEF_25–75% and FEF_75% (P < 0.01) were significantly lower in the remission group than in the atopy and control groups. Furthermore, 50% and 33% of the remission group had airway hyper‐responsiveness (AHR) and sputum eosinophilia, respectively. The eNO levels in the remission (P < 0.01) and atopy (P < 0.05) groups were significantly higher than in controls. Remission group members with AHR had a significantly longer period of childhood asthma, a shorter period of remission and greater airway eosinophilic inflammation than those without AHR (P < 0.05). Conclusion: One half of young adults with childhood asthma that remitted either during or before adolescence continued to have evidence of AHR and airway eosinophilic inflammation, and might be at risk of future relapse.     

Urinary cysteinyl leukotriene E4 significantly increases during pain in children and adults with sickle cell disease

Baseline level of the cysteinyl leukotriene (CysLT), leukotriene E₄ (LTE₄), is associated with an increased pain rate in children and adults with sickle cell disease (SCD). To provide additional evidence for a role of CysLTs in the pathogenesis of vaso‐occlusion, we tested the hypothesis that LTE₄ levels will increase within an individual during painful episodes compared to baseline. In a cohort of 19 children and adults with SCD, median LTE₄ levels increased from 82.36 pg/mg creatinine at baseline to 162.81 pg/mg creatinine during a painful episode (P < 0.001). These data further support a contribution of CysLTs to the process of vaso‐occlusion. Am. J. Hematol., 2009. © 2009 Wiley‐Liss, Inc.     

Effect of Suplatast Tosilate on Airway Hyperresponsiveness and Inflammation in Asthma Patients

Because eosinophilic airway inflammation is a characteristic of bronchial asthma, the treatment of such inflammation is important in the management of this disease. Suplatast tosilate is a novel anti-asthma drug that suppresses eosinophil proliferation and infiltration through selective inhibition of Th2 cytokine synthesis.

We investigated the effect of oral suplatast tosilate therapy in patients with mild and moderate asthma.

Twenty-eight asthma patients were randomized into two groups with or without suplatast tosilate treatment (100 mg t.i.d. for 28 days). We examined the blood eosinophil counts, eosinophilic cationic protein level, sputum eosinophil count, exhaled nitric oxide level, and airway responsiveness before and after treatment.

In patients treated with suplatast tosilate, the eosinophil count in the blood and sputum was significantly decreased after treatment, while there was no such change in the patients without suplatast treatment. The exhaled nitric oxide level and airway responsiveness (measured using an Astograph) were also decreased after treatment with suplatast tosilate, while there were no significant changes in patients without suplatast tosilate.

These results strongly suggest that oral administration of suplatast tosilate suppresses airway hyperresponsiveness in asthma patients by reducing eosinophilic inflammation in the airways.     

Relationship between exhaled nitric oxide and IgE sensitisation in patients with asthma: influence of steroid treatment

Introduction: The influence of the degree of immunoglobulin E (IgE) sensitisation on the fraction of expired nitric oxide (FE_NO) in asthma patients being treated with inhaled corticosteroids (ICS) is not well known. Objectives: To investigate the relationship between IgE sensitisation and FE_NO, and the effect of a step‐up in ICS treatment on this relationship, in patients with allergic asthma. Methods: A primary health care centre recruited 20 non‐smoking patients with perennial allergic asthma (18 years–50 years, six male) outside the pollen season. At every visit (0, 2, 4, 8 weeks), FE_NO was measured and an exposure questionnaire was completed. ICS dose was adjusted according to FE_NO (≥22 ppb prescribed increase in ICS). Quantitative analyses of serum IgE (eight common aeroallergens) confirmed allergy. Results: At baseline, FE_NO and the sum of IgE antibody titres for perennial allergens correlated significantly (r = 0.47, P = 0.04). After a step‐up in ICS treatment, this correlation had disappeared. Nine patients had persistently elevated FE_NO at last visit (mean 35 ppb vs 16 ppb). This group was more frequently exposed to relevant allergens or colds (89% vs 27% of patients, P < 0.05) and had higher IgE antibody titres (perennial allergens) compared with the normalised group (mean 28.9 kU/L vs 10.7 kU/L, P < 0.05). Conclusion: Serum IgE against perennial allergens and FE_NO correlate in patients with allergic asthma. However, this relationship disappears after a high‐dose ICS regimen, suggesting that FE_NO relates to bronchial inflammation and not IgE levels per se. High degree of IgE sensitisation together with allergen exposure may lead to ICS‐resistant airways inflammation. Please cite this paper as: Syk J, Undén AL and Alving K. Relationship between exhaled nitric oxide and IgE sensitisation in patients with asthma: influence of steroid treatment. The Clinical Respiratory Journal 2009; 3: 143–151.     

The mechanism of action of leukotrienes A4, C4 and D4 on human lung parenchymain vitro

Indomethacin (20μg.ml⁻¹), a cyclooxygenase inhibitor, and OKY-1581 (50 ug.ml⁻¹), a thromboxane synthetase inhibitor, did not affect contractions of the superfused human lung parenchymal strips induced by histamine, leukotriene C₄ (LTC₄) and leukotriene D₄ (LTD₄). Indomethacin but not OKY-1581 reduced by 50% the myotropic activity of leukotriene A₄ (LTA₄) on the human lung strips. Injections of LTD₄ (100 ng; 0.2 n mole) in the circulation of perfused specimens of human lung did not stimulate the release of prostaglandins (PGs) and thromboxanes (TXs) whereas they produced a large release of these icosanoids from perfused guinea-pig lungs. Perfused human lung specimens almost completely inactivated intraarterial injections of PGE₂ (50 ng) and released PGs and TXs upon mechanical stimulation. It is concluded that the actions of leukotrienes C₄ and D₄ in human lung (parenchymal strips and perfused specimens) are not mediated by the release of PGs and TXs.     

Explorations non invasives des voies aériennes : applications pratiques dans l'asthme et l'allergie

Non-invasive investigation of airway inflammation relies mainly on measurement of exhaled gases (essentially NO) and several markers of inflammation in exhaled breath condensate (EBC). Levels of exhaled nitric oxide (NO) are easily and quickly measured. International recommendations for standardized measurements of exhaled NO have been published. Exhaled NO is increased in patients with untreated asthma; the results of this measurement may be useful when the diagnosis is difficult or when there is a chronic asthma-like cough. Exhaled NO is reduced or normalized with inhaled corticosteroid therapy. An increase in exhaled NO in an asthmatic whose condition has been well controlled may signal a clinical exacerbation. The place of exhaled NO measurement in the diagnosis and treatment of asthma should rapidly be publicised because of its simplicity and because of the availability of reliable devices for its measurement. Many inflammatory mediators can be measured in EBC obtained by rapid cooling of exhaled air on a cold surface. Although collection of EBC is non-invasive, at present lack of standardisation limits its application and interpretation in practice. In cases of asthma, the pH of EBC is lower than normal and the concentrations of leukotrienes, 8-isoprostane and H₂O₂ are higher. Levels of the mediators detected in EBC decrease rapidly in asthmatic patients treated with steroids but this treatment is less effective on oxidative stress markers. Exhaled NO and EBC are complementary in the non-invasive approach to the evaluation of airway inflammation in asthma and atopy.     

Manganese enhances peroxynitrite and leukotriene E4 formation in bovine aortic endothelial cells exposed to arsenic

Long-term exposure to arsenic in drinking water has been linked to cancer and other health effects, including cardiovascular disease. Arsenic in the environment is found in combination with a range of metals that could influence its toxicity. Manganese, in particular, is a metal that is typically found in conjunction with arsenic in contaminated groundwater. Peroxynitrite is a powerful oxidant formed from the reaction between nitric oxide and superoxide anion. Arsenic has been shown to increase the formation of peroxynitrite in bovine aortic endothelial cells (BAECs) and promote the formation of 3-nitrotyrosine (3-NY) in the atherosclerotic plaque of ApoE^−/−/LDLr^−/− mice. Arsenic exposure also increases leukotriene E₄ (LTE₄) formation in both the mice and BAECs, an effect that is partially reversed by the addition of Nω-nitro-l-arginine methyl ester (l-NAME), a nitric oxide synthase (NOS) inhibitor. In the present study, we investigated the effect of adding nontoxic concentrations of manganese along with arsenic to BAEC cultures. Manganese increased arsenic toxicity and enhanced peroxynitrite, 3-NY, and LTE₄ formation in BAECs. Addition of l-NAME reduced 3-NY formation induced by arsenic/manganese mixtures, but in contrast to its effect on arsenic alone, l-NAME actually increased LTE₄ synthesis in BAECs treated with the arsenic/manganese combination. Overall, these data suggest that manganese may exacerbate the toxic effects of arsenic on the vascular system.     

Electromechanical effects of leukotriene D4 on ferret tracheal muscle and its muscarinic responsiveness

We investigated the possible electrophysiological processes by which leukotriene D₄ (LTD₄) affects airway smooth muscle and its responsiveness to acetylcholine (ACh). For study in vitro, preparations of ferret tracheal muscle (dissected free of overlying mucosal and submucosal layers) were used. These preparations were arranged so that force transducers and glass intracellular microelectrodes (having tip resistances of 35–60 megohm) could be used to measure isometric force generation and cell membrane potential (Em) simultaneously from muscle stimulated by LTD₄. At rest, the muscle was electrically and mechanically quiescent and had an Em of −59±0.2 mV (mean±SEM). We found that ferret tracheal muscle cells were relatively sensitive to LTD₄, and that both the resulting depolarization (beginning at 10⁻¹⁰ M LTD₄) and force generation (produced by higher concentrations) progressed in a concentration-dependent manner. Depolarization by 10⁻⁹ M LTD₄ elicited electrical oscillations. These oscillations were accompanied by phasic contractile activity at 5 × 10⁻⁹ M LTD₄. Verapamil abolished these oscillations and diminished force substantially. We also found that ACh depolarized and contracted the muscle in a concentration-dependent manner. It caused electrical oscillations at ≥ 10⁻⁶ M. Diltiazem abolished these oscillations and markedly diminished force generation without affecting Em. Preexposure of airway muscle preparations for 20 min to a concentration (10⁻¹⁰ M) of LTD₄ that, by itself, did not produce significant force, substantially augmented the voltage-tension relationship of the muscle upon ACh stimulation. We conclude that there is an electrical basis for the slow, prolonged force generation of airway muscle caused by LTD₄, and that LTD₄ potentiates the electromechanical responsiveness of the airway muscle to muscarinic stimulation.     

A review on leukotrienes and their receptors with reference to asthma

Abstract

Objective and methods: Leukotrienes (LTs) including cysteinyl leukotrienes (CysLTs) and LTB₄ are the most potent inflammatory lipid mediators and play a central role in the pathophysiology of asthma and other inflammatory diseases. These biological molecules mediate a plethora of contractile and inflammatory responses through specific interaction with distinct G protein-coupled receptors (GPCRs). The main objective of this review is to present an overview of the biological effects of CysLTs and their receptors, along with the current knowledge of mechanisms and role of LTs in the pathogenesis of asthma. Results: CysLTs including LTC₄, LTD₄ and LTE₄ are ligands for CysLT₁ and CysLT₂ receptors, and LTB₄ is the agonist for BLT₁ and BLT₂ receptors. The role of CysLT₁ receptor is well established, and most of the pathophysiological effects of CysLTs in asthma are mediated by CysLT₁ receptor. Several CysLT₁ antagonists have been developed to date and are currently in clinical practice. Most common among them are classical CysLT₁ receptor antagonists such as montelukast, zafirlukast, pranlukast, pobilukast, iralukast, cinalukast and MK571. The pharmacological role of CysLT₂ receptor, however, is less defined and there is no specific antagonist available so far. The recent demonstration that mice lacking both known CysLT receptors exhibit full/augmented response to CysLT points to the existence of additional subtypes of CysLT receptors. LTB₄, on the other hand, is another potent inflammatory leukotriene, which acts as a strong chemoattractant for neutrophils, but weaker for eosinophils. LTB₄ is known to play an important role in the development of airway hyper-responsiveness in severe asthma. However there is no LTB₄ antagonist available in clinic to date. Conclusion: This review gives a recent update on the LTs including their biosynthesis, biological effects and the role of anti-LTs in the treatment of asthma. It also discusses about the possible existence of additional subtypes of CysLT receptors.     

Pathogenesis and Management of Aspirin-Intolerant Asthma

In 2-23% of adults with asthma, and rarely in children with asthma, aspirin (acetylsalicylic acid) and non-steroidal anti-inflammatory drugs (NSAIDs) cause asthma exacerbations. Within 3 hours of ingestion of aspirin/NSAIDs, individuals with aspirin-intolerant asthma (AIA) develop bronchoconstriction, often accompanied by rhinorrhea, conjunctival irritation, and scarlet flush. In severe cases, a single therapeutic dose of aspirin/NSAIDs can provoke violent bronchospasm, loss of consciousness, and respiratory arrest. In order to diagnose AIA, oral, inhaled, nasal or intravenous aspirin challenge tests are performed in facilities where experienced physicians are present and emergency treatment is available. The exact differences in the pathogenesis of AIA and other types of asthma are not fully understood. The interference of aspirin/NSAIDs with arachidonic acid metabolism in the lungs plays an important role in the mechanism of AIA; inhibition of cyclo-oxygenase is accompanied by overproduction of cysteinyl leukotrienes (cys-LTs). It has been proposed that overproduction of cys-LTs, together with removal by aspirin/NSAIDs of the 'brake' imposed by the bronchodilator prostaglandin E2, may cause an asthma attack in patients with AIA. Development of a suitable animal model to investigate the pathogenesis of AIA would help to clarify this question. Although it is still controversial whether leukotriene modifiers are more effective in patients with AIA compared with other types of asthma, because LT plays an important role in the pathogenesis of AIA, leukotriene modifiers are the preferred medication for the long-term control of AIA. Add-on efficacy of leukotriene modifiers has been confirmed in patients with AIA already treated with inhaled corticosteroids. However, this does not mean that aspirin/NSAIDs can be safely taken by aspirin-sensitive patients treated with leukotriene modifiers. To prevent attacks of AIA, sensitive patients should avoid the use of aspirin/NSAIDs or use selective cyclo-oxygenase 2 inhibitors when required. When patients with AIA need aspirin for specific situations they should receive aspirin desensitization therapy or treatment with selective cyclo-oxygenase 2 inhibitors.