Leukotrienes and isocyanate-induced asthma: a pilot study

BACKGROUND: The role of leukotrienes (LTs) in the pathophysiology of isocyanate-induced asthma is not well known. OBJECTIVE: We sought to characterize the type of airway inflammation induced by exposure to isocyanates and to investigate whether exposure to isocyanates induced an increase in LT receptor cysteinyl leukotriene ((CysLT)(1), CysLT(2) and leukotriene B(4) receptor (BLT(1))) expression, as well as a release of LT (LTC(4) and leukotriene B(4) (LTB(4))) and IL-8 in both asthmatics with isocyanate-induced asthma and healthy subjects. METHODS: We investigated eight subjects with isocyanate-induced asthma and eight healthy subjects. Both groups underwent specific inhalation challenges to isocyanates in the laboratory. Induced sputum was collected before and after exposure to isocyanates. CysLT(1), CysLT(2) and BLT(1) expression was assessed by flow cytometry, whereas LTC(4), LTB(4) and IL-8 were measured in the sputum supernatants by enzyme immunoassay. RESULTS: Exposure to isocyanates induced an increase in sputum neutrophils only in subjects with occupational asthma. There was a significant increase in CysLT(1) and BLT(1) receptor expression, as well as a release of LTB(4) and IL-8 after exposure to isocyanates compared with the baseline, only in subjects with isocyanate-induced asthma, whereas there was no increase in LTC(4). Exposure to isocyanates did not induce any change in LT receptor expression nor in the levels of LTC(4), LTB(4) and IL-8, in healthy subjects. CONCLUSION: The neutrophilia observed after exposure to isocyanates is likely to be related to the release of LTB(4), probably enhanced by the increased expression of BLT(1) on neutrophils as well as by the release of IL-8. The significance of the increase of CysLT1 receptor expression on neutrophils is unknown and needs further investigation.     

Current perspective on eicosanoids in asthma and allergic diseases: EAACI Task Force consensus report,part I

Eicosanoids are biologically active lipid mediators, comprising prostaglandins, leukotrienes, thromboxanes, and lipoxins, involved in several pathophysiological processes relevant to asthma, allergies, and allied diseases. Prostaglandins and leukotrienes are the most studied eicosanoids and established inducers of airway pathophysiology including bronchoconstriction and airway inflammation. Drugs inhibiting the synthesis of lipid mediators or their effects, such as leukotriene synthesis inhibitors, leukotriene receptors antagonists, and more recently prostaglandin D₂ receptor antagonists, have been shown to modulate features of asthma and allergic diseases. This review, produced by an European Academy of Allergy and Clinical Immunology (EAACI) task force, highlights our current understanding of eicosanoid biology and its role in mediating human pathology, with a focus on new findings relevant for clinical practice, development of novel therapeutics, and future research opportunities.     

Mast cells and eicosanoid mediators: a system of reciprocal paracrine and autocrine regulation

Summary:  When activated by specific antigen, complement, or other transmembrane stimuli, mast cells (MCs) generate three eicosanoids: prostaglandin (PG)D₂, leukotriene (LT)B₄, and LTC₄, the parent molecule of the cysteinyl leukotrienes (cysLTs). These diverse lipid mediators, which are generated from a single cell membrane-associated precursor, arachidonic acid, can initiate, amplify, or dampen inflammatory responses and influence the magnitude, duration, and nature of subsequent immune responses. PGD₂ and cysLTs, which were originally recognized for their bronchoconstricting and vasoactive properties, also serve diverse and pivotal functions in effector cell trafficking, antigen presentation, leukocyte activation, matrix deposition, and fibrosis. LTB₄ is a powerful chemoattractant for neutrophils and certain lymphocyte subsets. Thus, MCs can contribute to each of these processes through eicosanoid generation. Additionally, MCs express G-protein-coupled receptors specific for cysLTs, LTB₄, and another eicosanoid, PGE₂. Each of these receptors can regulate MC functions in vivo by autocrine and paracrine mechanisms. This review focuses on the biologic functions for MC-associated eicosanoids, the regulation of their production, and the mechanisms by which eicosanoids may regulate MC function in host defense and disease.     

Asthma: beyond corticosteroid treatment

Asthma is one of the most common chronic diseases in the world, affecting over 300 million people. It is an inflammatory disorder characterized by bronchoconstriction and airway hyperresponsiveness, followed by inflammatory manifestations in the respiratory system. The prevalence of asthma is rising and there is a clinical need to develop more effective treatments. While corticosteroids (glucocorticosteroids) remain the mainstay of asthma therapy, they have limitations because of their potentially severe side-effects and the presence of corticosteroid resistance in some patients. This review discusses current strategies in the treatment of asthma and considers new therapeutic regimens of asthma in the drug development pipeline.     

Leukotrienes in gynaecology: the hypothetical value of anti-leukotriene therapy in dysmenorrhoea and endometriosis

The lipoxygenase products (leukotrienes) have been demonstrated in many mammalian tissues including humans. They are widely distributed in the lungs, gut, uterus, kidneys, skin, heart and the liver. Their roles as mediators of inflammation have made them therapeutic targets. Significant amounts of leukotrienes have been demonstrated in the endometrium of women with primary dysmenorrhoea who do not respond to treatment with anti-prostaglandins. Also, in endometriosis, cytokines, which can initiate the cascade for the biosynthesis of leukotrienes, have been shown to be elevated. It is estimated that 10-30% of patients with painful periods fail to respond to prostaglandin (PG) synthetase inhibitors. Of adult females approximately 40% have painful menstruation and 10% of these are incapacitated for 1-3 days per month, and approximately 10% of women aged between 15-45 years suffer from endometriosis, which is a significant cause of infertility. Leukotriene receptor antagonists have recently been licensed for the treatment of asthma in the UK. In this review, we present the case for the potential use of these products in the management of primary dysmenorrhoea (especially in patients who are not responding to the traditional treatment using PG synthetase inhibitors) and possibly also in cases of endometriosis.     

Childhood Asthma Control Test and airway inflammation evaluation in asthmatic children

Background:  The Childhood Asthma Control Test (C-ACT) has been proposed as a tool in assessing the level of disease control in asthmatic children. To evaluate the position of C-ACT in the clinical management of asthmatic children, in relationship to the level of airway inflammation as assessed by fractional exhaled nitric oxide (FeNO) and with lung function.
Methods:  A total of 200 asthmatic children were included in the study: 47 children with newly diagnosed asthma ('New') and without any regular controller therapy; and 153 children with previously diagnosed asthma, treated according to GINA guidelines, and evaluated during a scheduled follow-up visit ('Follow-up'). Childhood Asthma Control Test, FeNO and lung function [forced expiratory volume 1 (FEV1) and forced vital capacity (FVC)] were evaluated.
Results:  In New vs Follow-up participants, C-ACT score ( P  <   0.001), FVC ( P  <   0.005) and FEV1 ( P  <   0.05) were significantly lower, and FeNO ( P  =   0.011) were significantly higher. In New, but not in Follow-up participants, significant correlations were observed between C-ACT score and FeNO ( r  = −0.51; P  <   0.001), FEV1 ( r  =   0.34; P  =   0.022) and FEV1/FVC ( r  =   0.32; P  =   0.03). This lack of correlation in Follow-up visits seemed attributable to dissociation between inadequately controlled asthma by C-ACT ratings with normalization of other measures such as FeNO levels.
Conclusions:  This study confirms and expands the concept that C-ACT is complementary to, but not a substitute for, other markers of disease control in asthmatic children, especially in the context of follow-up visits.     

Leukotrienes (LTC4, LTD4) confer glass non-adherence on leukocytes of asthmatic individuals. Dependency on cyclooxygenase products and calcium ion

It has been suggested that cysteinyl-containing leukotrienes (LT) are important mediators in bronchial asthma. Since leukotrienes have been shown to mediate the leukocyte adherence inhibition (LAI) phenomenon observed in cancer-bearing host we have devised a modified LAI assay which determines the acquisition of non-adherence properties of leukocytes following a challenge with pure synthetic LT. Our results demonstrate that peripheral blood leukocytes of asthmatic individuals acquire non-adherence properties when challenged with pure synthetic leukotriene C₄ and D₄, a property not shared by peripheral blood leukocytes of control healthy individuals. Furthermore, we demonstrate that LT activity as manifested by the LAI assay is dependent on cycloxygenase products, since 2×10⁻⁶ M Indomethacin abrogated the LT-induced LAI and is restored by the addition of 2×10⁻⁶ M prostaglandin E₂ which is also synergistic to LT activity. Our results further suggest the possibility that leukotriene activity is dependent on calcium ions since it was negated by known calcium antagonists. It is thus suggested that the LT-induced LAI may serve as a tool for the study of the interrelationship between the metabolic pathways of arachidonic acid and calcium ion homeostasis.     

Emerging Biomarkers Beyond Leukotrienes for the Management of Nonsteroidal Anti-inflammatory Drug (NSAID)-Exacerbated Respiratory Disease

Nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD) is a unique condition characterized by aspirin/NSAID hypersensitivity, adult-onset asthma, and/or chronic rhinosinusitis with nasal polyps. Arachidonic acid metabolism dysregulation and intense eosinophilic/type 2 inflammation are central mechanisms in NERD. Studies have been conducted on various biomarkers, and urinary leukotriene E4 is considered the most available biomarker of NERD. However, the pathophysiology of NERD is heterogeneous and complex. Epithelial cells and platelets can interact with immune cells in NERD, and novel biomarkers related to these interactions have recently been investigated. We summarize emerging novel biomarkers of NERD and discuss their roles in the management of NERD.     

支气管哮喘患儿内皮素-1及相关炎性细胞因子测定

目的:探讨内皮素及相关炎性细胞因子在小儿哮喘发病机制中的作用。方法:分别用放射免疫分析及酶免法测定了42例哮喘患儿治疗前后内皮素-1、白细胞介素-5、白细胞介素-6及白细胞介素-8水平。结果:发作期组内皮素水平高于缓解组及对照组差异非常显著(P值均<0 01),缓解组较发作组水平下降显著但仍显著高于对照组(P<0 05)。3种细胞因子水平则发作期组均显著高于缓解组及对照组,统计差异极显著(P值均<0 01),缓解组前2种细胞因子仍显著高于对照组(P值均<0 05);而后一种细胞因子已下降至近对照组水平(P>0 05)。ET与IL-5呈显著正相关(发作期r=0 560,P<0 01;缓解期r=0 435,P<0 01)。结论:内皮素与细胞因子以不同方式参与了小儿哮喘的发病机制,其测定对于评价炎症程度及疗效、指导临床治疗有重要意义。     

Asthma and obesity

The prevalence and incidence of asthma have increased among obese children and adults, particularly among women. Obesity seems to be a predisposing factor for the development of asthma, but the underlying mechanisms of its influence are still uncertain. Various hypotheses have been proposed to explain the link between obesity and asthma such as a common genetic predisposition, developmental changes, altered lung mechanics, the presence of a systemic inflammatory process, and an increased prevalence of associated comorbid conditions. Over‐diagnosis of asthma does not seem to be more frequent in obese compared to non‐obese subjects, but the added effects of obesity on respiratory symptoms can affect asthma control assessment. Obesity can make asthma more difficult to control and is associated with a reduced beneficial effect of asthma medications. This could be due to a change in asthma phenotype, particularly evidenced as a less eosinophilic type of airway inflammation combined to the added effects of changes in lung mechanics. Weight loss is associated with a universal improvement of asthma and should be part of asthma management in the obese patient. Additional research should be conducted to better determine how obesity influences the development and clinical expression of asthma, establish the optimal management of asthma in this population and determine how obesity affects long‐term asthma outcomes in these patients.     

Maternal Transmission of Asthma Risk

Maternal asthma significantly increases the risk of asthma in offspring, but the mechanisms remain poorly defined. We review animal models used to study the maternal effect, focusing on a murine model developed in our laboratory. Mother mice rendered allergic to ovalbumin produce offspring that are more susceptible to allergic sensitization, seen as airway hyperresponsiveness and allergic airway inflammation after a sensitization protocol, which has minimal effects on newborns from normal mothers. Mechanistic analyses identify a role for interleukin-4 (based on pre-mating injection of neutralizing antibodies), dendritic cells and allergen-specific T cells (based on adoptive transfer experiments). Other maternal exposures (e.g. pollutant exposure and non-pulmonary allergy) can increase asthma susceptibility in offspring. This observation implies that the maternal transmission of asthma represents a final common pathway to various types of inflammatory stimuli. Identification of the shared molecular mechanisms in these models may allow better prevention and therapy. Current knowledge, gaps in knowledge and future directions are discussed.     

Prostaglandin, leukotriene, and lipoxin balance in chronic rhinosinusitis with and without nasal polyposis

BACKGROUND: Upper airway diseases and especially the aspirin hypersensitivity syndrome have been linked to changes in the arachidonic acid cascade; however, the specificity of these changes and their relation to inflammatory reactions in these diseases still remain controversial. OBJECTIVE: We aimed to study the tissue eicosanoid production in 3 subgroups of patients with chronic rhinosinusitis (CRS) and control subjects and to correlate it with the severity of inflammation and clinical manifestation of aspirin sensitivity. METHODS: Samples were prepared from sinonasal tissue of patients with CRS with (CRS-NP group, n = 13) and without nasal polyposis (CRS group, n = 11), sinonasal tissue of patients with nasal polyposis and aspirin sensitivity (CRS-ASNP group, n = 13), and normal nasal mucosa from healthy subjects (NM group, n = 8). Real-time PCR was applied for mRNA quantification of COX-2, 5-lipoxygenase, leukotriene C 4 synthase, and 15-lipoxygenase. Enzyme immunoassays were used to measure IL-5, eosinophil cationic protein, and eicosanoid (leukotriene [LT] C 4 , LTD 4 , and LTE 4 ; lipoxin A 4 ; and prostaglandin E 2 [PGE 2 ]) concentrations. RESULTS: COX-2 mRNA and PGE 2 concentrations were similar in the CRS and NM groups but significantly decreased in nasal polyp tissue, especially in the CRS-ASNP group. LTC 4 synthase, 5-lipoxygenase mRNA, LTC 4 , LTD 4 , and LTE 4 concentrations increased with disease severity among the patient groups. 15-Lipoxygenase and lipoxin A 4 concentrations were increased in all CRS groups compared with in the NM group but were significantly downregulated in the CRS-ASNP group when compared with the CRS-NP group. IL-5 and eosinophil cationic protein were increased in both groups of nasal polyp tissue compared with in the NM and CRS groups and correlated directly with LTC 4 , LTD 4 , and LTE 4 concentrations and inversely with PGE 2 concentrations. CONCLUSION: Changes of tissue eicosanoid metabolism do occur in CRS, even in the absence of clinical aspirin sensitivity, and these changes appear to be related to the severity of eosinophilic inflammation.