Corticosteroids and Leukotrienes: Chronobiology and Chronotherapy

Corticosteroids and leukotrienes play opposite roles in asthma. Corticosteroids, both endogenously secreted and exogenously administered, are antiinflammatory and are very effective in the treatment of asthma. They have also been evaluated chronotherapeutically and have been found to be very effective in reducing the enhanced airway inflammation and decrement in lung function associated with nocturnal worsening of asthma. Leukotrienes are potent proinflammatory and spasmogenic mediators that have been shown to be increased at night in patients with nocturnal asthma (NA). Leu-kotriene modifiers, a new class of medications to treat asthma, improve, but do not abolish, the symptoms and decrement in lung function associated with nocturnal asthma. However, they have not been evaluated chronotherapeutically. This article addresses the roles of corticosteroids and leukotrienes in nocturnal asthma and their position as therapeutic agents or targets for therapy.     

Location of Airway Inflammation in Asthma and the Relationship to Orcadian Change in Lung Function

Nocturnal asthma is an important part of asthma as the majority of patients with asthma have nocturnal worsening in lung function. The etiology of this process is multifactorial and interactive. There are many naturally occurring circadian rhythms, which for the normal individual have only a minor effect on lung function. However, in the asthmatic patient, these day-to-night alterations produce increased airway inflammation and worsening of asthma. Although asthma is considered an airway disease, the location of the inflammatory response may be greater in the alveolar tissue area. If correct, this could alter the therapeutic approach to this disease.     

Inflammation and the mechanism of action of anti-inflammatory drugs

Inflammation is caused by release of chemicals from tissues and migrating cells. Most strongly implicated are the prostaglandins (PGs), leukotrienes (LTs), histamine, bradykinin, and, more recently, platelet-activating factor (PAF) and interleukin-1. Evidence for their involvement comes from studies with competitive antagonists for their receptors and inhibitors of their synthesis. H1 histamine antagonists are effective for hay fever and some skin allergies such as urticaria, which indicates the importance of histamine in these conditions. Symptoms of rheumatoid arthritis are alleviated by the aspirinlike anti-inflammatory drugs, which inhibit the cyclo-oxygenase enzyme and reduce synthesis of prostanoids. Corticosteroids prevent the formation of both PGs and LTs by causing the release of lipocortin, which by inhibition of phospholipase A2 reduces arachidonic acid release. They suppress the inflammation of rheumatoid arthritis and asthma. Currently, high doses of nonsedating H1 antihistamines and PAF antagonists are being tested for the treatment of allergic asthma.     

Regulation of the activity of 5-lipoxygenase, a key enzyme in leukotriene biosynthesis

5-Lipoxygenase (5LO) catalyzes two steps in the biosynthesis of leukotrienes (LTs), lipid mediators of inflammation derived from arachidonic acid. LTs function in normal host defense, and have pathophysiological roles in chronic inflammatory diseases as asthma and atherosclerosis. Also, possible effects of 5LO products in relation to tumorigenesis have been described. Thus, insight regarding the biochemistry of 5LO is relevant for better understanding of normal physiology, and for development of therapy.     

Lipoxins and lipoxin analogs in asthma

The pathobiology of asthma is characterized by production of eicosanoids, a diverse family of bioactive fatty acids that play important roles in regulating airway inflammation and reactivity. Lipoxins (LXs) are products of arachidonic acid metabolism that are distinct from leukotrienes (LTs) and prostaglandins (PGs) in structure and function. Unlike the pro-inflammatory PGs and LTs, LXs display counter-regulatory actions. Cell-type specific biological actions have been uncovered for LXs and LX stable analogs that promote resolution of acute inflammatory responses. At least two classes of receptors, CysLT1 receptors and LXA4 receptors (named ALX), can interact with LXA4 and LXA4 analogs to mediate their biological actions. LXs are generated during asthma and LXA4 signaling blocks asthmatic responses in humans and experimental model systems. Of interest, respiratory diseases of increased severity, such as aspirin-intolerant asthma, cystic fibrosis and steroid-dependent, severe asthma, display defective generation of these protective lipid signals. Together, these findings indicate a pivotal role for LXs in mediating airway homeostasis.     

Targeting phosphoinositide 3-kinase δ for allergic asthma

Chronic inflammation in the lung has long been linked to the pathogenesis of asthma. Central to this airway inflammation is a T-cell response to allergens, with Th2 cytokines driving the differentiation, survival and function of the major inflammatory cells involved in the allergic cascade. PI3Kδ (phosphoinositide 3-kinase δ) is a lipid kinase, expressed predominantly in leucocytes, where it plays a critical role in immune receptor signalling. A selective PI3Kδ inhibitor is predicted to block T-cell activation in the lung, reducing the production of pro-inflammatory Th2 cytokines. PI3Kδ is also involved in B-cell and mast cell activation. Therefore the inhibition of PI3Kδ should dampen down the inflammatory cascade involved in the asthmatic response through a wide breadth of pharmacology. Current anti-inflammatory therapies, which are based on corticosteroids, are effective in controlling inflammation in mild asthmatics, but moderate/severe asthmatic patients remain poorly controlled, experiencing recurrent exacerbations. Corticosteroids have no effect on mast cell degranulation and do not act directly on B-cells, so, overall, a PI3Kδ inhibitor has the potential to deliver improvements in onset of action, efficacy and reduced exacerbations in moderate/severe asthmatics. Additionally, PI3Kδ inhibition is expected to block effects of Th17 cells, which are increasingly implicated in steroid-insensitive asthma.     

Negative feedback between secretory and cytosolic phospholipase A2 and their opposing roles in ovalbumin-induced bronchoconstriction in rats

Phospholipase A2 (PLA2) hydrolyzes cell membrane phospholipids (PL) to produce arachidonic acid and lyso-PL. The PLA2 enzymes include the secretory (sPLA2) and cytosolic (cPLA2) isoforms, which are assumed to act synergistically in production of eicosanoids that are involved in inflammatory processes. However, growing evidence raises the possibility that in airways and asthma-related inflammatory cells (eosinophils, basophils), the production of the bronchoconstrictor cysteinyl leukotrienes (CysLT) is linked exclusively to sPLA2, whereas the bronchodilator prostaglandin PGE2 is produced by cPLA2. It has been further reported that the capacity of airway epithelial cells to produce CysLT is inversely proportional to PGE2 production. This seems to suggest that sPLA2 and cPLA2 play opposing roles in asthma pathophysiology and the possibility of a negative feedback between the two isoenzymes. To test this hypothesis, we examined the effect of a cell-impermeable extracellular sPLA2 inhibitor on bronchoconstriction and PLA2 expression in rats with ovalbumin (OVA)-induced asthma. It was found that OVA-induced bronchoconstriction was associated with elevation of lung sPLA2 expression and CysLT production, concomitantly with suppression of cPLA2 expression and PGE2 production. These were reversed by treatment with the sPLA2 inhibitor, resulting in amelioration of bronchoconstriction and reduced CysLT production and sPLA2 expression, concomitantly with enhanced PGE2 production and cPLA2 expression. This study demonstrates, for the first time in vivo, a negative feedback between sPLA2 and cPLA2 and assigns opposing roles for these enzymes in asthma pathophysiology: sPLA2 activation induces production of the bronchoconstrictor CysLT and suppresses cPLA2 expression and the subsequent production of the bronchodilator PGE2.     

Mobile nocturnal long-term monitoring of wheezing and cough.

Changes in normal lung sounds are an important sign of pathophysiological processes in the bronchial system and lung tissue. For the diagnosis of bronchial asthma, coughing and wheezing are important symptoms that indicate the existence of obstruction. In particular, nocturnal long-term acoustic monitoring and assessment make sense for qualitative and quantitative detection and documentation. Previous methods used for lung function diagnosis require active patient cooperation that is not possible during sleep. We developed a mobile device based on the CORSA standard that allows the recording of respiratory sounds throughout the night. To date, we have recorded 133 patients with different diagnoses (80 male, 53 female), of whom 38 were children. In 68 of the patients we could detect cough events and in 87 we detected wheezing. The recording method was tolerated by all participating adults and children. Our mobile system allows non-invasive and cooperation-independent nocturnal monitoring of acoustic symptoms in the domestic environment, especially at night, when most ailments occur.     

Corticosteroids: the mainstay in asthma therapy

Inflammation is now marked as a central feature of asthma pathophysiology and aims of current asthma management are not only to treat acute symptoms of wheezing, breathlessness, chest tightness, cough but also to suppress the underlying inflammatory component. Despite the availability of a number of drugs, corticosteroids remain the mainstay in the management of all types of asthma as these are the most potent and effective antiinflammatory agents available so far. Corticosteroids suppress virtually every step in inflammation. However therapeutic doses of oral glucocorticoids are associated with a range of adverse reactions. To overcome these side effects, inhalations have been developed to deliver glucocorticoids directly to the lungs and in the process a number of aerosol preparations have become available, which have advantage of significantly lower toxicity due to low systemic absorption from the respiratory tract and rapid inactivation. Despite considerable efforts by pharmaceutical industry, it has been difficult to develop novel therapeutic agents for asthma management, which could surpass inhaled corticosteroids. Currently the data favours using inhaled corticosteroids as monotherapy in the majority of patients in all kinds of asthma. If combination therapy is recommended to achieve additional control in severe asthma cases, other drugs such as beta-agonists, antileukotrienes, theophylline, etc. are considered as adjunct therapies to corticosteroids. This review discusses the importance of corticosteroids as first line therapy for asthma treatment with the availability of inhaled corticosteroids for chronic treatment and oral formulations for treating acute exacerbations of moderate to severe asthma.     

Eosinophils and cysteinyl leukotrienes

Eosinophils are the main source of the cysteinyl leukotrienes, LTC(4)/D(4)/E(4), which are lipid mediators that play major roles in the pathogenesis of asthma and other forms of allergic inflammation. Here, we review the mechanisms governing eosinophil LTC(4) synthesis, focusing on the distinct intracellular domains that regulate eicosanoid formation and function within eosinophils. Cysteinyl leukotrienes exert their actions by engaging specific receptors. As recently shown, eosinophils express CysLT1 and CysLT2, the only cloned receptors for cysteinyl leukotrienes. Therefore, here we also present some of the new findings regarding the paracrine/autocrine activation of these CysLT receptors on eosinophils, and discuss some data on novel intracrine effects of LTC(4) triggered by a putative third CysLT receptor expressed intracellularly within eosinophils.     

Diagnosis and treatment of allergic bronchopulmonary aspergillosis

Allergic bronchopulmonary aspergillosis (ABPA) is a rare form of asthma that is most common in corticosteroid-dependent asthmatic patients and cystic fibrosis patients. It is caused by an abnormal T-helper class 2 response of the host to Aspergillus antigens. Although signs and symptoms of typical asthma are usually present with ABPA, unusual features such as fever, expectoration of brown plugs, and central bronchiectasis with or without mucoid impaction on chest radiographs may be present. ABPA is important to diagnose because inadequate therapy may lead to permanent lung destruction. Corticosteroids are the drug of choice for ABPA; however, the doses required are often greater than for routine asthma and corticosteroid dependence is not unusual. Azole therapy appears to have an adjunctive role in treatment in terms of improving signs and symptoms of the disease and demonstrating a corticosteroid-sparing effect.     

The analysis of the factors influencing the development of glucocorticoid resistance in the etiopathogenesis of severe bronchial asthma

Bronchial asthma is a disease of multi - factored etiology. Current data show that multiple genes may be involved in the pathogenesis of asthma. Corticosteroids (GCS) are the most effective anti-inflammatory therapy for inflammatory disease such as bronchial asthma. There are 2 major types of GCS-resistant asthma to treatment of high doses of inhaled and oral glucocorticoids. Type I GCS-resistant asthma is cytokine-induced or acquired. Type II GCS resistance involves generalized primary cortisol resistance, which affects all tissues and is likely associated with a mutation in the GCR gene or in genes that modulate GCR function. There are clear examples of glucocorticoid gene h-GCR/NR3C1 polymorphisms that can influence responses and sensitivity to glucocorticosteroids. This article may lead to holistic the development analysis of the factors determining the progress of the glucocorticoid resistance in the severe bronchial asthma with special acknowledgement of the influence of polymorphisms of the glucocorticoid receptor gene h-GCR/NR3C1 to formation GCS resistance.     

Treatment heterogeneity in asthma: genetics of response to leukotriene modifiers

Despite advances in treatment, asthma continues to be a significant health and economic burden. Although asthma cannot be cured, several drugs, including beta2 agonists, corticosteroids, and leukotriene (LT) modifiers, are well tolerated and effective in minimizing symptoms, improving lung function, and preventing exacerbations. However, inter-patient variability in response to asthma drugs limits their effectiveness. It has been estimated that 60-80% of this inter-patient variability may be attributable to genetic variation. LT modifiers, in particular, have been associated with heterogeneity in response. These drugs exert their action by inhibiting the activity of cysteinyl leukotrienes (CysLTs), which are potent bronchoconstrictors and pro-inflammatory agents. Two classes of LT modifiers are 5-lipoxygenase (ALOX5) inhibitors (zileuton) and leukotriene receptor antagonists (LTRAs) [montelukast, pranlukast, and zarfirlukast]. LT modifiers can be used as alternatives to low-dose inhaled corticosteroids (ICS) in mild persistent asthma, as add-on therapy to low- to medium-dose ICS in moderate persistent asthma, and as add-on to high-dose ICS and a long-acting ss2 agonist in severe persistent asthma. At least six genes encode key proteins in the LT pathway: arachidonate 5-lipoxygenase (ALOX5), ALOX5 activating protein (ALOX5AP [FLAP]), leukotriene A4 hydrolase (LTA4H), LTC4 synthase (LTC4S), the ATP-binding cassette family member ABCC1 (multidrug resistance protein 1 [MRP1]), and cysteinyl leukotriene receptor 1 (CYSLTR1). Studies have reported that genetic variation in ALOX5, LTA4H, LTC4S, and ABCC1 influences response to LT modifiers. Plasma concentrations of LTRAs vary considerably among patients. Physio-chemical characteristics make it likely that membrane efflux and uptake transporters mediate the absorption of LTRAs into the systemic circulation following oral administration. Genes that encode efflux and uptake transport proteins harbor many variants that could influence the pharmacokinetics, and particularly the bioavailability, of LTRAs, and could contribute to heterogeneity in response. In the future, large, well designed clinical trials studying the pharmacogenetics of LT modifiers in diverse populations are warranted to determine whether a genetic signature can be developed that will accurately predict which patients will respond.     

Investigation of Hydrogen Sulfide Exposure and Lung Function,Asthma and Chronic Obstructive Pulmonary Disease in a Geothermal Area of New Zealand

Background

Results have been conflicting whether long-term ambient hydrogen sulfide (H₂S) affects lung function or is a risk factor for asthma or chronic obstructive pulmonary disease (COPD). Rotorua city, New Zealand, has the world’s largest population exposed to ambient H₂S—from geothermal sources.

Objectives

We investigated associations of H₂S with lung function, COPD and asthma in this population.

Methods

1,204 of 1,639 study participants, aged 18–65 years during 2008–2010, provided satisfactory spirometry results. Residences, workplaces and schools over the last 30 years were geocoded. Exposures were estimated from data collected by summer and winter H₂S monitoring networks across Rotorua. Four metrics for H₂S exposure, representing both current and long-term (last 30 years) exposure, and also time-weighted average and peak exposures, were calculated. Departures from expected values for pre-bronchodilator lung function, calculated from prediction equations, were outcomes for linear regression models using quartiles of the H₂S exposure metrics. Separate models examined participants with and without evidence of asthma or COPD, and never- and ever-smokers. Logistic regression was used to investigate associations of COPD (a post-bronchodilator FEV₁/FVC < 70% of expected) and asthma (doctor-diagnosed or by FEV₁ response to bronchodilator) with H₂S exposure quartiles.

Results

None of the exposure metrics produced evidence of lung function decrement. The logistic regression analysis showed no evidence that long-term H₂S exposure at Rotorua levels was associated with either increased COPD or asthma risk. Some results suggested that recent ambient H₂S exposures were beneficially associated with lung function parameters.

Conclusions

The study found no evidence of reductions in lung function, or increased risk of COPD or asthma, from recent or long-term H₂S exposure at the relatively high ambient concentrations found in Rotorua. Suggestions of improved lung function associated with recent ambient H₂S exposures require confirmation in other studies.     

Allergic asthma: influence of genetic and environmental factors

Allergic asthma is a chronic airway inflammatory disease in which exposure to allergens causes intermittent attacks of breathlessness, airway hyper-reactivity, wheezing, and coughing. Allergic asthma has been called a "syndrome" resulting from a complex interplay between genetic and environmental factors. Worldwide, >300 million individuals are affected by this disease, and in the United States alone, it is estimated that >35 million people, mostly children, suffer from asthma. Although animal models, linkage analyses, and genome-wide association studies have identified numerous candidate genes, a solid definition of allergic asthma has not yet emerged; however, such studies have contributed to our understanding of the multiple pathways to this syndrome. In contrast with animal models, in which T-helper 2 (T(H)2) cell response is the dominant feature, in human asthma, an initial exposure to allergen results in T(H)2 cell-dependent stimulation of the immune response that mediates the production of IgE and cytokines. Re-exposure to allergen then activates mast cells, which release mediators such as histamines and leukotrienes that recruit other cells, including T(H)2 cells, which mediate the inflammatory response in the lungs. In this minireview, we discuss the current understanding of how associated genetic and environmental factors increase the complexity of allergic asthma and the challenges allergic asthma poses for the development of novel approaches to effective treatment and prevention.     

The interaction of histamine with other bronchoconstrictor mediators

The lack of therapeutic efficacy of antihistaminic drugs in the treatment of asthma has led to the search and discovery of other bronchoconstrictor agents, particularly leukotrienes, thromboxanes, and platelet-activating factor. However, specific receptor antagonist for any of these substances have also not been particularly effective in inhibiting allergic bronchoconstriction. It is now generally accepted that histamine, arachidonic acid metabolites, platelet-activating factor, and possibly other substances are all involved to varying degrees in asthma and may indeed interact. This paper reviews the interaction of these mediators and how they contribute to airway hyperreactivity.     

Substituted coumarins as potent 5-lipoxygenase inhibitors

Leukotriene biosynthesis inhibitors have potential as therapeutic agents for asthma and inflammatory diseases. A novel series of substituted coumarin derivatives has been synthesized and the structure-activity relationship was evaluated with respect to their ability to inhibit the formation of leukotrienes via the human 5-lipoxygenase enzyme.     

The prevalence and pulmonary consequences of anxiety and depressive disorders in patients with asthma

The aim of this study was to determine the prevalence of anxiety and depression symptoms in outpatients with treated asthma and to determine the influence of anxiety and depression symptoms on lung function and asthma symptoms. The study was conducted in the pulmonary clinic of the Department of Pulmonary Diseases, Osijek University Hospital Centre, on 200 outpatients with asthma, aged 18-50 years, of which there were 65.5% women and 35.5% men. Each patient underwent a clinical examination with an extensive anamnesis and lung auscultation. The lung function was tested by spirometry. Demographic data and data on general and socioeconomic characteristics were evaluated using a questionnaire created internally for the purposes of this research, psychological status was assessed by HAD questionnaire, and Q test was used as a measure of asthma control. Based on the HAD questionnaire, 44.5% of asthma patients met the criteria for anxiety, and 24.5% of asthma patients met the criteria for depression. There was no significant correlation between asthma symptoms and the degree of anxiety or depression, while the pulmonary function of asthma patients negatively correlated with the degree of anxiety and depression. Pulmonary function in asthma patients with symptoms of anxiety and depression was significantly poorer than in asthma patients without anxiety and/or depression symptoms. The results show that among asthma patients there are large number of those who have symptoms of anxiety and depression. Asthma patients with symptoms of anxiety and depression have poorer lung function than patients with only asthma symptoms, however there is no significant correlation between the lung function and symptoms of asthma. We have confirmed that patients with anxiety symptoms visit general practitioners or EMS significantly more when compared to patients with depression symptoms.     

Chronopharmacology of Albuterol in Hospitalized Asthmatic Children

Eleven children (8–16 years old) hospitalized for acute bronchospasm were included in this investigation. Throughout the study, the children received the standardized course of therapy for hospitalized asthmatics with corticosteroids and albuterol nebulizations. Children receiving ipratropium were excluded from the study. Spirometric measurements, including forced expiratory volume in 1s (FEV₁), were made immediately before and 30 min after each albuterol nebuliza-tion over a 24-h period. The well-known temporal changes in FEV₁, were observed in patients suffering from nocturnal asthma (NA): basal values were maximal at midday (10 a.m. to 2 p.m.) and lowest in the evening or at night (10 p.m. to 6 a.m.). This 24-h variation in lung function was not found in children without nocturnal exacerbations of their asthma. A 24-h variation was also observed in albuterol-induced bronchodilation in patients with NA: maximal effectiveness occurred at night, and lower effect was obtained with the midday administration. The albuterol-induced increases in FEV₁, were not clinically significant in children without nocturnal asthma except when the β₂-agonist was inhaled between 10 p.m. and 2 a.m. The data suggest that patients with nonnocturnal asthma might have different drug requirements than those with nocturnal symptoms. Key Words: Albuterol—Asthma—Circadian rhythms—-Children—FEV₁.     

New approaches in the treatment of asthma

Asthma is a common and complex inflammatory disease of the airways that remains incurable. Current forms of therapy are long term and may exhibit associated side-effect problems. Major participants in the development of an asthma phenotype include the triggering stimuli such as the allergens themselves, cells such as T cells, epithelial cells and mast cells that produce a variety of cytokines including IL-5, GM-CSF, IL-3, IL-4 and IL-13 and chemokines such as eotaxin. Significantly, the eosinophil, a specialized blood cell type, is invariably associated with this disease. The eosinophil has long been incriminated in the pathology of asthma due to its ability to release preformed and unique toxic substances as well as newly formed pro-inflammatory mediators. The regulation of eosinophil production and function is carried out by soluble peptides or factors. Of these IL-5, GM-CSF and IL-3 are of paramount importance as they control eosinophil functional activity and are the only known eosinophilopoietic factors. In addition they regulate the eosinophil life span by inhibiting apoptosis. While one therapeutic approach in asthma is directed at inhibiting single eosinophil products such as leukotrienes or single eosinophil regulators such as IL-5, we believe that the simultaneous inhibition of more than one component is preferable. This may be particularly important with eosinophil regulators in that not only IL-5, but also GM-CSF has been repeatedly implicated in clinical studies of asthma. The fact that GM-CSF is produced by many cells in the body and in copious amounts by lung epithelial cells highlights this need further. Our approach takes advantage of the fact that the IL-5 and GM-CSF receptors (as well as IL-3 receptors) utilize a shared subunit to bind, with high affinity, to these cytokines and the same common subunit mediates signal transduction culminating in all the biological activities mentioned. By generating the monoclonal antibody BION-1 to the cytokine binding region of the common subunit (betac) we have shown that the approach of inhibiting IL-5, GM-CSF and IL-3 binding and the resulting stimulation of eosinophil production and function with a single agent is feasible. Furthermore we have used BION-1 as a tool to crystallize and define the structure of the cytokine binding domain of betac. This knowledge and this approach may lead to the generation of novel therapeutics for the treatment of asthma.