Inflammatory Process In Asthma Research Articles

Adult Serum Cytokine Concentrations and the Persistence of Asthma

Background: Cytokines play a pivotal role in regulating the development and persistence of the inflammatory process in asthma. Our aim was to investigate whether asthma persistence or remission is associated with a specific cytokine profile. Methods: The Tasmanian Longitudinal Health Study followed participants from 7 to 44 years of age. Serum concentrations of interleukin (IL)-4, IL-5, IL-6, IL-8, IL-10 and tumor necrosis factor-alpha (TNF-α) were measured at age 44 years. Participants were categorized into five phenotypes (early-onset noncurrent asthma, early-onset current asthma, late-onset noncurrent asthma and late-onset current asthma). Those who had never had asthma formed the reference group. Multivariable linear regression was used to compare serum cytokine concentrations between each phenotype and the reference group. Results: IL-10 concentrations were significantly lower in serum from the early-onset current asthma group than in the reference group (ratio of geometric means 0.58; 95% confidence interval 0.33-0.99; p = 0.048). IL-6 concentrations for the late-onset remitted group were also significantly lower than in the reference group (p = 0.009). The TNF-α concentrations were significantly lower for both early-and late-onset remitted asthma phenotypes when compared with the reference group. No associations were detected between serum concentrations of IL-4, IL-5 or IL-8 and these specific longitudinal asthma phenotypes. Conclusion: Our findings suggest a possible role for deficient IL-10 responses in the persistence of early-onset asthma. Lower IL-6 and TNF-α concentrations in serum from those with remitted asthma suggest that these proinflammatory cytokines may be actively suppressed during asthma remission.

Relationship of Mannitol Challenge to Methacholine Challenge and Inflammatory Markers in Persistent Asthmatics Receiving Inhaled Corticosteroids

Mannitol is a novel osmotic indirect bronchial challenge agent used to aid asthma diagnosis and management and is thought to reflect underlying inflammatory processes in asthma. Our objective was to evaluate relationships between mannitol airway hyperresponsiveness (AHR) and other measures of airway inflammation as well as direct-acting methacholine challenge in persistent asthmatics receiving inhaled corticosteroids. We analysed screening data of mild to moderate persistent asthmatics, all receiving inhaled corticosteroids (ICS), who had mannitol and/or methacholine challenges, fractional exhaled nitric oxide (FeNO), and salivary eosinophilic cationic protein (ECP) performed as part of the same screen. Mannitol AHR was grouped by PD(10) (cumulative provocative dose required to produce a 10% fall in FEV(1)): mild (315-635mg), moderate (75-315mg), and severe (0-75mg). FeNO groups were low (<25ppb), medium (25-50ppb), and high (>50ppb) and methacholine PC(20) (provocative concentration of methacholine required to cause a 20% fall in FEV(1)) groups were mild (2-8mg/ml), moderate (0.5-2mg/ml), and severe (0-0.5mg/ml). Mannitol PD(10) groups were significantly different overall for FeNO (p=0.023): 43% higher in the severe vs. the mild group. There was a significant overall difference for methacholine PC(20) (p=0.006): a 2.1 doubling dilution difference between severe vs. mild mannitol groups. FeNO groups were significantly different overall for mannitol PD(10) (p=0.01) and methacholine PC(20) (p=0.029). Methacholine PC(20) groups were significantly different overall for mannitol PD(10) (p<0.001) and FeNO (p=0.005). No significant differences were found across any groups for salivary ECP, FEV(1) % predicted, or ICS dose. Mannitol PD(10), methacholine PC(20), and FeNO as continuous variables all correlated with each other. Mannitol challenge reflects underlying inflammation using FeNO and direct AHR using methacholine. Thus, mannitol may be a useful screening tool for the assessment of asthmatic patients receiving inhaled corticosteroids.

Newer approaches in the treatment of asthma

Asthma is a worldwide public health problem. The most effective anti-asthmatic drugs - inhaled β2-agonists and glucocorticoids controls asthma in about 90-95% of patients. However, severe glucocorticoid-dependent and resistant asthma presents a great clinical burden. Therefore, reducing glucocorticoids - related adverse effects using novel steroid-sparing agents is needed. Furthermore, the mechanisms involved in the persistence of inflammation are poorly understood and the reasons why some patients have severe life threatening asthma and others have very mild disease are still unknown. Although glucocorticoids effectively control the inflammatory process in asthma, they have little effect on the lower airway remodeling processes that appear to play a role in the pathophysiology of asthma. Several new drugs developed to target specific components of the inflammatory process in asthma [e.g. anti-IgE antibodies (omalizumab), cytokines and/or chemokines antagonists, immunomodulators, antagonists of adhesion molecules)], have not yet been proven to be particularly effective. Hence, considering the central role of T lymphocytes in the pathogenesis of asthma, drugs targeting disease-inducing Th2 cells are promising future therapeutic strategies. Some of these new anti-asthmatic treatment approaches may in the future not only control symptoms and modify the natural course of asthma, but also potentially prevent or cure the disease. Hence, the development of novel drugs may allow resolution of these changes.

The Editor takes a closer look at some of this month's articles

The Editor takes a closer look at some of this month's articles

Inhibitory effects of casticin on migration of eosinophil and expression of chemokines and adhesion molecules in A549 lung epithelial cells via NF-κB inactivation

The fruits of Vitex rotundifolia L. have long been used for the treatment of inflammation of the respiratory tract in East Asia. To determine if casticin, one of the constituents of Vitex rotundifolia L., has anti-allergic and anti-inflammatory effects in asthma. The in vitro anti-inflammatory activity of casticin was studied in A549 human type II-like epithelial lung cells using an eotaxin inhibition assay. Additionally, its effects on eotaxin, regulated on activation normal T cell expressed and secreted (RANTES), vascular cell adhesion molecule (VCAM)-1, and inter-cellular adhesion molecule (ICAM)-1 expression were investigated by real time-polymerase chain reaction (real time-PCR). The inhibition of nuclear factor κB (NF-κB) activity in the presence of casticin was determined by analyzing confocal microscopy images of fluorescence immunocytochemical analysis while the suppression of inhibitory κB (IκB)-α phosphorylation was studied using Western blot analysis. Finally, the inhibitory effect of casticin on eosinophil migration toward prestimulated A549 cell media was measured using the human eosinophilic leukemia cell line. Casticin significantly suppressed eotaxin production in cytokine activated A549 lung epithelial cells. Casticin also suppressed the mRNA expression levels of eotaxin, RANTES, VCAM-1, and ICAM-1, which subsequently contributed to the inhibition of eosinophil migration. Furthermore, casticin inhibited IκB-α phosphorylation and nuclear translocation of p65 in A549 cells. Casiticin inhibited the eosinophil migration and activity of chemokines and adhesion molecules involved in the inflammatory process of asthma by suppressing the NF-κB pathway. These results suggest that casticin has the potential for use in the treatment of allergic asthma.

Exercise but not mannitol provocation increases urinary Clara cell protein (CC16) in elite swimmers

Elite swimmers have an increased risk of developing asthma, and exposure to chloramine is believed to be an important trigger factor. The aim of the present study was to explore pathophysiological mechanisms behind induced bronchoconstriction in swimmers exposed to chloramine, before and after swim exercise provocation as well as mannitol provocation. Urinary Clara cell protein (CC16) was used as a possible marker for epithelial stress. 101 elite aspiring swim athletes were investigated and urinary samples were collected before and 1h after completed exercise and mannitol challenge. CC16, 11β-prostaglandin (PG)F(2α) and leukotriene E(4) (LTE(4)) were measured. Urinary levels of CC16 were clearly increased after exercise challenge, while no reaction was seen after mannitol challenge. Similar to CC16, the level of 11β-PGF(2α) was increased after exercise challenge, but not after mannitol challenge, while LTE(4) was reduced after exercise. There was no significant difference in urinary response between those with a negative compared to positive challenge, but a tendency of increased baseline levels of 11β-PGF(2α) and LTE(4) in individuals with a positive mannitol challenge. The uniform increase of CC16 after swim exercise indicates that CC16 is of importance in epithelial stress, and may as such be an important pathogenic factor behind asthma development in swimmers. The changes seen in urinary levels of 11β-PGF(2α) and LTE(4) indicate a pathophysiological role in both mannitol and exercise challenge.

Assessing clinical and spirometric control and the intensity of the inflammatory process in asthma

To review the role of clinical assessment, quality of life assessment, spirometry, bronchial responsiveness test and inflammatory markers for asthma assessment. Search run on MEDLINE and LILACS. Clinical assessment aids with assessing asthma control and is widely recommended. However, patients may have airway inflammation and obstruction despite normal clinical findings. Spirometry quantifies the degree of airway obstruction and helps with diagnosis, while the bronchial responsiveness test may be indicated for when asthma is suspected but spirometry is normal. The results of assaying the inflammatory markers in exhaled breath condensate, induced sputum, bronchoalveolar lavage and bronchial biopsy specimens are abnormal in asthma patients, but these are complex techniques almost always restricted to research. Fractional exhaled nitric oxide (FeNO) is elevated in patients with asthma, is reproducible and noninvasive and reduces with treatment. Studies have investigated using FeNO to help with adjusting inhaled corticoid dosages, but the benefits are not clear. A range of different methods are needed to accurately assess disease control, all with their advantages and limitations. Clinical and functional assessment is useful for diagnosing asthma, but is of limited use for precisely evaluating the intensity of the inflammatory process in the airways. More randomized and controlled studies with adequate statistical power should be carried out to investigate the true utility of noninvasive inflammatory markers, especially FeNO, for asthma management.

Genetics and pharmacogenetics of the leukotriene pathway

Leukotrienes are now established contributors to the inflammatory process in asthma, and leukotriene modifiers are mainstays in the therapy of asthma. This review focuses on published association studies implicating the role of leukotriene pathway genes in asthma pathogenesis and treatment response, specifically focusing on those genetic variants associated with asthma affection status, the development of aspirin-exacerbated respiratory disease, and pharmacogenetic response. Although published studies have been limited by small sample sizes and a lack of independent replication, multiple loci within multiple leukotriene pathway genes have now been associated in more than 1 study related to asthma or asthma treatment response. Those specific variants include 2 variants in the 5-lipoxygenase gene (ALOX5) that are both associated with response to 5-lipoxygenase inhibition and to leukotriene receptor antagonists, variants in genes encoding the 2 established cysteinyl leukotriene receptor antagonists (CYSLTR1 and CYSLTR2) that are both associated with asthma susceptibility in at least 2 independent populations, and a leukotriene C(4) synthase promoter polymorphism (LTC4s) that has been associated with asthma affection status and asthma-exacerbated respiratory disease. Despite these successes, genetic investigations into this pathway remain in their formative stages. Future studies aimed at providing a broader scope of investigation through increased sample sizes and through genome-wide approaches are needed.

Procaterol Potentiates the Anti-Inflammatory Activity of Budesonide on Eosinophil Adhesion to Lung Fibroblasts

Background: The interaction between leukocytes and various parenchymal cells is the first step of inflammation. Therefore, the adhesion of eosinophils to lung fibroblasts is thought to be a crucial step in the inflammatory process of asthma. Procaterol, a β₂-selective full agonist, is currently prescribed for patients with asthma. In addition to its potent bronchodilatory action, the agonist has been reported to have anti-inflammatory actions. In this study, to examine whether procaterol can potentiate the anti-inflammatory action of glucocorticoids, the effect of procaterol on eosinophil adhesion to normal human lung fibroblasts (NHLF) was assessed in the presence and absence of budesonide, one of the most potent glucocorticoids. Methods: Following pretreatment of NHLF with tumor necrosis factor-α (TNF-α) in the presence of various concentrations of procaterol and/or budesonide, the eotaxin-stimulated eosinophil adhesion was determined using the peroxidase activity of eosinophils. To investigate the mechanism of the inhibitory action of procaterol, TNF-α-induced expression of adhesion molecules, ICAM-1 and VCAM-1, in NHLF was also evaluated. Results: Pretreatment with procaterol inhibited the adhesion of eosinophils to NHLF in a concentration-dependent manner, and shifted the concentration-response curve of budesonide to the left. Both procaterol and budesonide resulted in concentration-dependent inhibition of expression of ICAM-1 and VCAM-1 in NHLF, and an additive inhibitory effect was found when the agents were combined. Conclusions: Given the results of this study which indicated that procaterol exerted an additive action on the anti-inflammatory effect of budesonide, procaterol and glucocorticoids may provide better control for asthma when used together than when used separately.

Chronic inflammation in asthma: a contest of persistence vs resolution

Recent investigations have highlighted that endogenous anti-inflammatory mediators and immune regulating mechanisms are important for the resolution of inflammatory processes. A disruption of these mechanisms can be causally related not only to the initiation of unnecessary inflammation, but also to the persistence of several chronic inflammatory diseases. In asthma, chronic Th-2 driven eosinophilic inflammation of the airways is one of the central abnormalities. To date, elucidating the role of the different pro-inflammatory mediators involved in orchestrating the inflammatory processes in asthma has been the subject of intense research in both humans and animal models. However, the counter-regulatory mechanisms that co-determine the outcome in the contest of resolution vs persistence of the eosinophilic airway inflammation remain poorly understood. These are currently being investigated in animal models of chronic asthma. Elucidating these mechanisms is of relevance, since it can give rise to a new therapeutic approach in the treatment of chronic airway inflammation in asthmatics. This novel concept of treatment involves the stimulation of endogenous anti-inflammatory pathways, rather than solely antagonising the various pro-inflammatory mediators. Here, we review and discuss the current knowledge about these endogenous anti-inflammatory mediators in clinical and experimental asthma.

New drugs targeting Th2 lymphocytes in asthma.

Asthma represents a profound worldwide public health problem. The most effective anti-asthmatic drugs currently available include inhaled β2-agonists and glucocorticoids and control asthma in about 90-95% of patients. The current asthma therapies are not cures and symptoms return soon after treatment is stopped even after long term therapy. Although glucocorticoids are highly effective in controlling the inflammatory process in asthma, they appear to have little effect on the lower airway remodelling processes that appear to play a role in the pathophysiology of asthma at currently prescribed doses. The development of novel drugs may allow resolution of these changes. In addition, severe glucocorticoid-dependent and resistant asthma presents a great clinical burden and reducing the side-effects of glucocorticoids using novel steroid-sparing agents is needed. Furthermore, the mechanisms involved in the persistence of inflammation are poorly understood and the reasons why some patients have severe life threatening asthma and others have very mild disease are still unknown. Drug development for asthma has been directed at improving currently available drugs and findings new compounds that usually target the Th2-driven airway inflammatory response. Considering the apparently central role of T lymphocytes in the pathogenesis of asthma, drugs targeting disease-inducing Th2 cells are promising therapeutic strategies. However, although animal models of asthma suggest that this is feasible, the translation of these types of studies for the treatment of human asthma remains poor due to the limitations of the models currently used. The myriad of new compounds that are in development directed to modulate Th2 cells recruitment and/or activation will clarify in the near future the relative importance of these cells and their mediators in the complex interactions with the other pro-inflammatory/anti-inflammatory cells and mediators responsible of the different asthmatic phenotypes. Some of these new Th2-oriented strategies may in the future not only control symptoms and modify the natural course of asthma, but also potentially prevent or cure the disease.

Bronchial asthma as neurogenic paroxysmal inflammatory disease: Do some antiepileptic drugs have antiasthmatic properties?

Bronchial asthma is an inflammatory disease, and neurogenic inflammation may play important role in asthma mechanisms. But asthma also is an inflammatory disease with paroxysmal clinical picture. It is known that migraine and trigeminal neuralgia also are inflammatory diseases with paroxysmal clinical picture, and neurogenic inflammation plays important role in their mechanisms. Antiepileptic drugs are highly effective in pharmacotherapy of migraine and trigeminal neuralgia, and these drugs completely prevent attacks of migraine and trigeminal pain in great majority of cases. Due to this it is possible that some antiepileptic drugs may be highly effective in pharmacotherapy of asthma. Bronchial asthma can be considered as peripheral paroxysmal and inflammatory disease with definite central neurogenic mechanism. It is also possible that some antiepileptic drugs can suppress inflammatory processes in asthma through the central neural influence, like in therapy of migraine and trigeminal neuralgia.

Transcription Factors in Asthma: Are Transcription Factors a New Target for Asthma Therapy?

The essential features of persistent severe asthma include structural changes in the airway wall (remodelling). It is not known whether these are the sequelae of chronic inflammation or indeed its initiators. Several transcription factors have been implicated in the inflammatory process in asthma, including the glucocorticoid receptor (GR), NFkappaB, Activator Protein-1 (AP-1), Nuclear Factor of Activated T-cells (NF-AT), cyclic AMP Response Element Binding Protein and more recently, the CCAAT/Enhancer Binding Protein (C/EBP), Peroxisome Proliferator-activated Receptor (PPAR) and the bZIP transcription factor, Nrf2. Could a pathological de-regulation of one of these transcription factors explain the broad spectrum of asthma pathology and can their modulation lead to better symptom control? Although some of the transcription factors seem to be valid targets (NFkappaB, Nrf2 or STAT6) or tools (PPARgamma, -alpha and C/EBP-alpha) for new therapeutic approaches, since many transcription factors play a central role in tissue and organ homeostasis, a longterm general suppression or overexpression, would cause severe side effects in other organs. Cell type specific application of decoy or antisense oligonucleotides for NFkappaB, Nrf2 or STAT6, or specific agonists for PPARgamma and -alpha may help to control the inflammatory response in lung epithelial cells and infiltrated immune cells, but additional, unwanted, effects on other resident cells of the lung cannot be excluded and a beneficial effect over known anti-asthma drugs has first to be proven. In order to progress with such novel therapeutic strategies, the only option seems to be to link transcription factor inhibitors/activators to a cell type specific delivery system.

Circulating LTB4and Eotaxin-1 in stable asthmatics on inhaled corticosteroids and long-acting β 2-agonists

<b>BACKGROUND</b> : Leukotrienes B4 (LTB4) and eotaxin-1 are thought to play a pivotal role in the pathogenesis of asthma. This study investigates the plasma levels of LTB4 and eotaxin-1 in symptom-free asthmatics on inhaled corticosteroids (ICS) and long-acting β2 (LABA)<b> .<br>MATERIALS AND METHODS</b> : Twenty asthmatic patients treated with ICS and LABA for 3 months and 17 matched healthy subjects were recruited. LTB4 and eotaxin-1 were measured in the serum by a specific enzyme immunoassay kit. <br><b> RESULTS</b> : Treatment resulted in significant improvement in FEV1 and disappearance of symptoms. LTB4 levels were significantly lower in the treated asthmatics compared to the healthy subjects (19.17 ± 0.8 pg/ml versus 23.34 ± 0.82 pg/ml respectively, <i>P</i> <0.001). However, there was no significant difference in the levels of eotaxin-1 between healthy subjects and asthmatic patients. <b> <br>CONCLUSION</b> : Asthmatics treated with ICS and LABA showed significantly lower levels of LTB4 compared to healthy subjects. Regular use of inhaled corticosteroids and long-acting β2 may help in controlling the inflammatory process in asthma. Further studies are needed to confirm these findings and assess the association between clinical and physiological parameters and circulating chemokines and cytokines.

Beta-adrenergic receptor agonists induce the release of granulocyte chemotactic protein-2, oncostatin M, and vascular endothelial growth factor from macrophages

Vascular endothelial growth factor (VEGF), oncostatin M (OSM), and granulocyte chemotactic protein-2 (GCP-2/CXCL6) are up-regulated in U937 macrophages and peripheral blood macrophages exposed to LPS, beta-adrenergic receptor (β 2-AR) agonists (e.g. zilpaterol, and clenbuterol) and some other agents that induce intracellular cAMP (prostaglandin E 2, forskolin, and butyryl cAMP). LPS in combination with β 2-agonists and cAMP elevating agents had an additional effect on the release of VEGF, OSM, and CXCL6. These proteins are up-regulated after 16–24 h of exposure and this is mediated by the β 2-AR, as determined by time course experiments and the use of a specific β 2-AR antagonist (ICI 118551). Beta 2-AR agonists are used as bronchodilators in the treatment of asthma, but appear to have no effect on the chronic inflammation of the disease. However, the up-regulation of VEGF, OSM, and CXCL6 may have adverse effects on the inflammatory process of asthma. These mediators are involved in the recruitment of neutrophils, airway remodelling and angiogenesis, known features of chronic inflammatory diseases. We propose that the up-regulation of these proteins could play a role in the adverse effects of prolonged excessive usage of β 2-AR agonists on the airways besides the desensitization of the β 2-AR.

Biochemical interaction between effects of beclomethasone dipropionate and salbutamol or formoterol in sputum cells from mild to moderate asthmatics

Several in vitro studies demonstrate that corticosteroids and long-acting beta(2) agonists may have a complementary and synergistic mode of action on the inflammatory processes in asthma. Sputum was induced in 20 mild to moderate asthmatic patients and the induced sputum cells (ISC) were cultured with beclomethasone dipropionate (BDP) 10(-7) M, salbutamol 10(-8) M and formoterol 10(-8) M either alone or in combination, BDP plus salbutamol and BDP plus formoterol, for 24 h. We measured the levels of growth macrophages-colony stimulating factor (GM-CSF), released on activation normal T cells expressed and activated (RANTES) and interleukin-8 (IL-8), in the supernatant of stimulated cells by ELISA. Furthermore, we assessed nuclear translocation of glucocorticoid receptor (GR) and the expression of beta(2) receptor in ISC by immunofluorescence and RT-PCR, respectively. The release of GM-CSF, RANTES and IL-8 in ISC was significantly reduced by BDP plus salbutamol or formoterol as compared with either drug alone (P < 0.0001). beta(2) receptor expression was increased after 30 min of incubation with BDP and continued to increase over a time period of 4 h (P < 0.0001). Furthermore after 30 min of incubation, nuclear translocation of GR was greater with BDP plus salbutamol or formoterol than with any of the drugs alone (P < 0.0001). The present ex vivo study demonstrates a complementary mode of action between BDP and salbutamol or formoterol leading to an enhanced anti-inflammatory activity.

Targeting Th2 cells in asthmatic airways.

The most effective anti-asthmatic drugs currently available include inhaled beta2-agonists and glucocorticoids and control asthma in about 95% of patients. The current asthma therapies are not cures and symptoms return soon after the treatment is stopped even after long-term therapy. In addition, severe glucocorticoid-dependent and -resistant asthma still represents a great clinical burden accounting for approximately 50% of the health care costs of asthma and reducing the side-effects of glucocorticoids using novel dissociated steroids, soft steroids or with steroid-sparing agents will prove beneficial. Furthermore, the mechanisms involved in the persistence of inflammation are poorly understood and the reasons why some patients have severe life threatening asthma and others have very mild disease are still unknown. Hopefully, it will soon be possible to identify and manipulate the molecular switches that result in asthmatic inflammation. This may lead to the treatment of susceptible individuals at birth or in the early years and thus prevent the disease from becoming established. Drug development for asthma has been directed at improving currently available drugs and finding new compounds that usually target the Th2-driven airway inflammatory response. Several new drugs have been developed to target specific components of the Th2-driven inflammatory process in asthma (e.g. IgE antibodies, cytokines and/or chemokines, immunomodulators, antagonists of adhesion molecules), although they have not yet been proven to be particularly effective. Some of these new Th2-oriented strategies may in the future not only control symptoms, but also potentially prevent or cure the disease.

Managing Asthma: Past, Present, and Future

Asthma has been recognized in the medical literature for almost 2000 years. Modern pharmaco-therapy for asthma began with the commencement of the 20(th) century following the development of epinephrine and the demonstration of its effectiveness for acute symptoms of asthma. Progressive development of this class of bronchodilator medication has provided greater β2 specificity and longer duration of action. Corticosteroids were introduced about 50 years ago. As a systemic medication, they provided anti-inflammatory activity that continues to be essential for exacerbations of symptoms that are unresponsive to a bronchodilator. Corticosteroids were subsequently developed as inhaled agents for long-term maintenance therapy. The availability of corticosteroids with high topical effect has permitted the use of smaller doses with minimal systemic effect; therefore, the inhaled corticosteroids have become the most effective monotherapeutic agents for chronic asthma.Both theophylline and long-acting β2 agonists (e.g., salmeterol) provide additive clinical effect to small doses of inhaled corticosteroids. This effect is greater than that achieved with larger doses of the inhaled steroid used alone. A new approach to managing allergic asthma is now available in the form of a monoclonal antibody directed against immunoglobulin E (IgE). This agent, omalizumab, binds to circulating IgE, thereby preventing IgE from binding to mast cells. This subsequently prevents the release of mediators for bronchospasm and inflammation. Under investigation are monoclonal antibodies to modify the effects of interleukins involved in the inflammatory process of asthma. Phosphodiesterase inhibitors that are more specific than theophylline and monoclonal antibodies that prevent the attachment of rhinovirus to respiratory mucosa are being studied. Since rhinoviruses are major causes of acute exacerbations of asthma, these and other measures to prevent or modify the common cold provide great potential for further improvement in the outcome of asthma.

Modulation by cAMP of IL-1beta-induced eotaxin and MCP-1 expression and release in human airway smooth muscle cells.

Inflammatory cells, such as eosinophils, seem to be key players in the inflammatory process of asthma. These cells are attracted by chemokines, for example eotaxin and monocyte chemotactic protein (MCP-1). In this study, the authors investigated whether eotaxin and MCP-1 expression and release in human airway smooth muscle cells could be modulated by an increase in intracellular cyclic adenosine monophosphate (cAMP) concentration. The possible involvement of cAMP-dependent protein kinase A (PKA) was also studied. Forskolin, a direct stimulator of adenylyl cyclase, decreased the interleukin (IL)-1beta-induced eotaxin and MCP-1 release by 73+/-8 and 65+/-6%, respectively. 8Bromo-cAMP, a cAMP analogue, similarly decreased the chemokine production by 58+/-9 and 63+/-8% for eotaxin and MCP-1, respectively. Prostaglandin E2, known as an activator of the prostanoid receptors EP2 and EP4, which are positively coupled to adenylyl cyclase, also decreased the IL-1beta-induced eotaxin and MCP-1 production by 57+/-17 and 53+/-4%, respectively. H-89, an inhibitor of PKA, was able to inhibit the decrease in eotaxin and MCP-1 protein release induced by forskolin. Using Western-blot analysis, no effect of cAMP was found on the IL-1beta-induced p38 mitogen-activated protein kinase, extracellular signal-related kinase or cJun N-terminal kinase activation. This study shows that an increase in intracellular cyclic adenosine monophosphate concentration may decrease the interleukin-1beta-induced eotaxin and monocyte chemotactic protein-1 expression and production. This can be inhibited by addition of H-89, an inhibitor of cyclic adenosine monophosphate-dependent protein kinase. No decrease was observed in interleukin-1beta-induced p38 mitogen-activated protein kinase, extracellular signal-related kinase or cJun N-terminal kinase activation. These findings may be important for the further development of new anti-inflammatory drugs.

Asthma in the school-aged child.

Understanding the role of inflammation in childhood asthma has led to major changes in the approach to management of this disease. Based on the guidelines from the NIH, inhaled long-term control medications that target the underlying inflammatory processes in asthma are now recommended as the mainstay of drug treatment. Long-term control medications are recommended for all children who have asthma symptoms that occur more frequently than twice weekly or nocturnal symptoms more than twice monthly. Environmental control measures to decrease allergen exposure are important, as is attention to sinusitis and GER. The main impediment to improved asthma care is poor patient compliance. Many patients do not understand the role and importance of prophylactic medications in asthma treatment. Further, inconvenient dosing regimens, difficulties with metered-dose inhalers, and fear of potential side effects have all contributed to poor patient compliance. Increased efforts at patient education are needed to improve adherence to asthma plans. These efforts at improving patient compliance, along with improved physician adherence to the guidelines from the NIH, are needed to decrease the morbidity and mortality of childhood asthma.