IL-6 Inhibitor Induction in Coculture Of Bronchial Epithelial Cells and Eosinophils

IL-6 Inhibitor
Eosinophil infiltration of the mucosa is a feature of asthmatic airways. Their adhesion to bronchial epithelial cells has been proposed to lead to the generation of inflammation mediators which may contribute to asthma pathology. Bronchial epithelial cells (BEAS-2B cell line) and peripheral blood eosinophils were cultured alone or in combination and the production of an inflammatory cytokine, IL-6, was measured. IL-6 was produced principally by epithelial cells and the production was enhanced more than 10-fold in the presence of eosinophils. Significant augmentation of epithelial IL-6 production persisted even when eosinophils were fixed with paraformaldehyde. The eosinophil-induced IL-6 production was extensively inhibited by inhibitors of p38 mitogen-activated protein (MAP) kinase or nuclear factor ??B (NF??B). (more…)

Long-Acting Beta Agonists: Salmeterol and Formeterol

Salmeterol and Formeterol
Two long-acting ß 2 -adrenergic agonists (LABAs), salmeterol and formoterol, have been demonstrated to be safe and effective agents in children, both in terms of bronchodilation and prevention of exercise-induced bronchospasm. Their onsets of action differ, with formoterol having an onset similar to albuterol (3 minutes), while salmeterol has a slower onset of action (10–20 minutes). Following a single-dose administration, both agents demonstrate durations of action up to 12 hours. Following regular twice-daily administration, bronchodilation remains effective; however, a level of tolerance (or tachyphylaxis) (more…)

Asthma Progression of Disease with Abnormality in Pulmonary Function

asthma progression
More severe asthma can persist from childhood into adulthood without remission. Another important tendency in the natural history is for symptoms to remit in adolescence only to return again in adulthood. In general, the amount of wheezing in early adolescence seems to be a guide for severity in early adult years, with 73% of those with few symptoms at age 14 years continuing to have little or no asthma progression at age 28 years. Similarly 68% of those with frequent wheezing at 14 years still suffered from recurrent asthma at age 28 years. Most subjects with frequent wheezing at 21 years continued to have comparable asthma at 28 years. In addition to the importance of symptoms in childhood, childhood degree of bronchial responsiveness in combination with a low FEV-1 were also related to the outcome of asthma in adulthood. (more…)

Requirement for Leukotriene B4 Receptor 1 in Allergen-Induced Airway Hyper-Responsiveness

Airway Hyper-Responsiveness
A role for Leukotriene B4 in the induction of airway hyper-responsiveness was explored through the use of transgenic mice deficient in the BLT1 receptor for LTB4 . Ovalbumin challenge of sensitized wild-type mice resulted in the usual features of experimental asthma, including goblet cell hyperplasia, hyper-responsiveness to inhaled methacholine and elevated BAL fluid concentrations of the Th2 cytokine IL-13. In contrast, BLT1 –/– mice (i.e. genetically modified mice lacking the gene coding for the BLT1 receptor) exhibited significantly lower responses. BLT1 –/– mice also exhibited lower numbers of IL-13-positive T lymphocytes of both the helper (CD4 T Cells) and cytotoxic/suppressor (CD8 + ) types. (more…)

Antileukotrienes in Acute Asthma: Zafirlukast, Montelukast, Leukotriene Receptor Antagonists

Leukotriene Receptor Antagonists
Leukotrienes can be found in the airway and urine following both spontaneous exacerbations of asthma and acute exposure to bronchoconstrictor stimuli in the laboratory. This in turn indicates that they may have a role in the pathogenesis of acute episodes of bronchoconstriction. Although antileukotrienes are not currently advocated in the management of acute asthma, there are data to suggest that they might be of some potential benefit. Prior treatment with montelukast asthma has been shown in several studies to significantly shorten the time taken to recover (in terms of FEV 1 ) following exposure to a bronchoconstrictor stimulus. (more…)

Long Acting Agonist (ß2) Therapy to Inhaled Corticosteroids in Persistent Asthma?

long acting agonist
Current internationally recognized guidelines indicate that symptomatic asthmatics using a low to medium inhaled corticosteroid dose (400–800 µg/day of beclomethasone or equivalent) alone should preferentially be commenced on a long-acting agonist ß2 prior to an leukotriene receptor antagonists LTRA (British guideline on the management of asthma 2003; GINA Workshop Report 2004). However, two recent large trials have performed head to-head comparisons of add-on long-acting ß2 agonist versus LTRA as therapeutic adjuncts to inhaled corticosteroids, using exacerbation frequency (rather than lung function and symptoms) as the primary end point. (more…)

Leukotriene Receptor Antagonists & 5-Lipoxygenase Inhibitors


Two main strategies have been developed to block the effects of cysteinyl leukotrienes in the airway. One method is to use drugs that prevent their synthesis (using a 5-lipoxygenase inhibitor) and the other involves interfering with the binding of cysteinyl leukotrienes to their cellular receptor using a leukotriene receptor antagonist (LTRA). (more…)

Sublingual Immunotherapy Mechanisms

sublingual immunotherapy
The immunologic mechanisms of sublingual immunotherapy are less established. In Cochrane analysis, the authors concluded that there was an increase in IgG4 but no stable effect on IgE levels in adults. In addition, the induction of allergen-specific IgA has been reported. There are conflicting data concerning lympho-proliferative responses. So far the evidence on changes in Th1/Th2/Treg activity induced by sublingual immunotherapy need to be confirmed. The effects on T-cell reactivity and cytokine secretion show strong variation in a number of studies. (more…)

Treg Cells In Allergen-Specific Immunotherapy

treg cells
Treg cells or regulatory T cells constitute a large population of cellular infiltrate in atopic/allergic inflammation and a dysregulated immune response appears to be an important pathogenetic factor. Cardinal events during allergic inflammation can be classified as activation, organ-selective homing, survival and reactivation, and effector functions of immune system cells. T cells are activated by aeroallergens, food antigens, autoantigens, and bacterial exotoxins superantigens in allergic inflammation. They are under the influence of the skin, lung, or nose-related chemokine network and show organ-selective homing. (more…)

Cysteinyl Leukotriene Biosynthesis

cysteinyl leukotrienes
The cysteinyl leukotrienes (LTC 4 , LTD 4 and LTE 4 ) are lipid mediators produced from an arachidonic acid precursor following a series of enzymatic steps. Arachidonic acid is firstly released from the phospholipid bilayer by phospholipase A 2 and may be metabolized by either the cyclooxygenase (COX) or 5-lipoxygenase pathway. Once the unstable precursor LTA 4 has been produced, it may be converted in neutrophils or monocytes to the noncysteinyl LTB 4 by LTA 4 hydrolase. In mast cells, eosinophils, macrophages, and basophils, LTA 4 may alternatively be converted into LTC 4 by LTC 4 synthase and subsequently into LTD 4 and LTE 4. (more…)

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