Toll-Like Receptors 2 and 4 Agonists Activate Airway Smooth Muscle via Mononuclear Leukocytes

Toll-Like Receptors
Toll-like receptors (TLRs) act as receptors for numerous stimuli of immune cells, including bacterial cell wall constituents (lipopolysaccharide [LPS] from Gram-negative bacteria and lipopeptides from Gram-positive species), plasma proteins and extracellular matrix breakdown products. TLR2 and TLR4 bind lipopeptide and LPS respectively, mediating responses of alveolar macrophages and other immune cells to bacterial infection in the lungs. Exposure of lungs to LPS leads to pro-inflammatory responses of a number of cell types, including airway smooth muscle, which secretes a number of cytokines involved in leucocyte recruitment and the Th2 polarization of immune responses. Human airway smooth muscle cells were cultured with LPS in the absence and presence of peripheral blood mononuclear cells to determine direct and leucocyte-dependent TLR-mediated responses. (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…)

Cromolyn, Nedocromil, Theophylline: Asthma Medications

asthma medications
Cromolyn sodium and nedocromil sodium are inhaled agents that are alternatives to inhaled corticosteroids (ICS) in the management of mild persistent asthma in children. Both drugs have been shown to possess anti inflammatory properties through nonsteroidal mechanisms, although the exact mechanisms for their actions remain unclear. (more…)

Vocal Cord Dysfunction: A Functional Respiratory Tract Disorder

Vocal Cord Dysfunction
Vocal cord dysfunction (VCD) is a functional respiratory tract disorder resulting from paradoxical adduction of the vocal cords, complicates the diagnosis and management of common respiratory tract problems, including asthma. The recognition of VCD in a patient with atypical or difficult-to-control asthma is critical in minimizing symptoms and potential side-effects associated with treatment of severe asthma. The symptoms of VCD are not unique to the disorder and include cough, wheeze, stridor, dyspnea, hoarseness, and choking. (more…)

Exposure to Inhalant Allergens Increase the Severity of Asthma

allergens asthma
Exposure and allergic sensitization to cockroach was associated with a significantly greater risk of asthma hospitalization and greater healthcare utilization among 476 children aged 4 to 9 years who participated in the National Cooperative Inner-City Asthma Study. Allergic sensitization to the mold Alternaria has been identified as a significant allergen in terms of increasing airway hyperresponsiveness and was associated with a nearly 200-fold increased risk of respiratory arrest due to asthma, emphasizing the importance of determining underlying allergic sensitivities in patients with asthma and providing patients with accurate and practical advice on allergen avoidance techniques. (more…)

Aspirin-Induced Asthma Treatment with Antileukotrienes

Aspirin Asthma
The prevalence of aspirin-sensitive asthma is uncertain although it may exist in up to 20% of all asthmatics patients. The characteristic features include profound bronchoconstriction asthma following aspirin ingestion, rhinosinusitis, nasal polyps, and abdominal cramps. Aspirin and nonsteroidal antiinflammatory drugs selectively inhibit COX-1, which in turn shunts arachidonic acid down the 5-lipoxygenase activating protein pathway, causing overproduction of cysteinyl leukotrienes. As a consequence, elevated levels of cysteinyl leukotrienes can be found in bronchial asthma and nasal aspirates, and in urine following aspirin challenge. (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…)

Montelukast Side Effects as Antileukotrienes Therapy to Inhaled Corticosteroids in Asthma

antileukotrienes therapy
Despite optimum drug delivery and good compliance with inhaled corticosteroids, many patients experience symptoms and exacerbations. Dose–response studies using inhaled corticosteroids have generally been unable to demonstrate any significant difference between individual doses of inhaled corticosteroids. For example, a metaanalysis evaluated eight studies (2324 asthmatics) where the effects of at least two doses of inhaled fluticasone were measured. (more…)

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