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…)

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…)

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…)

Asthma and Stress: How are They Related?

asthma stress
Negative family characteristics such as family conflict and family dysfunction discriminated children who died of asthma from children with equally severe asthma who did not die. Parenting difficulties have been associated with a higher risk for the development of asthma early in life. In addition, children with the highest risk of developing early-onset asthma were those in families with both parenting problems and high stress. Evidence for a asthma and stress link has been demonstrated through temporal studies, as experiencing an acute negative life event increased children’s risk for an asthma attack 4 to 6 weeks after the occurrence of the event. (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…)

Histamine Type-2 Receptor as Major Player in Peripheral Tolerance

histamine receptor
Histamine is a low-molecular-weight monoamine that binds to four different G-protein-coupled receptors, and has recently been demonstrated to regulate several essential events in the immune response. The histamine receptor type 2 (HR2) is coupled to adenylate cyclase and studies in different species and several human cells have demonstrated that inhibition of characteristic features of the cells by primarily cAMP formation dominates in HR2-dependent effects of histamine. (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…)

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