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Asthma Treatment Could Get Tastier

Asthma Helper

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Researchers at the University of Maryland School of Medicine in Baltimore have discovered functioning bitter taste receptors (TAS2Rs) on bronchial smooth muscle. Although identical to receptors on the tongue, the receptors in the bronchi are not clustered in buds and do not send signals to the brain. The lung receptors do, however, respond to substances that have a bitter taste. The team initially thought that the purpose of the lung receptors would be to reinforce the warning provided by those on the tongue against bitter substances, many of which are toxic. When the team tested such compounds on individual airway smooth muscle cells, or human and mouse airways, they found, however, that instead of causing contraction – which would lead to unpleasant feelings of chest tightness and coughing – the compounds had the opposite effect.

In laboratory tests, TAS2R agonists such as chloroquine and denatonium opened the airways more effectively than drugs currently used to treat asthma or COPD, and aerosols containing the bitter substances were also effective in a mouse model of asthma. At a cellular level, the effect of bitter compounds also provided a surprise: although the compounds cause the airway muscles to relax, they lead to an increase in intracellular Ca2+, which would usually be expected to cause muscle contraction.

Although the bitter tasting substances used in the current study may not be suitable for aerosol formulation, the team believe that it should be possible to discover other compounds with similar bronchodilating properties that could be formulated for delivery by an inhaler and used to treat patients with asthma and COPD.

The study is published in Nature Medicine.


Role for NOX-4 in Pulmonary Fibrosis

pulmonary fibrosisIdiopathic pulmonary fibrosis is characterised by gradual scarring of the lungs until they become so thickened and damaged that they can no longer exchange oxygen with the blood; patients experience extreme fatigue, weight loss, chronic cough and shortness of breath. The disease affects mainly people over the age of 50 and, although progression varies from individual to individual, there is currently no cure and many people die within 5 years of diagnosis.

Researchers working at the University of Michigan have, however, discovered that the enzyme NOX-4 plays a key role in the development of lung scarring, a finding that could lead to new treatments for pulmonary fibrosis. The NOX family of enzymes are NADPH oxidases which catalyse the reduction of O2 to reactive oxygen species. Although specific roles for the seven known NOX isoforms have not been fully elucidated, roles in host defence against pathogens and the development of atherosclerosis have been proposed, as well as roles in other physiological processes that involve reactive oxygen species. In the present study, which is published in the August 23rd online edition of Nature Medicine, the researchers found that NOX-4 is up-regulated in tissue samples from humans with idiopathic pulmonary fibrosis and also in the lungs of mice subjected to non-infectious injury. Genetic knockout of NOX-4 or treatment with an inhibitor were shown to prevent the progression of fibrosis in two mouse models of lung injury.

This is the first study that links NOX-4 to the development of pulmonary fibrosis and the team, some of whom are now at the University of Alabama, believe that their findings may lead to the development of treatments for fibrosis in other organs as well as the lung. Although it remains to be seen whether such treatment would reverse existing fibrosis, the researchers hope that it would, at least, prevent progression of the disease.


More on Mice and Men

In a previous post we reported on a study that shows that mice may not be a good model for human diabetes. A new study now provides a mechanistic explanation for the well-documented toxicity invoked by Toll-like receptor 9 (TLR9) signalling in rodents, which is not observed in humans or non-human primates. Immunostimulatory DNA sequences (ISS) containing CpG (cytosine-phosphate-guanine) motifs which signal through TLR9 are being developed to treat asthma. These are safe and well tolerated in both healthy human volunteers and asthmatics when delivered to the airways, but cause lung inflammation and weight loss in mice at therapeutic doses. Writing in the Journal of Clinical Investigation, scientists at Dynavax Technologies Corporation and Astra Zeneca have shown that these differences in toxicity can be explained by differential TLR9 expression patterns in humans and rodents. cartoon mouseIn humans, TLR9 expression in mononuclear blood cells and lymphoid organs is restricted to B cells and plasmacytoid dendritic cells whereas, in mice, TLR9 is additionally expressed on macrophages, myeloid dendritic cells and activated T-cells. An investigation into the cell types and cytokines responsible for ISS-induced toxicity in mice showed that this could largely be attributed to production of TNF-α by monocytes and macrophages, cells that do not express TLR9 in primates.

The authors conclude that this fundamental difference in TLR9 expression patterns accounts for much of the exaggerated toxicity observed in rodents exposed to high doses of ISS in the respiratory tract. The new mechanistic insights into species-specific toxicities should help in the interpretation of toxicology studies of ISS in animals.


New Indication for Aldose Reductase Inhibitors?

crystal structure of aldose reductaseThe physiological role of aldose reductase (AR) is still incompletely understood, although it has long been associated with the pathogenesis of diabetes-associated diseases such as cataract and neuropathy. In the last twenty years a number of AR inhibitors have entered clinical trials for the potential treatment of diabetic neuropathy. Whilst the compounds have generally been well tolerated, efficacy has not been clearly established (although one compound, Epalrestat, is approved in Japan for treatment of subjective neuropathy symptoms associated with diabetic peripheral neuropathy).

The rationale for use of AR inhibitors in diabetic complications is based on the ability of AR to reduce glucose to sorbitol, levels of which are elevated in tissues of diabetic patients. Although glucose does not have high affinity for AR, the pathway is believed to be relevant in hyperglycaemia.

lungsAR is also known to reduce lipid aldehydes and their glutathione conjugates in response to reactive oxygen species (ROS). The products of the AR-catalysed reduction mediate activation of NFκB and the subsequent generation of inflammatory proteins. This observation led researchers at University of Texas Medical Branch and Louisiana State University Health Sciences Center to hypothesise that AR inhibitors may be useful in inflammatory diseases such as asthma. In a study published in PLoSone, the scientists stimulated primary human small airway epithelial cells (SAEC) with ragweed pollen extract (RWE). In this in vitro experiment, AR inhibition prevented RWE-induced apoptosis and expression of inflammatory mediators. Further, AR inhibition prevented allergic airway inflammation in mice sensitised with endotoxin-free RWE.

The results encourage exploration of AR inhibitors in inflammatory diseases such as asthma.


TRPA1 Linked to Asthma

Asthma involves an immune response to inhaled allergens and chemical irritants, but the limited efficacy of existing treatments aimed at modifying this response suggest that additional physiological mechanisms may be at work in the disease process. In a report published in the May 19th online Early Edition of PNAS, US researchers have now found that the ion channel, TRPA1, plays a key role in allergic asthma. cigarette smokeTRPA1 is a ‘chemosensor’ that is activated by mustard oil as well as by a number of endogenous and exogenous stimuli known to be triggers of asthmatic inflammation. The team found that, compared with wild type mice, animals that did not express TRPA1 showed fewer asthma symptoms, with reduced inflammation, airway mucus and bronchoconstriction. Although the exact role of TRPA1 in asthmatic inflammation is not yet understood, the ion channel is known to be activated by allergens such as cigarette smoke that can trigger asthma attacks. TRPA1 is found in airway nerves and the researchers believe that blocking TRPA1 may prevent infiltration of the lung by the inflammatory cells responsible for asthma symptoms such as wheezing and overproduction of mucus. HC-030031 structureIn further studies, the team went on to show that treatment with the TRPA1 antagonist, HC-030031, reduced the symptoms of allergic asthma in mice. TRPA1 antagonists have previously been shown to reduce chronic inflammatory and neuropathic pain. The discovery of a role for TRPA1 as a neuronal mediator of allergic airway inflammation could lead to new treatments for allergic asthma and Hydra Biosciences, whose scientists contributed to the study, hope to start human clinical trials with a novel TRPA1 inhibitor within 12 months.


β2-Inverse Agonists for Asthma?

lungsβ2-Adrenergic receptor agonists, which act directly on smooth muscle in the airways causing dilation and increased air flow, are standard therapy for treating bronchospasm in asthmatics. Both short- and long-acting agonists are used in the management of asthma, although there are increasing concerns that chronic use of β2-agonists is associated with loss of disease control and may increase mortality in asthmatics. A study published in the journal PNAS has now shown that β2-adrenergic receptor inverse agonists reduce symptoms in an allergen-driven mouse model of asthma.

Although acute inhibition of β2-adrenergic receptor signalling narrows the airways, long term administration of a β2-inverse agonist caused similar improvements in asthma symptoms to genetic knock-out of the receptor. The researchers also found that chronic administration of alprenolol, a β-blocker without inverse agonist properties, did not reduce the symptoms, suggesting that basal signalling by empty receptors, rather than agonist-induced signalling, causes asthma. nadolol structureWhereas chronic exposure to β2-agonists leads to receptor down-regulation and worsening of asthma control, chronic blockade of the receptors may result in up-regulation and better control. Small scale clinical trials are being carried out to assess the effect of chronic dosing with the non-selective β-blocker, nadolol, in asthmatic patients.


Childhood Asthma Linked to Common Cold

rsvThe prevalence of asthma is increasing, with up to one in four urban children now affected. Episodes may be triggered by environmental factors, exertion, emotional stress or infection. A recent study by research workers at the University of Texas Southwestern Medical Center, which is available in the Nov 15 issue of the Journal of Infectious Diseases, suggests that infection with respiratory syncytial virus (RSV) may lead to recurrent wheezing, even after the acute symptoms of infection have resolved. The study, which was carried out in mice, showed a striking correlation between the amount of virus detected in the lungs of the mice with the severity of airway hyper-reactivity. The group had previously shown that mice infected with RSV were more likely to develop chronic lung disease than uninfected mice. They also found that treatment of the infected mice with an anti-RSV antibody reduced the amount of virus in the lungs as well as the extent of hyper-reactivity and inflammation in the lungs.

Almost all children have had at least one RSV infection by the age of three, and a study is currently underway to determine whether treating children with an antibody against RSV can prevent wheezing during a one year follow-up period. The findings could lead to the development of treatments for children with recurrent wheezing caused by RSV infection.