Tag: Airway

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Therapeutic Potential of ASP3258, a Selective Phosphodiesterase 4 Inhibitor, on Chronic Eosinophilic Airway Inflammation.

Therapeutic Potential of ASP3258, a Selective Phosphodiesterase 4 Inhibitor, on Chronic Eosinophilic Airway Inflammation.

Pharmacology. 2012;90(3-4):223-32

Authors: Kobayashi M, Kubo S, Shiraki K, Iwata M, Hirano Y, Ohtsu Y, Takahashi K, Shimizu Y

Abstract
We investigated and compared the pharmacological effects of a PDE4 inhibitor ASP3258 (3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] propanoic acid), with those of roflumilast, the most clinically advanced PDE4 inhibitor known. ASP3258 inhibited human PDE4A, 4B, 4C, and 4D with respective IC(50) values of 0.036, 0.050, 0.45, and 0.035 nmol/l, all approximately 3-6 times more potent than roflumilast. ASP3258 inhibited LPS-induced TNF-? production and PHA-induced IL-5 production in human whole blood cells with respective IC(50) values of 110 and 100 nmol/l, both approximately 10 times less potent than roflumilast. Repeatedly administered ASP3258 and roflumilast both suppressed chronic airway eosinophilia induced by repeated exposure to ovalbumin in Brown Norway rats with respective ED(50) values of 0.092 and 0.17 mg/kg. We also evaluated the toxicological profiles of ASP3258. Although PDE4 inhibitors induce emesis by mimicking the pharmacological action of an ?(2)-adrenoceptor antagonist, repeated administration of ASP3258 (3 mg/kg) had no such inhibitory effect on rats anesthetized with ?(2) – adrenoceptor agonist. PDE4 inhibitors are also known to induce vascular injury in rats. Although repeatedly administered ASP3258 (3 and 10 mg/kg) significantly increased plasma fibrinogen, a biomarker for toxicity, 1 mg/kg of ASP3258 did not. These results suggest that ASP3258 is an attractive PDE4 inhibitor for treating chronic eosinophilic airway inflammation due to asthma.

PMID: 23038661 [PubMed – in process]

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Children exposed to 2 phthalates have elevated risk of asthma-related airway … – Science Codex

Children exposed to 2 phthalates have elevated risk of asthma-related airway …
Science Codex
Children exposed to diethyl phthalate (DEP) and butylbenzyl phthalate (BBzP)—phthalate chemicals commonly found in personal care and plastic products—have elevated risk of asthma-related airway inflammation, according to researchers at Columbia …
Prenatal exposure to pesticide additive linked with childhood coughMedical Xpress

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Chlamydia muridarum Lung Infection in Infants Alters Hematopoietic Cells to Promote Allergic Airway Disease in Mice.

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Chlamydia muridarum Lung Infection in Infants Alters Hematopoietic Cells to Promote Allergic Airway Disease in Mice.

PLoS One. 2012;7(8):e42588

Authors: Starkey MR, Kim RY, Beckett EL, Schilter HC, Shim D, Essilfie AT, Nguyen DH, Beagley KW, Mattes J, Mackay CR, Horvat JC, Hansbro PM

Abstract
BACKGROUND: Viral and bacterial respiratory tract infections in early-life are linked to the development of allergic airway inflammation and asthma. However, the mechanisms involved are not well understood. We have previously shown that neonatal and infant, but not adult, chlamydial lung infections in mice permanently alter inflammatory phenotype and physiology to increase the severity of allergic airway disease by increasing lung interleukin (IL)-13 expression, mucus hyper-secretion and airway hyper-responsiveness. This occurred through different mechanisms with infection at different ages. Neonatal infection suppressed inflammatory responses but enhanced systemic dendritic cell:T-cell IL-13 release and induced permanent alterations in lung structure (i.e., increased the size of alveoli). Infant infection enhanced inflammatory responses but had no effect on lung structure. Here we investigated the role of hematopoietic cells in these processes using bone marrow chimera studies.
METHODOLOGY/PRINCIPAL FINDINGS: Neonatal (<24-hours-old), infant (3-weeks-old) and adult (6-weeks-old) mice were infected with C. muridarum. Nine weeks after infection bone marrow was collected and transferred into recipient age-matched irradiated naïve mice. Allergic airway disease was induced (8 weeks after adoptive transfer) by sensitization and challenge with ovalbumin. Reconstitution of irradiated naïve mice with bone marrow from mice infected as neonates resulted in the suppression of the hallmark features of allergic airway disease including mucus hyper-secretion and airway hyper-responsiveness, which was associated with decreased IL-13 levels in the lung. In stark contrast, reconstitution with bone marrow from mice infected as infants increased the severity of allergic airway disease by increasing T helper type-2 cell cytokine release (IL-5 and IL-13), mucus hyper-secretion, airway hyper-responsiveness and IL-13 levels in the lung. Reconstitution with bone marrow from infected adult mice had no effects.
CONCLUSIONS: These results suggest that an infant chlamydial lung infection results in long lasting alterations in hematopoietic cells that increases the severity of allergic airway disease in later-life.

PMID: 22870337 [PubMed – in process]

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Therapeutical Measures to Control Airway Tolerance in Asthma and Lung Cancer.

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Therapeutical Measures to Control Airway Tolerance in Asthma and Lung Cancer.

Front Immunol. 2012;3:216

Authors: Andreev K, Graser A, Maier A, Mousset S, Finotto S

Abstract
Airway tolerance is a specialized immunological surveillance which is activated by the cells of the lung to deal with and distinguish between innocuous and pathogenic inhalants. However, this distinction does not always occur. Airway tolerance is necessary to avoid the development of allergic disorders, such as asthma, which is dominated by a pathological expansion of Th2 and Th17 cells in the airways. By contrast, tumor cells induce tolerogenic factors in their microenvironment to evade T-cell mediated anti-tumor-immune responses. This review updates current understandings on the effect of the cytokines TGF-?, IL-10, and IL-17A on the lung immune responses to antigen, and analyzes their involvement in allergic asthma and lung cancer. The aim of the review is to evaluate where therapeutic intervention may be feasible and where it might fail. The multifunctional role of these cytokines further complicates the decision on the timing and concentration for their use as therapeutical targets. In fact, TGF-? has suppressive activity in early tumorigenesis, but may become tumor-promoting in the later stages of the disease. This dual behavior is sometimes due to changes in the cellular target of TGF-?, and to the expansion of the induced (i)-Tregs. Similarly, IL-17A has been found to elicit pro- as well as anti-tumor properties. Thus, this pro-inflammatory cytokine induces the production of IL-6 which interferes with Treg development. Yet IL-17A could promote tumor growth in conjunction with IL-6-dependent activation of Stat3. Thus, understanding the mechanisms of airway tolerance could help to improve the therapy to both, allergic asthma and lung cancer. Hereby, asthma therapy aims to induce and maintain tolerance to inhaled allergens and therapy against lung cancer tries to inhibit the tolerogenic response surrounding the tumor.

PMID: 22855687 [PubMed – as supplied by publisher]

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Study identifies Olympic athletes with asthma and airway hyper-responsiveness – News-Medical.net

Study identifies Olympic athletes with asthma and airway hyper-responsiveness
News-Medical.net
Based on data from the last five Olympic games, a study by the University of Western Australia has identified those athletes with asthma and airway hyper-responsiveness. With a prevalence of around 8% they are the most common chronic conditions among …

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Humid air increases airway resistance in asthmatic patients – Zee News


Zee News

Humid air increases airway resistance in asthmatic patients
Zee News
Washington: A new study has shed light on why patients with mild asthma have such difficulty breathing during hot, humid weather. The study found that patients who inhaled an asthma drug before breathing in hot, humid air were able to prevent airway …
Why hot, humid air triggers symptoms in patients with mild asthmaScience Daily (press release)

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Airway inflammation linked with asthma-related mortality rates in older adults – News-Medical.net

Airway inflammation linked with asthma-related mortality rates in older adults
News-Medical.net
Higher mortality rates among older adult asthma patients compared to their younger counterparts may be due, at least in part, to an increase in airway inflammation, according to a study conducted by researchers in Canada, who note that their results …

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Sphingosine-1-phosphate induced airway hyperreactivity in rodents is mediated by the S1P3 receptor.

Sphingosine-1-phosphate induced airway hyperreactivity in rodents is mediated by the S1P3 receptor.

J Pharmacol Exp Ther. 2012 May 8;

Authors: Trifilieff A, Fozard JR

Abstract
There is a need to better understand the mechanism of airway hyperreactivity, a key feature of asthma. Evidence suggests that sphingosine-1-phosphate (S1P) could be a major player in this phenomenon. The purpose of this work was to define the S1P receptor responsible for this phenomenon. We have studied, in the rat, the effect of two S1P synthetic receptor ligands, FTY720 (which in its phosphorylated form is a potent agonist at each S1P receptor except S1P2) and AUY954 (a highly selective S1P1 agonist) on lung function in vivo. This was complemented by in vitro studies using isolated trachea from the rat, the S1P3 receptor-deficient mouse and its wild type counterpart. Following oral administration, FTY720 induced a generalized airway hyperreactivity to a range of contractile stimuli. This was observed as early as one hour post dosing, lasted for at least 24 hours and was not subject to desensitization. In both the rat and wild type mouse isolated trachea, pre-incubation with the active phosphorylated metabolite of FTY720, induced hyperresponsiveness to 5-HT. This effect was not seen in the isolated tracheas from S1P3 receptor-deficient mice. AUY954, did not mimic the effect of FTY720 either in vivo or in vitro. Our data are consistent with activation of the S1P pathway inducing a generalized airway hyperreactivity in rats and mice that is mediated by the S1P3 receptor. S1P3 receptor antagonists might prove useful as new therapeutic strategies aimed at blocking the airway hyperreactivity observed in asthma.

PMID: 22570366 [PubMed – as supplied by publisher]

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Bacteria in sputum of stable severe asthma and increased airway wall thickness – 7thSpace Interactive (press release)

Bacteria in sputum of stable severe asthma and increased airway wall thickness
7thSpace Interactive (press release)
Patients with chronic asthma have thicker intrapulmonary airways measured on high resolution computed tomography (HRCT). We determined whether the presence of lower airway bacteria was associated with increased airway wall thickness.

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