Important research - mouse model of Samter's

[Guest guest]

A team of japanese researchers has published a really good piece of research this week. They have engineered a mouse model of Samter's, namely a breed of mice overexpressing Leukotriene-C4-synthase, which is one of the major suspects in the mechanism of Samter's.It turned out that these mice specifically engineered to overproduce LTC4 :- overreacted to the NSAID sulpyrin,- demonstrated threshold effects,- displayed the same kind of immune biais as that found in Samter's patients (ie a Th2-biais),- were helped by a leukotriene inhibitor (Pranlukast),- overreacted to allergens even in the absence of NSAIDS,which is not a bad overall approximation of mainstream Samter's.Of course, this is not the only conceivable model for Samter's (for instance, one could breed mice designed to underproduce prostaglandin E2, or overproduce leukotriene receptors, and so on), and it does not help answer why there is an overproduction of LTC4-synthase in the first place, but it does represent in my opinion a major milestone in the modeling of AERDs.The authors' conclusion may overlook causes other than LTC4S overproduction, or causes that combine with LTC4S production, but they feel sufficiently comfortable with their model to state their opinion pretty clearly :"an over-expression of LTC4S, perhaps driven by a genetic anomaly and exacerbated by positive feedback from Th2 cytokines, is the primary aetiological factor in human AIA."(AIA=Aspirin-Induced Asthma)This is pretty positive for us, at least on the long term because : - it reinforces current concepts on the causes of AERDs,- it provides a mouse model on which to base future experiments,- it paves the way for better, perhaps more personalized models and, ultimately, treatments.------------------Clin Exp Allergy. 2011 Mar 24. doi: 10.1111/j.1365-2222.2011.03720.x. [Epub ahead of print]Over-expression of the LTC(4) synthase gene in mice reproduces human aspirin-induced asthma.Hirata H, Arima M, Fukushima Y, Honda K, Sugiyama K, Tokuhisa T, Fukuda T.Department of Pulmonary Medicine and Clinical Immunology, Dokkyo University School of Medicine, Tochigi, Japan Department of Developmental Genetics, Chiba University Graduate School of Medicine, Chiba, Japan.AbstractBackground The pathogenesis of aspirin-induced asthma (AIA) is presumed to involve the aspirin/non-steroidal anti-inflammatory drug (NSAID)-induced abnormal metabolism of arachidonic acid, resulting in an increase in 5-lipoxygenase (5-LO) metabolites, particularly leukotriene C(4) (LTC(4) ). However, the role of LTC(4) in the development of AIA has yet to be conclusively demonstrated. Objective The aim of this study was to evaluate the contribution of the lipid product LTC(4) secreted by the 5-LO pathway to the pathogenesis of AIA. Methods To evaluate antigen-induced airway inflammation, the concentrations of T-helper type 2 cytokine in bronchoalveolar lavage fluid (BALF) obtained from LTC(4) synthase-transgenic (Tg) and wild-type (WT) mice after challenge with ovalbumin were measured. Subsequently, the ex vivo and in vivo effects of the NSAID sulpyrine were investigated in these Tg and WT mice by measuring the secretion of LTC(4) from sulpyrine-treated BAL cells and the levels of LTC(4) in BALF following challenge with sulpyrine. Finally, the sulpyrine-induced airway response by the administration of pranlukast, an antagonist of the cysteinyl (cs)-LT1 receptor, was analysed. Results The concentrations of IL-4, -5, and -13 in BALF from Tg mice were significantly higher than those in WT mice. In addition, sulpyrine augmented the secretion of LTC(4) in BALF and by BAL cells in Tg mice, but not in WT mice. Additionally, the increased airway resistance induced by sulpyrine could be reduced by treatment with pranlukast. Furthermore, the secretion of LTC(4) from mast cells, eosinophils, and macrophages was increased in the allergen-stimulated LTC(4) synthase gene Tg mice, even in the absence of sulpyrine, as well as in BAL cells after sulpyrine. Conclusion and clinical relevance The over-expression of the LTC(4) synthase in a mouse asthma model also replicates the key features of AIA. And our study supports that cys-LTs play a major role in the pathogenesis of AIA in patients with chronic asthma.

[Guest guest]

Thanks Asfy, this is pretty exciting stuff! Oh for a cure soon!!

I also like your two other articles on Vit D and gut flora - al very useful,

Besy wishes

Becky

From: asfy <asfyso@...>samters Sent: Sat, 26 March, 2011 17:03:06Subject: Important research - mouse model of Samter's

A team of japanese researchers has published a really good piece of research this week. They have engineered a mouse model of Samter's, namely a breed of mice overexpressing Leukotriene-C4-synthase, which is one of the major suspects in the mechanism of Samter's.

It turned out that these mice specifically engineered to overproduce LTC4 :

- overreacted to the NSAID sulpyrin,

- demonstrated threshold effects,

- displayed the same kind of immune biais as that found in Samter's patients (ie a Th2-biais),

- were helped by a leukotriene inhibitor (Pranlukast),

- overreacted to allergens even in the absence of NSAIDS,

which is not a bad overall approximation of mainstream Samter's.

Of course, this is not the only conceivable model for Samter's (for instance, one could breed mice designed to underproduce prostaglandin E2, or overproduce leukotriene receptors, and so on), and it does not help answer why there is an overproduction of LTC4-synthase in the first place, but it does represent in my opinion a major milestone in the modeling of AERDs.

The authors' conclusion may overlook causes other than LTC4S overproduction, or causes that combine with LTC4S production, but they feel sufficiently comfortable with their model to state their opinion pretty clearly :

"an over-expression of LTC4S, perhaps driven by a genetic anomaly and exacerbated by positive feedback from Th2 cytokines, is the primary aetiological factor in human AIA."

(AIA=Aspirin-Induced Asthma)

This is pretty positive for us, at least on the long term because :

- it reinforces current concepts on the causes of AERDs,

- it provides a mouse model on which to base future experiments,

- it paves the way for better, perhaps more personalized models and, ultimately, treatments.

------------------

Clin Exp Allergy. 2011 Mar 24. doi: 10.1111/j.1365-2222.2011.03720.x. [Epub ahead of print]

Over-expression of the LTC(4) synthase gene in mice reproduces human aspirin-induced asthma.

Hirata H, Arima M, Fukushima Y, Honda K, Sugiyama K, Tokuhisa T, Fukuda T.

Department of Pulmonary Medicine and Clinical Immunology, Dokkyo University School of Medicine, Tochigi, Japan Department of Developmental Genetics, Chiba University Graduate School of Medicine, Chiba, Japan.

Abstract

Background The pathogenesis of aspirin-induced asthma (AIA) is presumed to involve the aspirin/non-steroidal anti-inflammatory drug (NSAID)-induced abnormal metabolism of arachidonic acid, resulting in an increase in 5-lipoxygenase (5-LO) metabolites, particularly leukotriene C(4) (LTC(4) ). However, the role of LTC(4) in the development of AIA has yet to be conclusively demonstrated.

Objective The aim of this study was to evaluate the contribution of the lipid product LTC(4) secreted by the 5-LO pathway to the pathogenesis of AIA.

Methods To evaluate antigen-induced airway inflammation, the concentrations of T-helper type 2 cytokine in bronchoalveolar lavage fluid (BALF) obtained from LTC(4) synthase-transgenic (Tg) and wild-type (WT) mice after challenge with ovalbumin were measured. Subsequently, the ex vivo and in vivo effects of the NSAID sulpyrine were investigated in these Tg and WT mice by measuring the secretion of LTC(4) from sulpyrine-treated BAL cells and the levels of LTC(4) in BALF following challenge with sulpyrine. Finally, the sulpyrine-induced airway response by the administration of pranlukast, an antagonist of the cysteinyl (cs)-LT1 receptor, was analysed.

Results The concentrations of IL-4, -5, and -13 in BALF from Tg mice were significantly higher than those in WT mice. In addition, sulpyrine augmented the secretion of LTC(4) in BALF and by BAL cells in Tg mice, but not in WT mice. Additionally, the increased airway resistance induced by sulpyrine could be reduced by treatment with pranlukast. Furthermore, the secretion of LTC(4) from mast cells, eosinophils, and macrophages was increased in the allergen-stimulated LTC(4) synthase gene Tg mice, even in the absence of sulpyrine, as well as in BAL cells after sulpyrine.

Conclusion and clinical relevance The over-expression of the LTC(4) synthase in a mouse asthma model also replicates the key features of AIA. And our study supports that cys-LTs play a major role in the pathogenesis of AIA in patients with chronic asthma.