Novel Inhibitory Effect of a Lysophosphatidic Acid 2 Agonist on Allergen-Driven Airway Inflammation

Knowlden, Sara A.; Hillman, Sara; Chapman, Timothy J.; Patil, Renukadevi; Miller, Duane D.; Tigyi, Gábor; Georas, Steve N.

doi:10.1165/rcmb.2015-0124oc

Cited by 26 publications

(22 citation statements)

References 61 publications

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“…The fact that LPA, produced by ATX, induces plasma exudation and accelerates development of human mast cells supports this hypothesis. 39) ATX was shown to play a role in eosinophil trafficking into inflamed skin tissues 16) and lymphocyte homing in allergic airway inflammation and asthma. 40) Thus, GEF-mediated inhibitory effects on the serum ATX activity and levels could be further linked to suppressive effects on AD-induced skin inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…39) ATX was shown to play a role in eosinophil trafficking into inflamed skin tissues 16) and lymphocyte homing in allergic airway inflammation and asthma. 40) Thus, GEF-mediated inhibitory effects on the serum ATX activity and levels could be further linked to suppressive effects on AD-induced skin inflammation. Finally, the GEF-mediated dual actions on the immune system and serum ATX activity and levels might contribute to its anti-AD effects in animals.…”

Section: Discussionmentioning

confidence: 99%

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Effects of Gintonin-Enriched Fraction in an Atopic Dermatitis Animal Model: Involvement of Autotaxin Regulation

Lee

Kim

Jang

et al. 2017

Biological & Pharmaceutical Bulletin

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Ginseng extract has been used for prevention of atopic dermatitis (AD) in experimental animal models. However, little is known about its active ingredients and the molecular mechanisms underlying its anti-AD effects. Recently, we isolated a unique lysophosphatidic acid (LPA) receptor ligand, gintonin, from ginseng. Gintonin, the glycolipoprotein fraction of ginseng, contains LPAs, mainly LPA C with other minor lysophospholipid components. A line of evidence showed that serum autotaxin (ATX) activity and level are significantly elevated in human AD patients compared to those in normal controls, which indicates that ATX may be involved in human AD. In a previous study, we demonstrated that gintonin exerted anti-inflammatory effects via inhibition of microglial activation and proinflammatory cytokine production by immune cells and that it strongly inhibited ATX activity. In this study, we investigated whether oral administration of the gintonin-enriched fraction (GEF) could ameliorate the symptoms of 2,4-dinitrofluorobenzene (DNFB)-induced AD in NC/Nga mice. We found that oral administration of GEF to DNFB-induced AD mice for 2 weeks reduced ear swelling and AD skin index. In addition, oral administration of GEF reduced the serum levels of immunoglobulin E, histamine, interleukin-4, and interferon-γ. Histological examination showed that oral administration of GEF attenuated skin inflammation and significantly reduced eosinophil and mast cell infiltration into the skin. Moreover, oral administration of GEF not only decreased serum ATX level but also reduced serum ATX activity. The present study shows that the anti-AD effects of ginseng might be attributed to GEF-induced anti-inflammatory activity and ATX regulation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effects of Gintonin-Enriched Fraction in an Atopic Dermatitis Animal Model: Involvement of Autotaxin Regulation

Lee

Kim

Jang

et al. 2017

Biological & Pharmaceutical Bulletin

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“…When LPAR2 agonists were used, the inflammation of the lungs and airways of mice caused by allergen sensitization and challenge by HDM (dermatophagoides pteronyssinus) was significantly reduced. This may be related to reduced chemokine production and inhibition of cell migration [151].…”

Section: Lpar and Asthmamentioning

confidence: 99%

Lysophosphatidic Acid Receptors: Biochemical and Clinical Implications in Different Diseases

Xiang¹,

Lü²,

Shao³

et al. 2020

J. Cancer

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Lysophosphatidic acid (LPA, 1-acyl-2-hemolytic-sn-glycerol-3-phosphate) extracted from membrane phospholipid is a kind of simple bioactive glycophospholipid, which has many biological functions such as stimulating cell multiplication, cytoskeleton recombination, cell survival, drug-fast, synthesis of DNA and ion transport. Current studies have shown that six G-coupled protein receptors (LPAR1-6) can be activated by LPA. They stimulate a variety of signal transduction pathways through heterotrimeric G-proteins (such as Gα12/13, Gαq/11, Gαi/o and GαS). LPA and its receptors play vital roles in cancers, nervous system diseases, cardiovascular diseases, liver diseases, metabolic diseases, etc. In this article, we discussed the structure of LPA receptors and elucidated their functions in various diseases, in order to better understand them and point out new therapeutic schemes for them.

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“…A role for ATX in allergic asthmatic airway inflammation was further established, as ATX-overexpressing transgenic mice exhibited a more robust response with increased eosinophilic airway inflammation and Th2 cytokine responses, whereas blocking ATX activity with an inhibitor, GWJ-23 and knockdown of LPA 2 receptor in mice attenuated allergic airway inflammation and Th2 cytokine responses [8], confirming a role for the ATX/LPA/LPA receptor pathway in the pathogenesis of asthma. However, in a recent study, pharmacological activation of LPA 2 with a small molecule LPA 2 agonist (2-[4-(1,3-Dioxo-1H,3H-benzoisoquinolin-2-yl) butylsulfamoyl]benzoic acid (DBIBB) attenuated Th2-driven allergic airway inflammation in a mouse model of asthma [52]. The discrepancy between genetic deletion of LPA 2 and LPA 2 agonist in affecting allergen-driven airway inflammation is unclear, and the effect of the LPA 2 agonist on the expression of other LPA receptors and LPA metabolism in vivo needs to be established.…”

Section: Autotaxin Expression In Bal Fluid Of Asthma Subjects During mentioning

confidence: 99%

Polyunsaturated Lysophosphatidic Acid as a Potential Asthma Biomarker

et al. 2016

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Lysophosphatidic acid (LPA), a lipid mediator in biological fluids and tissues, is generated mainly by autotaxin that hydrolyzes lysophosphatidylcholine to LPA and choline. Total LPA levels are increased in bronchoalveolar lavage fluid from asthmatic lung, and are strongly induced following subsegmental bronchoprovocation with allergen in subjects with allergic asthma. Polyunsaturated molecular species of LPA (C22:5 and C22:6) are selectively synthesized in the airways of asthma subjects following allergen challenge and in mouse models of allergic airway inflammation, having been identified and quantified by LC/MS/MS lipidomics. This review discusses current knowledge of LPA production in asthmatic lung and the potential utility of polyunsaturated LPA molecular species as novel biomarkers in bronchoalveolar lavage fluid and exhaled breath condensate of asthma subjects.

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Novel Inhibitory Effect of a Lysophosphatidic Acid 2 Agonist on Allergen-Driven Airway Inflammation

Cited by 26 publications

References 61 publications

Effects of Gintonin-Enriched Fraction in an Atopic Dermatitis Animal Model: Involvement of Autotaxin Regulation

Effects of Gintonin-Enriched Fraction in an Atopic Dermatitis Animal Model: Involvement of Autotaxin Regulation

Lysophosphatidic Acid Receptors: Biochemical and Clinical Implications in Different Diseases

Polyunsaturated Lysophosphatidic Acid as a Potential Asthma Biomarker

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