Recent research and developmental strategy of anti-asthma drugs

Nagai, Hiroichi

doi:10.1016/j.pharmthera.2011.09.001

Cited by 26 publications

(15 citation statements)

References 127 publications

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“…The pathophysiology of asthma involves various cellular components and many inflammatory protein mediators, including chemokines, cytokines, growth factors, and various lipid mediators (24). Bioactive lipid mediators such as cysteinyl leukotrienes and prostaglandins are believed to play an important role in asthma pathophysiology, and interdiction with leukotriene receptor antagonists is an effective and widely used treatment that alleviates symptoms in some patients with asthma (25). Recent evidence suggests that prostaglandin D2 may play an important role in orchestrating interaction between mast cells, lymphocytes, and eosinophils (26), and this finding is currently being translated into antiasthmatic therapeutics with some initial evidence of efficacy (27).…”

Section: Discussionmentioning

confidence: 99%

Autotaxin Production of Lysophosphatidic Acid Mediates Allergic Asthmatic Inflammation

Park¹,

Lee

Berdyshev

et al. 2013

Am J Respir Crit Care Med

116

167

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Rationale: Bioactive lipid mediators, derived from membrane lipid precursors, are released into the airway and airspace where they bind high-affinity cognate receptors and may mediate asthma pathogenesis. Lysophosphatidic acid (LPA), a bioactive lipid mediator generated by the enzymatic activity of extracellular autotaxin (ATX), binds LPA receptors, resulting in an array of biological actions on cell proliferation, migration, survival, differentiation, and motility, and therefore could mediate asthma pathogenesis.Objectives: To define a role for the ATX-LPA pathway in human asthma pathogenesis and a murine model of allergic lung inflammation. Methods: We investigated the profiles of LPA molecular species and the level of ATX exoenzyme in bronchoalveolar lavage fluids of human patients with asthma subjected to subsegmental bronchoprovocation with allergen. We interrogated the role of the ATX-LPA pathway in allergic lung inflammation using a murine allergic asthma model in ATX-LPA pathway-specific genetically modified mice. Measurements and Main Results: Subsegmental bronchoprovocation with allergen in patients with mild asthma resulted in a remarkable increase in bronchoalveolar lavage fluid levels of LPA enriched in polyunsaturated 22:5 and 22:6 fatty acids in association with increased concentrations of ATX protein. Using a triple-allergen mouse asthma model, we showed that ATX-overexpressing transgenic mice had a more severe asthmatic phenotype, whereas blocking ATX activity and knockdown of the LPA 2 receptor in mice produced a marked attenuation of Th2 cytokines and allergic lung inflammation. Conclusions: The ATX-LPA pathway plays a critical role in the pathogenesis of asthma. These preclinical data indicate that targeting the ATX-LPA pathway could be an effective antiasthma treatment strategy.Keywords: asthma; lysophosphatidic acid; autotaxin; allergic airway inflammation supplied the ATX inhibitor, GWJ-23. V.A., E.K., and I.N. were involved in discussions related to animal dosage. A.J.M. and S.S.S. provided breeding pairs of ATX-Tg and ATX 1/2 mice. S.J.A. managed the inflammatory cell purification core lab for the SBP-AG protocol, designed experiments, interpreted data, coordinated regular scientific research meetings for the project, and edited the manuscript. V.N. conceptualized the study, designed mouse experiments, interpreted data, provided genetically modified mice, and wrote part of and edited the manuscript. J.W.C. obtained the SBP-AG IRB and IND approval, supervised mouse experiments and performance of the human SBP-AG protocol, designed experiments, interpreted and analyzed data, and edited the manuscript. All authors contributed to data discussion and review of the manuscript.Correspondence and requests for reprints should be addressed to John W. What This Study Adds to the FieldThe enzyme autotaxin (ATX) and two of its LPA products, LPA 22:5 and LPA 22:6, are markedly and selectively increased in the bronchoalveolar lavage fluid of human patients with asthma in response to airway allergen ch...

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Section: Discussionmentioning

confidence: 99%

Autotaxin Production of Lysophosphatidic Acid Mediates Allergic Asthmatic Inflammation

Park¹,

Lee

Berdyshev

et al. 2013

Am J Respir Crit Care Med

116

167

View full text Add to dashboard Cite

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“…Asthma is a major cause of chronic morbidity and mortality throughout the world and its prevalence increased considerably over the past 20 years, especially in children (Stevenson and Birrell, 2011;Nagai, 2012;Ezeamuzie et al, 2014). Asthma is a condition characterized by persistent or recurrent airway inflammation, airway hyperresponsiveness (AHR), chronic airway remodeling and various degrees of reversible airflow limitation (Bousquet et al, 2000;Nials and Uddin, 2008;Blume and Davies, 2013).…”

Section: Introductionmentioning

confidence: 99%

Activation of angiotensin-converting enzyme 2 (ACE2) attenuates allergic airway inflammation in rat asthma model

Dhawale

Amara

Karpe

et al. 2016

Toxicology and Applied Pharmacology

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“…The previous results suggest the possibility of immunomodulating agents for clinical application as a remedy for IBD. During our investigation of antiallergic drugs, vitamin U derivative, suplatast was found to have potent immunomodulating and anti-inflammatory activity in Th2 polarized immune processes [57][58][59][60]. Table 1 shows a summary of the basic research on the pharmacological activity of suplatast as reported [60].…”

Section: Possible Pharmacological Acting Points Of Suplatast On the Pmentioning

confidence: 99%

Accumulation of Mast Cells in the Lesions and Effects of Antiallergic Drugs on the Patients with Inflammatory Bowel Disease

Kurosawa

Nagai

2013

Ulcers

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The pathomechanism of inflammatory bowel disease (IBD) has not yet been fully demonstrated. However, it is well known that mast cells are present in the gastrointestinal tract, suggesting that mast cells may take part in it. So, we investigated the number of mast cells in IBD, such as ulcerative colitis (UC) and eosinophilic colitis, and showed that the number of mast cells was increased in the inflammatory lesions. We also presented a case of UC which was treated successfully with an antiallergic drug, tranilast. Furthermore, possible new approaches to treating the disease with immunomodulators including suplatast are introduced. However, our investigations were performed with a limited number of patients with IBD, and additional further studies are required to confirm the findings.

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Recent research and developmental strategy of anti-asthma drugs

Cited by 26 publications

References 127 publications

Autotaxin Production of Lysophosphatidic Acid Mediates Allergic Asthmatic Inflammation

Autotaxin Production of Lysophosphatidic Acid Mediates Allergic Asthmatic Inflammation

Activation of angiotensin-converting enzyme 2 (ACE2) attenuates allergic airway inflammation in rat asthma model

Accumulation of Mast Cells in the Lesions and Effects of Antiallergic Drugs on the Patients with Inflammatory Bowel Disease

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