BAY u3405, a Thromboxane A2 Antagonist, Reduces Bronchial Hyperresponsiveness in Asthmatics

Aizawa, Hisamichi; Shigyo, Mutsumi; Nogami, Hirofumi; Hirose, Takahito; Hara, Nobuyuki

doi:10.1378/chest.109.2.338

Cited by 58 publications

(27 citation statements)

References 25 publications

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“…They found that the H1-receptor antagonist triprolidine was ineffective, and CysLT-or TP-receptor blockade was effective only in some cases. These findings are in line with no proven and documented benefit of antihistamines in asthma [48], and with the clinical observations of CysLT1-and TP-receptor antagonists being effective only in subsets of patients [46][47][48][49][50][51]. Notably, however, simultaneous blockade of CysLT-and TPreceptors provided nearly complete protection from antigeninduced airway contraction in PCLS from all individuals.…”

Section: Mediators Of the Early Allergic Responsesupporting

confidence: 71%

The early allergic response in small airways of human precision-cut lung slices

Wohlsen

Martin²,

Vollmer³

et al. 2003

Eur Respir J

122

125

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To study the role of small airways in the early allergic response (EAR), the method of human precision-cut lung slices (PCLS) was developed and used to examine the bronchoconstriction elicited by passive sensitisation and allergen provocation.Viable human PCLS of 250-mm thickness containing airways v1.5 mm in outer diameter were prepared from lung lobes obtained from lung resection and taken into culture. According to the low release of lactate dehydrogenase and the constant ciliary beat frequency, human PCLS were viable for at least 3 days.Following overnight passive sensitisation with serum from allergic individuals, administration of grass-pollen extract or activating immunoglobulin E antibody resulted in immediate airway contraction that was quantified by videomicroscopy. The extent of the EAR increased with decreasing airway size (outer airway diameter), with the strongest response occurring in the terminal bronchioles.Histamine receptor antagonism was ineffective, and leukotriene or thromboxane receptor antagonism attenuated the early allergic response only in some cases. However, simultaneous blockade of leukotriene and thromboxane receptors almost completely prevented the early allergic response in the precision-cut lung slices from all individuals, suggesting such a dual treatment as a potential future asthma therapy.

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Section: Mediators Of the Early Allergic Responsesupporting

confidence: 71%

The early allergic response in small airways of human precision-cut lung slices

Wohlsen

Martin²,

Vollmer³

et al. 2003

Eur Respir J

122

125

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“…Moreover, the TXA 2 antagonist BAYu0345 reduced airway hyper-responsiveness in human asthmatic subjects (52). In another study, AA-2414, a TXA 2 antagonist, reduced the infiltration of eosinophil and T lymphocytes into the lungs.…”

Section: Discussionmentioning

confidence: 92%

Pulmonary Surfactant Phosphatidylglycerol Inhibits Mycoplasma pneumoniae-stimulated Eicosanoid Production from Human and Mouse Macrophages

Kandasamy¹,

Zarini

Chan³

et al. 2011

Journal of Biological Chemistry

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Mycoplasma pneumoniae is a human pathogen causing respiratory infections that are also associated with serious exacerbations of chronic lung diseases. Membranes and lipoproteins from M. pneumoniae induced a 4-fold increase in arachidonic acid (AA) release from RAW264.7 and a 2-fold increase in AA release from primary human alveolar macrophages. The bacterial lipoprotein mimic and TLR2/1 agonist Pam3Cys and the TLR2/6 agonist MALP-2 produced effects similar to those elicited by M. pneumoniae in macrophages by inducing the phosphorylation of p38 MAPK and p44/42 ERK1/2 MAP kinases and cyclooxygenase-2 (COX-2) expression. M. pneumoniae induced the generation of prostaglandins PGD 2 and PGE 2 from RAW264.7 cells and thromboxane B 2 (TXB 2 ) from human alveolar macrophages. Anti-TLR2 antibody completely abolished M. pneumoniae-induced AA release and TNF␣ secretion from RAW264.7 cells and human alveolar macrophages. Disruption of the phosphorylation of p44/ 42 ERK1/2 or inactivation of cytosolic phospholipase A 2 ␣ (cPLA 2 ␣) completely inhibited M. pneumoniae-induced AA release from macrophages. The minor pulmonary surfactant phospholipid, palmitoyl-oleoyl-phosphatidylglycerol (POPG), antagonized the proinflammatory actions of M. pneumoniae, Pam3Cys, and MALP-2 by reducing the production of AA metabolites from macrophages. The effect of POPG was specific, insofar as saturated PG, and saturated and unsaturated phosphatidylcholines did not have significant effect on M. pneumoniae-induced AA release. Collectively, these data demonstrate that M. pneumoniae stimulates the production of eicosanoids from macrophages through TLR2, and POPG suppresses this pathogen-induced response.

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“…The role of TBXA2 in asthma can be evident through its induction of bronchoconstriction and AHR [11][12][13] and its receptor antagonist can be used for asthma management [15][16][17]. However, until now there has been no published data to demonstrate any association with AIA pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Association of thromboxane A2 receptor gene polymorphism with the phenotype of acetyl salicylic acid‐intolerant asthma

Kim

Choi

Park

et al. 2005

Clin Experimental Allergy

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SummaryBackground and objective The thromboxane A2 receptor (TBXA2R) is a receptor for a potent bronchoconstrictor, TBXA2 which is known to be related to bronchial asthma and myocardial infarction. TBXA2R antagonist and TBX synthase inhibitors have been found to be effective in the management of asthmatic patients. This study was aimed to evaluate whether genetic variants of TBXA2R may be related with development of acetyl salicylic acid (ASA)-intolerant asthma (AIA). Methods TBXA2R gene polymorphisms (TBXA2R1795T4C, TBXA2R1924T4C) were determined using a single-base extension method in 93 AIA patients compared with 172 patients with ASA-tolerant asthma (ATA) and 118 normal controls (NCs) recruited from the Korean population. HLA DPB1*0301 genotype was performed using a direct sequencing method.Results The rare C allele frequency of TBXA2R1795T4C was significantly higher in AIA than in ATA (P 5 0.03) and the TBXA2R1795T4C polymorphism was also associated with extent of percent fall in forced expiratory volume in 1 s (FEV 1 ) after the inhalation of lysine-acetyl salicylic acid in AIA patients (P 5 0.009); AIA patients homozygous for the 1795 C allele had a greater percent fall of FEV 1 compared with individuals with TBXA2R1795 CT or TT genotypes. The frequency of patients carrying both the TBXA2R1795T4C rare allele and HLA DPB1*0301 was significantly higher in AIA patients (29.4%) than in ATA patients (7.3%) (P 5 0.008, odds ratio 5 5.3). Conclusion These results suggest that the polymorphism of TBXA2R1795T4C may increase bronchoconstrictive response to ASA, which could contribute to the development of the AIA phenotype.

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BAY u3405, a Thromboxane A2 Antagonist, Reduces Bronchial Hyperresponsiveness in Asthmatics

Cited by 58 publications

References 25 publications

The early allergic response in small airways of human precision-cut lung slices

The early allergic response in small airways of human precision-cut lung slices

Pulmonary Surfactant Phosphatidylglycerol Inhibits Mycoplasma pneumoniae-stimulated Eicosanoid Production from Human and Mouse Macrophages

Association of thromboxane A2 receptor gene polymorphism with the phenotype of acetyl salicylic acid‐intolerant asthma

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