Effects of leukotriene B 4 receptor antagonist, LY293111Na, on antigen-induced bronchial hyperresponsiveness and leukocyte infiltration in sensitized guinea pigs

Asanuma, Fujio; Kuwabara, Kenji; Arimura, Akinori; Furue, Yoko; Fleisch, Jerome H.; Hori, Yozo

doi:10.1007/s000110050737

Cited by 19 publications

(13 citation statements)

References 30 publications

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“…Pharmacological blockade of the LTB4 receptor confirmed these results as treatment with the LTB4 receptor antagonist prevented the induction of increased airway reactivity following T EFF transfer into passively sensitized and OVA-exposed CD8 Ϫ/Ϫ mice as well as in WT mice. Other antagonists of the LTB4 receptor have also been reported to suppress AHR in rodent models (49,50), consistent with the present data.…”

Section: Discussionsupporting

confidence: 92%

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The Leukotriene B4 Receptor (BLT1) Is Required for Effector CD8+ T Cell-Mediated, Mast Cell-Dependent Airway Hyperresponsiveness

Taube

Miyahara

Ott

et al. 2006

The Journal of Immunology

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Studies in both humans and rodents have suggested that CD8+ T cells contribute to the development of airway hyperresponsiveness (AHR) and that leukotriene B4 (LTB4) is involved in the chemotaxis of effector CD8+ T cells (TEFF) to the lung by virtue of their expression of BLT1, the receptor for LTB4. In the present study, we used a mast cell-CD8-dependent model of AHR to further define the role of BLT1 in CD8+ T cell-mediated AHR. C57BL/6+/+ and CD8-deficient (CD8−/−) mice were passively sensitized with anti-OVA IgE and exposed to OVA via the airways. Following passive sensitization and allergen exposure, C57BL/6+/+ mice developed altered airway function, whereas passively sensitized and allergen-exposed CD8−/− mice failed to do so. CD8−/− mice reconstituted with CD8+ TEFF developed AHR in response to challenge. In contrast, CD8−/− mice reconstituted with BLT1-deficient effector CD8+ T cells did not develop AHR. The induction of increased airway responsiveness following transfer of CD8+ TEFF or in wild-type mice could be blocked by administration of an LTB4 receptor antagonist confirming the role of BLT1 in CD8+ T cell-mediated AHR. Together, these data define the important role for mast cells and the LTB4-BLT1 pathway in the development of CD8+ T cell-mediated allergic responses in the lung.

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Section: Discussionsupporting

confidence: 92%

“…All passively sensitized and challenged WT mice (independent of the strain) showed an increased response to EFS (defined as a decrease in ES 50 ) when compared with the passively sensitized but saline-challenged or nonsensitized but allergen-challenged animals (Figs. 1, A-C).…”

Section: Development Of Increased Airway Reactivity Following Passivementioning

confidence: 99%

The Leukotriene B4 Receptor (BLT1) Is Required for Effector CD8+ T Cell-Mediated, Mast Cell-Dependent Airway Hyperresponsiveness

Taube

Miyahara

Ott

et al. 2006

The Journal of Immunology

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“…High-affinity LTB 4 receptors are on peripheral blood leukocytes as well as in the spleen and thymus, while low-affinity LTB 4 receptors are present on granulocytes and in the spleen [36]. The potent role of LTB 4 receptors in many different inflammatory diseases has led to the development of LTB 4 receptor antagonists as potential anti-inflammatory therapeutic treatments for pulmonary [37] and cutaneous [38][39][40] inflammatory states as well as immunosuppressive agents [41]. Such studies demonstrate that the LTB 4 receptor could be a potential target for therapeutic treatments for SMinduced skin injury.…”

Section: Discussionmentioning

confidence: 99%

Time- and dose-dependent analysis of gene expression using microarrays in sulfur mustard-exposed mice

Sabourin

Rogers

Choi

et al. 2005

J. Biochem. Mol. Toxicol.

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The chemical warfare agent sulfur mustard (SM) produces blister formation with a severe inflammatory reaction in skin of exposed individuals. The development of efficacious countermeasures against SM vesication requires an understanding of the cellular and molecular mechanism of SM-induced tissue injury. This study examined SM-induced alterations in gene expression using Atlas Mouse 5K DNA microarrays (5002 genes) to identify transcriptional events associated with SM skin injury. Mice (N=3) were exposed topically to SM (0.04, 0.08, and 0.16 mg; 48.8, 97.5, and 195 mM) on the inner surface of the right ear and skin tissues were harvested at 1.5, 3, 6, and 12 h. Genes were selected based on the three mice in the same dose group demonstrating a > or =2-fold increase or decrease in gene expression for the SM-exposed tissue when compared to the dichloromethane vehicle control ear at all three doses and four time points. At the 0.04 mg SM dose, the genes observed were primarily involved in inflammation, apoptosis, and cell cycle regulation. Exposure to 0.08 mg SM increased the expression of genes related to inflammation and cell cycle regulation. Exposure to 0.16 mg SM led to a total of six genes that were changed at all observed time periods; however, these genes do not appear to be directly influential in biological mechanisms such as inflammation, apoptosis, and cell cycle regulation as was observed at the lower SM doses of 0.04 and 0.08 mg. These functional categories have been observed in previous studies utilizing both in vivo and in vitro model systems of SM-induced dermal injury, suggesting that molecular mechanisms associated with inflammation, apoptosis, and cell cycle regulation may be appropriate targets for developing prophylactic/therapeutic treatments for SM skin injury.

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“…Other reports, though, have shown significant contraction of lung parenchymal strips by nanomolar concentrations of LTB 4 (24). Some studies have concluded that LTB 4 antagonists have minor effects on leukocyte accumulation but decrease bronchial hyperreactivity (25,26), another showed decreased leukocyte recruitment but no effect on pulmonary function (27), and another found that antigen-induced bronchoconstriction was decreased but eosinophil accumulation and acute bronchial hyperreactivity were unaffected (28).…”

Section: Discussionmentioning

confidence: 99%

Alternative splicing of the G protein-coupled receptor superfamily in human airway smooth muscle diversifies the complement of receptors

Einstein¹,

Jordan²,

Zhou³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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G protein-coupled receptors (GPCRs) are the largest signaling family in the genome, serve an expansive array of functions, and are targets for Ϸ50% of current therapeutics. In many tissues, such as airway smooth muscle (ASM), complex, unexpected, or paradoxical responses to agonists/antagonists occur without known mechanisms. We hypothesized that ASM express many more GPCRs than predicted, and that these undergo substantial alternative splicing, creating a highly diversified receptor milieu. Transcript arrays were designed detecting 434 GPCRs and their predicted splice variants. In this cell type, 353 GPCRs were detected (including 111 orphans), with expression levels varying by Ϸ900-fold. Receptors used for treating airway disease were expressed lower than others with similar signaling properties, indicating potentially more effective targets. A disproportionate number of Class-A peptide-group receptors, and those coupling to G q/11 or Gs (vs. Gi), was found. Importantly, 192 GPCRs had, on average, five different expressed receptor isoforms because of splicing events, including alternative splice donors and acceptors, novel introns, intron retentions, exon(s) skips, and novel exons, with the latter two events being most prevalent. The consequences of splicing were further investigated with the leukotriene B4 receptor, known for its aberrant responsiveness in lung. We found transcript expression of three variants because of alternative donor and acceptor splice sites, representing in-frame deletions of 38 and 100 aa, with protein expression of all three isoforms. Thus, alternative splicing, subject to conditional, temporal, and cell-type regulation, is a major mechanism that diversifies the GPCR superfamily, creating local recepteromes with specialized environments.pharmacogenetics ͉ signal transduction ͉ splice variants

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Effects of leukotriene B 4 receptor antagonist, LY293111Na, on antigen-induced bronchial hyperresponsiveness and leukocyte infiltration in sensitized guinea pigs

Abstract: These results indicate that LTB4 may participate in antigen-induced BHR but not in eosinophil infiltration and acute bronchoconstriction in guinea pigs.

Cited by 19 publications

References 30 publications

The Leukotriene B4 Receptor (BLT1) Is Required for Effector CD8+ T Cell-Mediated, Mast Cell-Dependent Airway Hyperresponsiveness

The Leukotriene B4 Receptor (BLT1) Is Required for Effector CD8+ T Cell-Mediated, Mast Cell-Dependent Airway Hyperresponsiveness

Time- and dose-dependent analysis of gene expression using microarrays in sulfur mustard-exposed mice

Alternative splicing of the G protein-coupled receptor superfamily in human airway smooth muscle diversifies the complement of receptors

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