Possible Novel Receptor for PGD&lt;sub&gt;2&lt;/sub&gt; on Human Bronchial Epithelial Cells

Chiba, Takahito; Kanda, Akira; Ueki, Shigeharu; Ito, Wataru; Yamaguchi, K.; Kamada, Yumiko; Takeda, Masahide; Tanigai, Tomomi; Oyamada, Hirokazu; Kayaba, Hiroyuki; Chihara, Junichi

doi:10.1159/000101400

Cited by 9 publications

(5 citation statements)

References 55 publications

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“…The epithelial cell acts as a first line of defense against harmful components in cigarette smoke, and DP2 is expressed on human bronchial epithelial cells (Chiba et al, 2006;Sargent et al, 2009). Intracellular expression of DP2 was demonstrated in NCI-H292 and normal human bronchial epithelial cells by both reverse transcription-polymerase chain reaction and flow cytometry (Chiba et al, 2007). The functional implications of DP2 expression on this cell type have yet to be fully elucidated; however, our data suggest that the efficacy of DP2 antagonists on cigarette smoke-induced pulmonary inflammation and mucus hypersecretion may be due to the direct effect of the DP2 antagonist on the epithelial cells, although, as stated above, a role for the DP2-neutrophil-epithelial cell axis cannot be ruled out.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Blockade of the DP2 Receptor Inhibits Cigarette Smoke-Induced Inflammation, Mucus Cell Metaplasia, and Epithelial Hyperplasia in the Mouse Lung

Stebbins¹,

Broadhead²,

Baccei³

et al. 2009

J Pharmacol Exp Ther

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Prostaglandin D 2 (PGD 2 ) is one of a family of biologically active lipids derived from arachidonic acid via the action of COX-1 and COX-2. PGD 2 is released from mast cells and binds primarily to two G protein-coupled receptors, namely DP1 and DP2, the latter also known as chemoattractant receptor-homologous molecule expressed on Th2 cells. DP2 is predominantly expressed on eosinophils, Th2 cells, and basophils, but it is also expressed to a lesser extent on monocytes, mast cells, and epithelial cells. Interaction of PGD 2 and its active metabolites with DP2 results in cellular chemotaxis, degranulation, up-regulation of adhesion molecules, and cytokine production. Chronic obstructive pulmonary disease (COPD) is a chronic progressive inflammatory disease characterized by elevated lung neutrophils, macrophages, and CD8ϩ T lymphocytes and mucus hypersecretion. Cigarette smoke contributes to the etiology of COPD and was used here as a provoking agent in a murine model of COPD. In an acute model, {2Ј-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-6-methoxy-4Ј-trifluoro-methyl-biphenyl-3-yl}-acetic acid, sodium salt (AM156) and (5-{2-[(benzoyloxycarbonyl-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-pyridin-3-yl)-acetic acid, sodium salt) (AM206), potent DP2 receptor antagonists, dosedependently inhibited influx of neutrophils and lymphocytes to smoke-exposed airways. In a subchronic model, AM156 and AM206 inhibited neutrophil and lymphocyte trafficking to the airways. Furthermore, AM156 and AM206 treatment inhibited mucus cell metaplasia and prevented the thickening of the airway epithelial layer induced by cigarette smoke. These data suggest that DP2 receptor antagonism may represent a novel therapy for COPD or other conditions characterized by neutrophil influx, mucus hypersecretion, and airway remodeling.Chronic obstructive pulmonary disease (COPD) is a complex disease in which airflow obstruction is not fully reversible. It is a chronic, progressive inflammatory condition of the small airways and lung parenchyma that is characterized by elevated pulmonary macrophages, neutrophils, and CD8ϩ T cells. Proinflammatory mediators, including IL-8, MCP-1, and IL-1␤, are elevated in bronchoalveolar lavage fluid (BALF) and sputum samples obtained from patients with COPD (Keatings et al., 1996;Yamamoto et al., 1997;Hill et al., 1999;Soler et al., 1999). Chronic inflammation contributes to the decline in pulmonary function associated with chronic bronchitis, mucus hypersecretion, and emphysema via the release of proinflammatory mediators, reactive oxygen species, and tissue degradation enzymes (Corrigan and

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Section: Discussionmentioning

confidence: 99%

Pharmacological Blockade of the DP2 Receptor Inhibits Cigarette Smoke-Induced Inflammation, Mucus Cell Metaplasia, and Epithelial Hyperplasia in the Mouse Lung

Stebbins¹,

Broadhead²,

Baccei³

et al. 2009

J Pharmacol Exp Ther

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“… 34 We found that DP2 was expressed on epithelial cells within biopsy specimens from asthmatic patients. Although previous publications have described the expression of DP2 on cultured normal human epithelial cells and H292 cells, 35 our report is the first to demonstrate the in vivo expression of DP2 on epithelial cells within bronchial biopsy specimens. A recent report has described expression of DP2 on epithelial cells in lung volume reduction tissue from patients with COPD, 17 but whether this expression was associated with disease severity was not investigated because no healthy control tissue was included.…”

Section: Discussionmentioning

confidence: 51%

“… 39 In our study DP2 was found to have intracellular and extracellular expression on epithelial cells similar to that seen in previous studies for this receptor. 14,35 DP2 activation caused functional consequences on epithelial cells that were likely mediated through cell-surface receptors. However, intracellular receptor activation can also occur, as has been reported for other G protein–coupled receptors, 40 and its functional importance requires further study.…”

Section: Discussionmentioning

confidence: 99%

D prostanoid receptor 2 (chemoattractant receptor–homologous molecule expressed on TH2 cells) protein expression in asthmatic patients and its effects on bronchial epithelial cells

Stinson

Amrani²,

Brightling³

2015

Journal of Allergy and Clinical Immunology

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BackgroundThe D prostanoid receptor 2 (DP2; also known as chemoattractant receptor–homologous molecule expressed on TH2 cells) is implicated in the pathogenesis of asthma, but its expression within bronchial biopsy specimens is unknown.ObjectivesWe sought to investigate the bronchial submucosal DP2 expression in asthmatic patients and healthy control subjects and to explore its functional role in epithelial cells.MethodsDP2 protein expression was assessed in bronchial biopsy specimens from asthmatic patients (n = 22) and healthy control subjects (n = 10) by using immunohistochemistry and in primary epithelial cells by using flow cytometry, immunofluorescence, and quantitative RT-PCR. The effects of the selective DP2 agonist 13, 14-dihydro-15-keto prostaglandin D2 on epithelial cell migration and differentiation were determined.ResultsNumbers of submucosal DP2+ cells were increased in asthmatic patients compared with those in healthy control subjects (mean [SEM]: 78 [5] vs 22 [3]/mm2 submucosa, P < .001). The bronchial epithelium expressed DP2, but its expression was decreased in asthmatic patients compared with that seen in healthy control subjects (mean [SEM]: 21 [3] vs 72 [11]/10 mm2 epithelial area, P = .001), with similar differences observed in vitro by primary epithelial cells. Squamous metaplasia of the bronchial epithelium was increased in asthmatic patients and related to decreased DP2 expression (rs = 0.69, P < .001). 13, 14-Dihydro-15-keto prostaglandin D2 promoted epithelial cell migration and at air-liquid interface cultures increased the number of MUC5AC+ and involucrin-positive cells, which were blocked with the DP2-selective antagonist AZD6430.ConclusionsDP2 is expressed by the bronchial epithelium, and its activation drives epithelial differentiation, suggesting that in addition to its well-characterized role in inflammatory cell migration, DP2 might contribute to airway remodeling in asthmatic patients.

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“…It is released into the airway following an antigen challenge during an acute allergic response [30]. PGD 2 induces chemotaxis of Th2 cells, eosinophils, and basophils as a consequence of the activation of its receptors [31]. This suggests that PGD 2 promotes inflammation in allergic asthma.…”

Section: Airway Inflammatory Effect Through Ahr Activation In Asthmentioning

confidence: 99%

Role of the Arylhydrocarbon Receptor (AhR) in the Pathology of Asthma and COPD

2012

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The dioxins and dioxin-like compounds in cigarette smoke and environmental pollutants modulate immunological responses. These environmental toxicants are known to cause lung cancer but have also recently been implicated in allergic and inflammatory diseases such as bronchitis, asthma, and chronic obstructive pulmonary disease (COPD). In a novel pathway of this response, the activation of a nuclear receptor, arylhydrocarbon receptor (AhR), mediates the effects of these toxins through the arachidonic acid cascade, cell differentiation, cell-cell adhesion interactions, cytokine expression, and mucin production that are implicated in the pathogenesis and exacerbation of asthma/COPD. We have previously reported that human bronchial epithelial cells express AhR, and AhR activation induces mucin production through reactive oxygen species. This review discusses the role of AhR in asthma and COPD, focusing in particular on inflammatory and resident cells in the lung. We describe the important impact that AhR activation may have on the inflammation phase in the pathology of asthma and COPD. In addition, crosstalk of AhR signaling with other ligand-activated transcription factors such as peroxisome proliferator-activated receptors (PPARs) has been well documented.

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Possible Novel Receptor for PGD<sub>2</sub> on Human Bronchial Epithelial Cells

Cited by 9 publications

References 55 publications

Pharmacological Blockade of the DP2 Receptor Inhibits Cigarette Smoke-Induced Inflammation, Mucus Cell Metaplasia, and Epithelial Hyperplasia in the Mouse Lung

Pharmacological Blockade of the DP2 Receptor Inhibits Cigarette Smoke-Induced Inflammation, Mucus Cell Metaplasia, and Epithelial Hyperplasia in the Mouse Lung

D prostanoid receptor 2 (chemoattractant receptor–homologous molecule expressed on TH2 cells) protein expression in asthmatic patients and its effects on bronchial epithelial cells

Role of the Arylhydrocarbon Receptor (AhR) in the Pathology of Asthma and COPD

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