Up‐Regulation of Endothelin Receptor Function and mRNA Expression in Airway Smooth Muscle Cells Following Sephadex‐Induced Airway Inflammation

Granström, Bengt; Xu, Cang‐Bao; Nilsson, Elisabet; Bengtsson, Ursula Hultkvist; Edvinsson, Lars

doi:10.1111/j.1742-7843.2004.pto950109.x

Cited by 11 publications

(9 citation statements)

References 32 publications

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“…The tracheal instillation of Sephadex is a fairly common method for inducing airway inflammation. This method resulted in an enhanced contractile response to S6c and ET-1 and elevated ET B receptor mRNA in the bronchioles but not in the trachea [33]. It would appear that the role of upregulated ET B receptors in the bronchioles was the most prominent.…”

Section: Discussionmentioning

confidence: 94%

Secondhand Smoke Exposure Causes Bronchial Hyperreactivity via Transcriptionally Upregulated Endothelin and 5-hydroxytryptamine 2A Receptors

et al. 2012

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BackgroundCigarette smoke exposure is strongly associated with airway hyperreactivity (AHR) which is the main characteristic seen in asthma. The intracellular MAPK signaling pathways are suggested to be associated with the airway damage to the AHR. In the present study, we hypothesize that secondhand cigarette smoke (SHS) exposure upregulates the bronchial contractile receptors via activation of the Raf/ERK/MAPK pathway.Methodology/Principal FindingsRats were exposed to SHS for 3 h daily for up to 8 weeks. The receptor agonists-induced bronchial contractile reactivity was analyzed with a sensitive myograph system. The mRNA transcription and protein translation of the target receptors and the kinases in Raf/ERK/MAPK pathway were investigated by real-time PCR, Western blotting and immunofluorescence, respectively. Compared with exposure to fresh air, SHS induced enhanced bronchial contractile responses mediated by the 5-hydroxytryptamine 2A (5-HT2A) receptors as well as the endothelin type B (ETB) and type A (ETA) receptors. The response curves were shifted toward the left with an increased maximal contraction (Emax) demonstrating that SHS induced AHR. Additionally, the mRNA and protein levels of the 5-HT2A, ETB and ETA receptors were increased. Furthermore, SHS exposure increased the phosphorylation of Raf-1 and ERK1/2, but it did not alter p38 or JNK. A Raf-1 inhibitor (GW5074) suppressed the SHS-induced increase in the expression of 5-HT2A and ETA receptors and the receptor-mediated AHR.Conclusions/SignificanceOur findings show that SHS exposure induces transcriptional upregulation of the 5-HT2A, ETB and ETA receptors in rat bronchial smooth muscle cells, which mediates AHR. The Raf/ERK/MAPK pathway is involved in SHS-associated receptor upregulation and AHR.

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Section: Discussionmentioning

confidence: 94%

Secondhand Smoke Exposure Causes Bronchial Hyperreactivity via Transcriptionally Upregulated Endothelin and 5-hydroxytryptamine 2A Receptors

et al. 2012

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“…It is important to recognize that in lung diseases ET receptors are upregulated (Möller et al. 1997, Granström et al. 2004), which further adds to their importance in pulmonary obstructive disease.…”

Section: Discussionmentioning

confidence: 99%

“…Many studies have indicated that ET-1 is an important neuropeptide in lung diseases such as asthma bronchiale (Goldie et al 1996). It is important to recognize that in lung diseases ET receptors are upregulated (Mö ller et al 1997, Granströ m et al 2004, which further adds to their importance in pulmonary obstructive disease. The present study is a description of an isolated lung model in which complex interactions between the airways and the vascular tree can be characterized.…”

Section: Due To High Concentration Of Predominantly Etmentioning

confidence: 99%

Analysis of ET‐A and ET‐B receptors using an isolated perfused rat lung preparation

Granström¹,

Nilsson²,

Hultkvist-Bengtsson

et al. 2004

Acta Physiologica Scandinavica

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Aims and Methods: The pulmonary and vascular effects of endothelin‐1 receptor activation were studied in isolated perfused and ventilated lung preparations from rat. The responses to endothelin‐1 (ET‐1) and the endothelin B (ETB) receptor agonist sarafotoxin 6c (S6c) were characterized using the endothelin A (ETA)‐receptor antagonist FR 139317, the ETB‐receptor antagonist BQ 788 and the combined ETA/ETB‐receptor antagonist Bosentan. The respiratory parameter airway conductance (Gaw) and the vascular parameter perfusion flow were analysed simultaneously. Results: Concentration–response curves for ET‐1 administered intra‐arterially revealed that its most potent effect was on the vascular side while S6c had a more potent effect on airway conductance. ET‐1, given as a bolus dose intra‐arterially (100 μL of 0.2 nm), induced a strong‐ and long‐lasting contraction of the vasculature while only a less pronounced contraction was seen in the airways. Neither of the antagonists had a significant effect per se on Gaw or perfusion flow. FR 139317 reduced the effect of ET‐1 on perfusion flow by about 50%, while airway conductance was augmented. BQ 788 enhanced the decrease in perfusion flow by ET‐1 while Gaw was not influenced. The combined ETA/ETB antagonist Bosentan powerfully prevented the ET‐1‐induced decrease in Gaw but did not alter its reduction in perfusion flow. Conclusions: The potent effect of ET‐1 on the vascular side of the lung is mediated mainly through ETA receptors, whereas both ETA and ETB receptors are involved in Gaw in the rat lung.

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“…Both ET A R and ET B R expression in bronchial smooth muscle cells is increased upon experimentally induced airway inflammation (22). ET A R activation is also required for endotoxin-induced inflammation (23) or T-cell homing to the lungs after allergenic or inflammatory stimuli, whereas experimental airway inflammation is abrogated by ET A R inhibition (24, 25).…”

Section: Introductionmentioning

confidence: 99%

Endothelin B Receptor, a New Target in Cancer Immune Therapy

Kandalaft

Facciabene

Buckanovich

et al. 2009

Clinical Cancer Research

100

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The endothelins and their G protein-coupled receptors A and B have been implicated in numerous diseases and have recently emerged as pivotal players in a variety of malignancies. Tumors overexpress the endothelin 1 (ET-1) ligand and the endothelin-A-receptor (ET A R). Their interaction induces tumor growth and metastasis by promoting tumor cell survival and proliferation, angiogenesis, and tissue remodeling. On the basis of results from xenograft models, drug development efforts have focused on antagonizing the autocrine-paracrine effects mediated by ET-1/ET A R. In this review, we discuss a novel role of the endothelin-B-receptor (ET B R) in tumorigenesis and the effect of its blockade during cancer immune therapy.We highlight key characteristics of the B receptor such as its specific overexpression in the tumor compartment; and specifically, in the tumor endothelium, where its activation by ET-1suppressesT-cell adhesion and homing to tumors. We also review our recent findings on the effects of ET B R-specific blockade in increasing T-cell homing to tumors and enhancing the efficacy of otherwise ineffective immunotherapy.

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Up‐Regulation of Endothelin Receptor Function and mRNA Expression in Airway Smooth Muscle Cells Following Sephadex‐Induced Airway Inflammation

Cited by 11 publications

References 32 publications

Secondhand Smoke Exposure Causes Bronchial Hyperreactivity via Transcriptionally Upregulated Endothelin and 5-hydroxytryptamine 2A Receptors

Secondhand Smoke Exposure Causes Bronchial Hyperreactivity via Transcriptionally Upregulated Endothelin and 5-hydroxytryptamine 2A Receptors

Analysis of ET‐A and ET‐B receptors using an isolated perfused rat lung preparation

Endothelin B Receptor, a New Target in Cancer Immune Therapy

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