Investigation of 5-HT4 receptors in bronchial hyperresponsiveness in cigarette smoke-exposed mice

Dupont, Lisa L.; Bracke, Ken R.; Maeyer, Joris H. De; Compan, Valérie; Joos, Guy; Lefebvre, Romain

doi:10.1016/j.pupt.2013.10.003

Cited by 9 publications

(6 citation statements)

References 32 publications

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“…We did not find that HTR4 deficiency leads to altered responses to either bacterial LPS or bleomycin. Combined with published work showing no difference in response to cigarette smoke between WT and Htr4 ‐/‐ mice (54), the evidence suggests that the differences in baseline lung function do not reflect differential susceptibility to these common environmental exposures.…”

Section: Discussionsupporting

confidence: 54%

Genetic variation in HTR4 and lung function: GWAS follow‐up in mouse

House

DeGraff

et al. 2014

FASEB j.

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Human genome-wide association studies (GWASs) have identified numerous associations between single nucleotide polymorphisms (SNPs) and pulmonary function. Proving that there is a causal relationship between GWAS SNPs, many of which are noncoding and without known functional impact, and these traits has been elusive. Furthermore, noncoding GWAS-identified SNPs may exert trans-regulatory effects rather than impact the proximal gene. Noncoding variants in 5-hydroxytryptamine (serotonin) receptor 4 (HTR4) are associated with pulmonary function in human GWASs. To gain insight into whether this association is causal, we tested whether Htr4-null mice have altered pulmonary function. We found that HTR4-deficient mice have 12% higher baseline lung resistance and also increased methacholine-induced airway hyperresponsiveness (AHR) as measured by lung resistance (27%), tissue resistance (48%), and tissue elastance (30%). Furthermore, Htr4-null mice were more sensitive to serotonin-induced AHR. In models of exposure to bacterial lipopolysaccharide, bleomycin, and allergic airway inflammation induced by house dust mites, pulmonary function and cytokine profiles in Htr4-null mice differed little from their wild-type controls. The findings of altered baseline lung function and increased AHR in Htr4-null mice support a causal relationship between genetic variation in HTR4 and pulmonary function identified in human GWAS.-House, J. S., Li, H., DeGraff, L. M., Flake, G., Zeldin, D. C., London, S. J. Genetic variation in HTR4 and lung function: GWAS follow-up in mouse. FASEB J. 29, 323-335 (2015). www.fasebj.org

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Section: Discussionsupporting

confidence: 54%

Genetic variation in HTR4 and lung function: GWAS follow‐up in mouse

House

DeGraff

et al. 2014

FASEB j.

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“…In the enteric nervous system, 5-HT4 receptor activation stimulates gastrointestinal motility in the GI tract5657. In respiratory system, 5-HT4 receptor mediates respiratory efforts on stimulate breathing in human lung tissue3158, and is related with pulmonary function in mice59. To investigate the potential regulatory functions of 5-HT4 receptor in A. japonicus , the expression profile of Aj5-HT4R in respiratory tree, intestine and muscle tissues of active and aestivated A. japonicus was quantitively analysed in the current study.…”

Section: Discussionmentioning

confidence: 99%

Identification and functional characterisation of 5-HT4 receptor in sea cucumber Apostichopus japonicus (Selenka)

Wang

Yang

Zhou

et al. 2017

Sci Rep

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Serotonin (5-HT) is an important neurotransmitter and neuromodulator that controls a variety of sensory and motor functions through 5-HT receptors (5-HTRs). The 5-HT4R subfamily is linked to Gs proteins, which activate adenylyl cyclases (ACs), and is involved in many responses in peripheral organs. In this study, the 5-HT4R from Apostichopus japonicus (Aj5-HT4R) was identified and characterised. The cloned full-length Aj5-HT4R cDNA is 1,544 bp long and contains an open reading frame 1,011 bp in length encoding 336 amino acid proteins. Bioinformatics analysis of the Aj5-HT4R protein indicated this receptor was a member of class A G protein coupled receptor (GPCR) family. Further experiments using Aj5-HT4R-transfected HEK293 cells demonstrated that treatment with 5-HT triggered a significant increase in intracellular cAMP level in a dose-dependent manner and induced a rapid internalisation of Aj5-HT4R fused with enhanced green fluorescent protein (Aj5-HT4R-EGFP) from the cell surface into the cytoplasm. In addition, the transcriptional profiles of Aj5-HT4R in aestivating A. japonicas and phosphofructokinase (AjPFK) in 5-HT administrated A. japonicus have been analysed by real-time PCR assays. Results have led to a basic understanding of Aj5-HT4R in A. japonicus, and provide a foundation for further exploration of the cell signaling and regulatory functions of this receptor.

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“…The variable components largely derive from the acute release of pro‐inflammatory mediators, while the persistent components result from structural changes in the airways and loss of elastic recoil due to emphysema 1 . Previous studies have shown that acute CS exposure for a period of three to 4 days leads to induction of AHR in mice 29,30 . Thus, acute CS exposure in mice is useful for the investigation of early signalling events that mediate AHR relevant to the nascent stages of COPD, as it removes the additional impact of structural changes which develop following chronic smoke exposure 31 …”

Section: Introductionmentioning

confidence: 99%

RAGE and TLR4 differentially regulate airway hyperresponsiveness: Implications for COPD

Allam

Faiz

Lam

et al. 2020

Allergy

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Background The receptor for advanced glycation end products (RAGE) and Toll‐like receptor 4 (TLR4) is implicated in COPD. Although these receptors share common ligands and signalling pathways, it is not known whether they act in concert to drive pathological processes in COPD. We examined the impact of RAGE and/or TLR4 gene deficiency in a mouse model of COPD and also determined whether expression of these receptors correlates with airway neutrophilia and airway hyperresponsiveness (AHR) in COPD patients. Methods We measured airway inflammation and AHR in wild‐type, RAGE−/−, TLR4−/− and TLR4−/−RAGE−/− mice following acute exposure to cigarette smoke (CS). We also examined the impact of smoking status on AGER (encodes RAGE) and TLR4 bronchial gene expression in patients with and without COPD. Finally, we determined whether expression of these receptors correlates with airway neutrophilia and AHR in COPD patients. Results RAGE−/− mice were protected against CS‐induced neutrophilia and AHR. In contrast, TLR4−/− mice were not protected against CS‐induced neutrophilia and had more severe CS‐induced AHR. TLR4−/−RAGE−/− mice were not protected against CS‐induced neutrophilia but were partially protected against CS‐induced mediator release and AHR. Current smoking was associated with significantly lower AGER and TLR4 expression irrespective of COPD status, possibly reflecting negative feedback regulation. However, consistent with preclinical findings, AGER expression correlated with higher sputum neutrophil counts and more severe AHR in COPD patients. TLR4 expression did not correlate with neutrophilic inflammation or AHR. Conclusions Inhibition of RAGE but not TLR4 signalling may protect against airway neutrophilia and AHR in COPD.

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Investigation of 5-HT4 receptors in bronchial hyperresponsiveness in cigarette smoke-exposed mice

Cited by 9 publications

References 32 publications

Genetic variation in HTR4 and lung function: GWAS follow‐up in mouse

Genetic variation in HTR4 and lung function: GWAS follow‐up in mouse

Identification and functional characterisation of 5-HT4 receptor in sea cucumber Apostichopus japonicus (Selenka)

RAGE and TLR4 differentially regulate airway hyperresponsiveness: Implications for COPD

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