Muscarinic receptors involved in airway vascular leakage induced by experimental gastro-oesophageal reflux

Cui, Yong-Yao; Zhu, Liang; Wang, Hao; Advenier, C.; Chen, Hongzhuan; Devillier, Philippe

doi:10.1016/j.lfs.2008.02.008

Cited by 18 publications

(9 citation statements)

References 30 publications

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“…Also, animal studies showed that anticholinergics are capable of reducing neutrophilic and eosinophilic inflammation induced by inhaled diesel-soot [10], inhaled allergen [11], or LPS [12]. Furthermore, it has been reported that airway vascular leakage is mediated by muscarinic receptors [13]. Collectively, these findings suggest a role in pro-inflammatory responses for muscarinic receptors.…”

Section: Introductionmentioning

confidence: 99%

Pro-inflammatory mechanisms of muscarinic receptor stimulation in airway smooth muscle

et al. 2010

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BackgroundAcetylcholine, the primary parasympathetic neurotransmitter in the airways, plays an important role in bronchoconstriction and mucus production. Recently, it has been shown that acetylcholine, by acting on muscarinic receptors, is also involved in airway inflammation and remodelling. The mechanism(s) by which muscarinic receptors regulate inflammatory responses are, however, still unknown.MethodsThe present study was aimed at characterizing the effect of muscarinic receptor stimulation on cytokine secretion by human airway smooth muscle cells (hASMc) and to dissect the intracellular signalling mechanisms involved. hASMc expressing functional muscarinic M2 and M3 receptors were stimulated with the muscarinic receptor agonist methacholine, alone, and in combination with cigarette smoke extract (CSE), TNF-α, PDGF-AB or IL-1β.ResultsMuscarinic receptor stimulation induced modest IL-8 secretion by itself, yet augmented IL-8 secretion in combination with CSE, TNF-α or PDGF-AB, but not with IL-1β. Pretreatment with GF109203X, a protein kinase C (PKC) inhibitor, completely normalized the effect of methacholine on CSE-induced IL-8 secretion, whereas PMA, a PKC activator, mimicked the effects of methacholine, inducing IL-8 secretion and augmenting the effects of CSE. Similar inhibition was observed using inhibitors of IκB-kinase-2 (SC514) and MEK1/2 (U0126), both downstream effectors of PKC. Accordingly, western blot analysis revealed that methacholine augmented the degradation of IκBα and the phosphorylation of ERK1/2 in combination with CSE, but not with IL-1β in hASMc.ConclusionsWe conclude that muscarinic receptors facilitate CSE-induced IL-8 secretion by hASMc via PKC dependent activation of IκBα and ERK1/2. This mechanism could be of importance for COPD patients using anticholinergics.

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Section: Introductionmentioning

confidence: 99%

Pro-inflammatory mechanisms of muscarinic receptor stimulation in airway smooth muscle

et al. 2010

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“…In animal models, we and others have previously reported that bilateral vagotomy or atropine pretreatment inhibit the increase in airway resistance and the microvascular leakage induced by acute oesophageal acid instillation [7,8]. We have also shown that airway microvascular leakage caused by single HCl intra-oesophageal instillation in guinea pigs involved both M1 and M3 receptors [9]. These results indicate that the release of acetylcholine, acting through the activation of muscarinic receptors, contributes to the airway responses caused by oesophageal stimulation with HCl.…”

mentioning

confidence: 53%

“…We have previously shown in guinea pigs that the airway vascular leakage induced by acute intra-oesophageal HCl instillation involving acetylcholine release from vagus nerve terminals, was blocked by atropine and was mediated through the activation of M1 and M3 receptors [9]. In this previous study, the upper portion of the oesophagus was ligated to prevent stimulation of the larynx by HCl and to ensure an oesophageal origin of the cholinergic reflex-induced airway leakage [9]. In these previous experimental conditions, however, we used a concentration of HCL (1 N) far above the physiological range to trigger a cholinergic reflex.…”

Section: Discussionmentioning

confidence: 99%

Tiotropium reduction of lung inflammation in a model of chronic gastro-oesophageal reflux

Cui

Devillier²,

Kuang³

et al. 2009

Eur Respir J

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Gastro-oesophageal reflux is frequent in chronic airway diseases and is considered a trigger for symptoms. In animal models, bilateral vagotomy or muscarinic antagonists prevent the increase in airway resistance and the microvascular leakage induced by acute oesophageal acid instillation.The present study investigates lung inflammation and remodelling in an animal model of chronic gastro-oesophageal reflux disease (GORD), and the effectiveness of pretreatments with tiotropium, atropine and dexamethasone.Mice were exposed to twice-daily intra-oesophageal HCl instillations for 21 days. Exposure to HCl causes: marked infiltration by inflammatory cells of the airways and of peribronchial areas; an increase in epithelial thickness; histological features of interstitial pneumonitis; an increase in cell numbers and in the levels of interleukin-8; and soluble intercellular adhesion molecule in bronchoalveolar lavage fluids, as well as of in vitro tracheal contractility. The administration of nebulised tiotropium or intraperitoneal atropine prior to each instillation of HCl, considerably inhibited all these changes.These results indicate a major role of acetylcholine in airway inflammation and remodelling in a GORD model, and demonstrate that tiotropium and atropine can prevent lung inflammation with an effectiveness similar to intraperitoneal dexamethasone, providing additional evidence that anticholinergics might contribute to the control of inflammatory processes in airway diseases.

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“…Some experimental evidence of the anti-inflammatory effects of anticholinergics has also been obtained in animal models (Table IV). Additionally, M 1 and M 3 receptors are involved in cholinergic-induced microvascular leakage induced by instillation of hydrochloride acid into the esophagus of guinea-pigs [93]. In the same way, atropine attenuates turpentine-induced leukocytic infiltration and tissue injury, and inhibits chemotaxis of leukocytes toward neutrophil and monocyte/lymphocyte chemoattractants in rats [92].…”

Section: Anti-inflammatory Effects Of Anticholinergic Agentsmentioning

confidence: 96%

Can β₂‐adrenoceptor agonists, anticholinergic drugs, and theophylline contribute to the control of pulmonary inflammation and emphysema in COPD?

Zhang

Cui

et al. 2011

Fundamemntal Clinical Pharma

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Chronic obstructive pulmonary disease (COPD) has become a global epidemic disease with an increased morbidity and mortality in the world. Inflammatory process progresses and contributes to irreversible airflow limitation. However, there is no available therapy to better control the inflammatory progression and therefore to reduce the exacerbations and mortality. Thus, the development of efficient anti-inflammatory therapies is a priority for patients with COPD. β(2) -Adrenoceptor agonists and anticholinergic agents are widely used as first line drugs in management of COPD because of their efficient bronchodilator properties. At present, many studies in vitro and some data obtained in laboratory animals reveal the potential anti-inflammatory effects of these bronchodilators but their protective role against chronic inflammation and the development of emphysema in patients with COPD remains to be investigated. The anti-inflammatory effects of theophylline at low doses have also been identified. Beneficial interactions between glucocorticoids and bronchodilators have been reported, and signaling pathways explaining these synergistic effects begin to be understood, especially for theophylline. Recent data demonstrating interactions between anticholinergics with β(2) -adrenoceptor agonists aiming to better control the pulmonary inflammation and the development of emphysema in animal models of COPD justify the priority to investigate the interactive effects of a tritherapy associating corticoids with the two main categories of bronchodilators.

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Muscarinic receptors involved in airway vascular leakage induced by experimental gastro-oesophageal reflux

Cited by 18 publications

References 30 publications

Pro-inflammatory mechanisms of muscarinic receptor stimulation in airway smooth muscle

Pro-inflammatory mechanisms of muscarinic receptor stimulation in airway smooth muscle

Tiotropium reduction of lung inflammation in a model of chronic gastro-oesophageal reflux

Can β₂‐adrenoceptor agonists, anticholinergic drugs, and theophylline contribute to the control of pulmonary inflammation and emphysema in COPD?

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Muscarinic receptors involved in airway vascular leakage induced by experimental gastro-oesophageal reflux

Cited by 18 publications

References 30 publications

Pro-inflammatory mechanisms of muscarinic receptor stimulation in airway smooth muscle

Pro-inflammatory mechanisms of muscarinic receptor stimulation in airway smooth muscle

Tiotropium reduction of lung inflammation in a model of chronic gastro-oesophageal reflux

Can β2‐adrenoceptor agonists, anticholinergic drugs, and theophylline contribute to the control of pulmonary inflammation and emphysema in COPD?

Contact Info

Product

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Can β₂‐adrenoceptor agonists, anticholinergic drugs, and theophylline contribute to the control of pulmonary inflammation and emphysema in COPD?