Enhancement of goblet cell hyperplasia and airway hyperresponsiveness by salbutamol in a rat model of atopic asthma

Kamachi, Atsuko; Munakata, Mitsuru; Nasuhara, Yasuyuki; Nishimura, Masaharu; Ohtsuka, Yoshinori; Amishima, Masaru; Takahashi, Tohru; Homma, Yukihiko; Kawakami, Yuko

doi:10.1136/thorax.56.1.19

Cited by 37 publications

(32 citation statements)

References 30 publications

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“…Bond, personal communication). Increased β 2 -adrenoceptor signaling from agonist stimulation did not augment mucin accumulation in this model [11•], although it did (two-fold) in another model [35]. Together, these results suggest that the high density of β 2 -adrenoceptors in airway epithelium provides sufficient signaling from empty receptors or receptors bound by endogenous ligands to fully support mucous metaplasia induced by strong inflammatory stimuli, but that exogenous β-agonists might augment mucous metaplasia induced by weak stimuli.…”

Section: Control Of Polymeric Mucin Productionmentioning

confidence: 99%

Mucus hypersecretion in asthma: causes and effects

Evans

Kim

Tuvim

et al. 2009

Current Opinion in Pulmonary Medicine

236

201

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Purpose of review-Airway mucus plugging has long been recognized as a principal cause of death in asthma. However, molecular mechanisms of mucin overproduction and secretion have not been understood until recently. These mechanisms are reviewed together with ongoing investigations relating them to lung pathophysiology.Recent findings-Of the five secreted gel-forming mucins in mammals, only MUC5AC and MUC5B are produced in significant quantities in intrapulmonary airways. MUC5B is the principal gel-forming mucin at baseline in small airways of humans and mice, and therefore likely performs most homeostatic clearance functions. MUC5AC is the principal gel-forming mucin upregulated in airway inflammation and is under negative control by forkhead box a2 and positive control by hypoxia inducible factor-1. Mucin secretion is regulated separately from production, principally by extracellular triphosphate nucleotides that bind P2Y 2 receptors on the lumenal surface of airway secretory cells, generating intracellular second messengers that activate the exocytic proteins, Munc13-2 and synaptotagmin-2.Summary-Markedly upregulated production of MUC5AC together with stimulated secretion leads to airflow obstruction in asthma. As MUC5B appears to mediate homeostatic functions, it may be possible to selectively inhibit MUC5AC production without impairing airway function. The precise roles of mucin hypersecretion in asthma symptoms such as dyspnea and cough and in physiologic phenomena such as airway hyperresponsiveness remain to be defined.

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Section: Control Of Polymeric Mucin Productionmentioning

confidence: 99%

Mucus hypersecretion in asthma: causes and effects

Evans

Kim

Tuvim

et al. 2009

Current Opinion in Pulmonary Medicine

236

201

View full text Add to dashboard Cite

show abstract

“…One of the most upregulated genes in both CF and non-CF donors was MUC5AC, 1 of 2 primary airway mucins. Mucus metaplasia has been previously reported in allergic inflammation-primed animal models following chronic β2AR-agonist exposure, but to our knowledge has not been identified in a nonsensitized human cell model (55)(56)(57). The relevance of these findings is unknown, but we speculate that CFTR defects and mucin changes may have contributed to the reduction in MCC (Figure 4), and may further contribute to suboptimal patient responses to modulator therapy.…”

Section: Discussionmentioning

confidence: 53%

Chronic β2AR stimulation limits CFTR activation in human airway epithelia

et al. 2018

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“…However, recent pieces of evidence suggest that (S)-albuterol is not a true β 2 -adrenergic agonist [9,10,28,29,30]. Prolonged administration of racemic albuterol leads to increased airway responsiveness to spasmogens and may result in loss of asthma control [7,8,31]. In this study, WEB 2170, a PAF receptor antagonist, inhibited (S)-albuterol’s effect in HBSMCs.…”

Section: Discussionmentioning

confidence: 67%

Albuterol Isomers Modulate Platelet-Activating Factor Synthesis and Receptor Signaling in Human Bronchial Smooth Muscle Cells

Bae

Arteaga

Raj³

et al. 2011

Int Arch Allergy Immunol

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Background: Racemic albuterol is a 50:50 mixture of the (R)- and (S)-enantiomers of albuterol. Its clinical efficacy resides in the (R)-enantiomer (levalbuterol). Studies have shown that (S)-albuterol induces human bronchial smooth muscle cell (HBSMC) proliferation via a pathway linked to platelet-activating factor (PAF), but the underlying mechanism by which (S)-albuterol augments PAF effects is not clear. In this study, we compared effect of levalbuterol and (S)-albuterol on PAF receptor (PAFr)-mediated signaling and PAF metabolism by HBSMCs after incubation with the albuterol isomers. Methods: PAF binding and inositol phosphate (IP₃) release were studied on adherent cultured cells. PAFr protein expression was measured by Western blotting, PAF synthesis and catabolism were measured in membrane and cytosolic proteins of cells incubated with albuterol isomers. Results: Compared to control conditions, (S)-albuterol increased PAF binding by 70% after 30 min of preincubation and by 150% after 24 h of preincubation. Levalbuterol had no effect on PAF binding under both conditions. (S)-albuterol also augmented PAF stimulation of IP₃ release, while levalbuterol and the racemic mixture had no effect. WEB 2170, a PAFr antagonist, inhibited the ability of (S)-albuterol to increase PAF binding or stimulate IP₃ release. (S)-albuterol stimulated PAFr protein expression. With PAF metabolism, (S)-albuterol treatment augmented PAF synthesis, but significantly inhibited PAF catabolism. Conclusions: Our data suggest that one mechanism by which (S)-albuterol stimulates HBSMC proliferation involves upregulation of PAFr-mediated effects including increased PAF synthesis and decreased PAF catabolism.

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Enhancement of goblet cell hyperplasia and airway hyperresponsiveness by salbutamol in a rat model of atopic asthma

Cited by 37 publications

References 30 publications

Mucus hypersecretion in asthma: causes and effects

Mucus hypersecretion in asthma: causes and effects

Chronic β2AR stimulation limits CFTR activation in human airway epithelia

Albuterol Isomers Modulate Platelet-Activating Factor Synthesis and Receptor Signaling in Human Bronchial Smooth Muscle Cells

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