Characterization of airway plugging in fatal asthma

Kuyper, Laura M.; Paré, Peter D.; Hogg, James C.; Lambert, Robert A.; Ionescu, Diana N.; Woods, Ryan; Bai, Tony R.

doi:10.1016/s0002-9343(03)00241-9

Cited by 279 publications

(232 citation statements)

References 22 publications

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“…This suggests a mechanism for LTE 4 -mediated airflow obstruction that is distinct from the bronchoconstricting effects of the other CysLTRs and that depends on precedent lung disease. As mucus secretion can contribute to airway obstruction (35,36), it is possible that the sensitivity to LTE 4 -induced obstruction reflects a contribution of GPR99 in the setting of the GC expansion seen in asthmatic lung. Furthermore, targeting GPR99, which is resistant to commercially available CysLTR antagonists, may have therapeutic benefit in airway diseases characterized by abnormalities of mucin secretion and clearance.…”

Section: Discussionmentioning

confidence: 99%

Leukotriene E₄elicits respiratory epithelial cell mucin release through the G-protein–coupled receptor, GPR99

Bankova

Lai

Yoshimoto

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cysteinyl leukotrienes (cysLTs), leukotriene C 4 (LTC 4 ), LTD 4 , and LTE 4 are proinflammatory lipid mediators with pathobiologic function in asthma. LTE 4 , the stable cysLT, is a weak agonist for the type 1 and type 2 cysLT receptors (CysLTRs), which constrict airway smooth muscle, but elicits airflow obstruction and pulmonary inflammation in patients with asthma. We recently identified GPR99 as a high-affinity receptor for LTE 4 that mediates cutaneous vascular permeability. Here we demonstrate that a single intranasal exposure to extract from the respiratory pathogen Alternaria alternata elicits profound epithelial cell (EpC) mucin release and submucosal swelling in the nasal mucosa of mice that depends on cysLTs, as it is absent in mice deficient in the terminal enzyme for cysLT biosynthesis, LTC 4 synthase (LTC 4 S). These mucosal changes are associated with mast cell (MC) activation and absent in MC-deficient mice, suggesting a role for MCs in control of EpC function. Of the three CysLTRs, only GPR99-deficient mice are fully protected from EpC mucin release and swelling elicited by Alternaria or by intranasal LTE 4 . GPR99 expression is detected on lung and nasal EpCs, which release mucin to doses of LTE 4 one log lower than that required to elicit submucosal swelling. Finally, mice deficient in MCs, LTC 4 S, or GPR99 have reduced baseline numbers of goblet cells, indicating an additional function in regulating EpC homeostasis. These results demonstrate a novel role for GPR99 among CysLTRs in control of respiratory EpC function and suggest that inhibition of LTE 4 and of GPR99 may have therapeutic benefits in asthma.C ysteinyl leukotrienes (cysLTs), leukotriene C 4 (LTC 4 ), LTD 4 , and LTE 4 are lipid mediators detected during asthma exacerbations triggered by allergen (1), aspirin (2, 3), and respiratory viruses (4). The cysLTs elicit vascular permeability, inflammation, and bronchoconstriction through three G-protein-coupled receptors. The type 1 cysLT receptor (CysLTR), CysLT 1 R, is the highaffinity receptor for LTD 4 and the dominant CysLTR mediating airway smooth muscle constriction (5-8). The type 2 CysLTR, CysLT 2 R, has prominent effects on the vascular endothelium (9-12) and also elicits bronchial constriction (13,14). LTE 4 , the stable cysLT (15-18), is a weak agonist for CysLT 1 R and CysLT 2 R in transfected cells (5, 19), but elicits airflow obstruction in patients with asthma (20-22). Moreover, LTE 4 has comparable activity to LTC 4 and LTD 4 in eliciting a wheal and flare response in human skin (23), and LTE 4 elicits cutaneous vascular permeability in mice lacking both CysLT 1 R and CysLT 2 R, suggesting the existence of a high-affinity receptor for LTE 4 , which was recently identified as GPR99 (24,25). However, the mechanism by which LTE 4 induces lung pathobiology and the role of GPR99 remain poorly understood.The cysLTs are derived from arachidonate through the serial enzymatic actions of 5-lipoxygenase and leukotriene C 4 synthase (LTC 4 S). LTC 4 , the terminal product of intrac...

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Section: Discussionmentioning

confidence: 99%

Leukotriene E₄elicits respiratory epithelial cell mucin release through the G-protein–coupled receptor, GPR99

Bankova

Lai

Yoshimoto

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…But in inflammatory airway diseases such as asthma and COPD, the surface goblet cells expand considerably (mucous cell hyperplasia/metaplasia), and submucosal gland frequency and size increase (9). The increase in surface goblet cells and sub-mucosal glands in these diseases may be what causes the excessive mucus secretion seen in these disorders (2,3,5).…”

Section: Mucins Expressed In the Lungsmentioning

confidence: 99%

“…443-538). To accomplish this function, secretory cells in the airways secrete a viscous mucus layer that helps to trap incoming particles, whereas coordinated beating of cilia from ciliated cells moves them cephalad, where the particles are eventually either expectorated or swallowed into the gastrointestinal (GI) tract (2).…”

Section: Introductionmentioning

confidence: 99%

Regulation of Airway Mucin Gene Expression

Thai

Loukoianov

Wachi

et al. 2008

Annu. Rev. Physiol.

193

223

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Mucins are important components that exert a variety of functions in cell-cell interaction, epidermal growth factor receptor signaling, and airways protection. In the conducting airways of the lungs, mucins are the major contributor to the viscoelastic property of mucous secretion, which is the major barrier to trapping inhaled microbial organism, particulates, and oxidative pollutants. The homeostasis of mucin production is an important feature in conducting airways for the maintenance of mucociliary function. Aberrant mucin secretion and accumulation in airway lumen are clinical hallmarks associated with various lung diseases, such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, emphysema, and lung cancer. Among 20 known mucin genes identified, 11 of them have been verified at either the mRNA and/or protein level in airways. The regulation of mucin genes is complicated, as are the mediators and signaling pathways. This review summarizes the current view on the mediators, the signaling pathways, and the transcriptional units that are involved in the regulation of airway mucin gene expression. In addition, we also point out essential features of epigenetic mechanisms for the regulation of these genes.

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“…Furthermore, airway remodeling as evident by increased layer thickness of the adventitia, submucosal, and smooth muscle area is significantly higher in distal airways of these patients compared to healthy controls or patients suffering from chronic obstructive pulmonary disease (COPD) [7]. The most striking finding that underpins their contribution to fatal asthma is vast plugging of distal airways by mucoinflammatory exsudates that inhibits ventilation of the attached alveolar structures and thus can be described as a major contributing cause of death in asthma [8].…”

Section: Commentarymentioning

confidence: 99%

Small Airways in Asthma: Distal is Different

Vock¹,

Lunding²,

Fehrenbach³

et al. 2017

J Clin Cell Immunol

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Characterization of airway plugging in fatal asthma

Cited by 279 publications

References 22 publications

Leukotriene E₄elicits respiratory epithelial cell mucin release through the G-protein–coupled receptor, GPR99

Leukotriene E₄elicits respiratory epithelial cell mucin release through the G-protein–coupled receptor, GPR99

Regulation of Airway Mucin Gene Expression

Small Airways in Asthma: Distal is Different

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Characterization of airway plugging in fatal asthma

Cited by 279 publications

References 22 publications

Leukotriene E4elicits respiratory epithelial cell mucin release through the G-protein–coupled receptor, GPR99

Leukotriene E4elicits respiratory epithelial cell mucin release through the G-protein–coupled receptor, GPR99

Regulation of Airway Mucin Gene Expression

Small Airways in Asthma: Distal is Different

Contact Info

Product

Resources

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Leukotriene E₄elicits respiratory epithelial cell mucin release through the G-protein–coupled receptor, GPR99

Leukotriene E₄elicits respiratory epithelial cell mucin release through the G-protein–coupled receptor, GPR99