Increased expression of the epithelial anion transporter pendrin/SLC26A4 in nasal polyps of patients with chronic rhinosinusitis

Seshadri, Sudarshan; Lu, Xiang; Purkey, Matthew R.; Homma, Tetsuya; Choi, Andrew; Carter, Roderick; Suh, Lydia; Norton, James E.; Harris, Kathleen E.; Conley, David B.; Kato, Atsushi; Avila, Pedro C.; Czarnocka, Barbara; Kopp, Peter; Peters, Anju T.; Grammer, Leslie C.; Chandra, Rakesh K.; Tan, Bruce K.; Liu, Zheng; Kern, Robert C.; Schleimer, Robert P.

doi:10.1016/j.jaci.2015.05.024

Cited by 55 publications

(72 citation statements)

References 40 publications

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“…Similar results were found in HBE and CFBE cultures. Quantitative PCR analysis indicated that pendrin transcript levels were increased by 30-to 35-fold in the HBE and CFBE cultures (data not shown), similar to fold increases previously reported in similar cell systems (24,25,35).…”

Section: Specificity Of Pds Inh -A01 In Human Airway Epithelial Cell supporting

confidence: 87%

“…More recently, Button and colleagues (52) showed that tethered mucins in the PCL form a mesh to prevent entry of gel-forming mucins and support ciliary beating, and they proposed a gel-onbrush model to describe the ASL. Photobleaching studies support this concept and have established that the fluid phase viscosity of the mucus layer and PCL are similar in non-CF subjects (7-10 times more viscous than saline), but significantly elevated in both regions in CF cultures (25)(26)(27)(28)(29)(30) times more viscous than saline) (51). In addition to forming a permeability barrier, tethered mucins in the PCL generate an osmotic pressure to regulate PCL hydration (52).…”

mentioning

confidence: 90%

“…Pendrin up-regulation is seen in: 1) airway epithelial cultures chronically exposed to cytokines, including IL-4, IL-13, and IL-17A; 2) rodent models of inflammatory lung disease, including allergen (ovalbumin)-induced asthma, chronic obstructive pulmonary disease, infection, and industrial toxin exposure; and 3) humans with rhinovirus infection, asthma, cystic fibrosis (CF), rhinitis, and chronic rhinosinusitis (10,11,(17)(18)(19)(20)(21)(22)(23)(24)(25). Pendrin knockout is also associated with reduced lung inflammation in a murine model of Bordetella pertussis lung infection (26).…”

mentioning

confidence: 99%

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Inhibitors of pendrin anion exchange identified in a small molecule screen increase airway surface liquid volume in cystic fibrosis

Haggie

Phuan²,

Tan³

et al. 2016

FASEB j.

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Pendrin (SLC26A4) is a Cl 2 /anion exchanger expressed in the epithelium of inflamed airways where it is thought to facilitate Cl 2 absorption and HCO 3 2 secretion. Studies using pendrin knockout mice and airway epithelial cells from hearing-impaired subjects with pendrin loss of function suggest involvement of pendrin in inflammatory lung diseases, including cystic fibrosis (CF), perhaps by regulation of airway surface liquid (ASL) volume. Here we identified small-molecule pendrin inhibitors and demonstrated their efficacy in increasing ASL volume. A cell-based, functional high-throughput screen of ∼36,000 synthetic small molecules produced 3 chemical classes of inhibitors of human pendrin. After structure-activity studies, tetrahydropyrazolopyridine and pyrazolothiophenesulfonamide compounds reversibly inhibited pendrin-facilitated Cl 2 exchange with SCN 2 , I 2 , NO 3 2 , and HCO 3 2 with drug concentration causing 50% inhibition down to ∼2.5 mM. In well-differentiated primary cultures of human airway epithelial cells from non-CF and CF subjects, treatment with IL-13, which causes inflammation with strong pendrin up-regulation, strongly increased Cl 2 /HCO 3 2 exchange and the increase was blocked by pendrin inhibition. Pendrin inhibition significantly increased ASL depth (by ∼8 mm) in IL-13-treated non-CF and CF cells but not in untreated cells. These studies implicate the involvement of pendrin-facilitated Cl 2 / HCO 3 2 in the regulation of ASL volume and suggest the utility of pendrin inhibitors in inflammatory lung diseases, including CF

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Section: Specificity Of Pds Inh -A01 In Human Airway Epithelial Cell supporting

confidence: 87%

mentioning

confidence: 90%

mentioning

confidence: 99%

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Inhibitors of pendrin anion exchange identified in a small molecule screen increase airway surface liquid volume in cystic fibrosis

Haggie

Phuan²,

Tan³

et al. 2016

FASEB j.

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“…For example, levels of epithelial-derived antimicrobial proteins including lysozyme, S100A7, S100A8/9, beta-defensins, and Palate, Lung, and Nasal Epithelial Clone (PLUNC) proteins were reduced in CRSwNP patients compared to healthy controls 2728–30 . Pendrin, an epithelial ion transporter that can increase mucus production, and Muc5AC, a type of mucin, were elevated in CRSwNP versus controls 3132 . These findings suggest that impairment in mucociliary clearance, reduction in antimicrobial defense protein secretion, and breakdown in the physical barrier can lead to chronic exposure of pathogenic and non-pathogenic mediators and the development of a chronic inflammatory response.…”

Section: Pathophysiologymentioning

confidence: 95%

Chronic Rhinosinusitis with Nasal Polyps

Stevens

Schleimer

Kern

2016

The Journal of Allergy and Clinical Immunology: In Practice

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356

314

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Chronic rhinosinusitis with nasal polyps (CRSwNP) is an important clinical entity diagnosed by the presence of both subjective and objective evidence of chronic sinonasal inflammation. Symptoms include anterior or posterior rhinorrhea, nasal congestion, hyposmia and/or facial pressure or pain that last for greater than 12 weeks duration. Nasal polyps are inflammatory lesions that project into the nasal airway, are typically bilateral, and originate from the ethmoid sinus. Males are more likely to be affected than females but no specific genetic or environmental factors have been strongly linked to the development of this disorder to date. CRSwNP is frequently associated with asthma and allergic rhinitis but the cellular and molecular mechanisms that contribute to the clinical symptoms are not fully understood. Defects in the sinonasal epithelial cell barrier, increased exposure to pathogenic and colonized bacteria, and dysregulation of the host immune system are all thought to play prominent roles in disease pathogenesis. Additional studies are needed to further explore the clinical and pathophysiological features of CRSwNP so that biomarkers can be identified and novel advances can be made to improve the treatment and management of this disease.

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“…The reciprocal regulatory interaction between the SLC26 and CFTR involves binding of the STAS domain to the regulatory domain of CFTR (see section on pancreas). The SLC26 transporter SLC26A4, pendrin, has been shown to be upregulated in inflammatory conditions in airway epithelia such as chronic rhinosinusitis [92, 93], upon stimulation with IL-17 [94] and in response to bacterial infections [95]. The other mechanism that involves CFTR in ASL pH regulation is its capacity to regulate Cl − /HCO 3 − anion exchange, and more particularly, SLC26A4 in airway epithelial cells.…”

Section: Role Of Cftr In the Lungsmentioning

confidence: 99%

Role of CFTR in epithelial physiology

Saint‐Criq

Gray

2016

Cell. Mol. Life Sci.

303

291

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Salt and fluid absorption and secretion are two processes that are fundamental to epithelial function and whole body fluid homeostasis, and as such are tightly regulated in epithelial tissues. The CFTR anion channel plays a major role in regulating both secretion and absorption in a diverse range of epithelial tissues, including the airways, the GI and reproductive tracts, sweat and salivary glands. It is not surprising then that defects in CFTR function are linked to disease, including life-threatening secretory diarrhoeas, such as cholera, as well as the inherited disease, cystic fibrosis (CF), one of the most common life-limiting genetic diseases in Caucasian populations. More recently, CFTR dysfunction has also been implicated in the pathogenesis of acute pancreatitis, chronic obstructive pulmonary disease (COPD), and the hyper-responsiveness in asthma, underscoring its fundamental role in whole body health and disease. CFTR regulates many mechanisms in epithelial physiology, such as maintaining epithelial surface hydration and regulating luminal pH. Indeed, recent studies have identified luminal pH as an important arbiter of epithelial barrier function and innate defence, particularly in the airways and GI tract. In this chapter, we will illustrate the different operational roles of CFTR in epithelial function by describing its characteristics in three different tissues: the airways, the pancreas, and the sweat gland.

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Increased expression of the epithelial anion transporter pendrin/SLC26A4 in nasal polyps of patients with chronic rhinosinusitis

Cited by 55 publications

References 40 publications

Inhibitors of pendrin anion exchange identified in a small molecule screen increase airway surface liquid volume in cystic fibrosis

Inhibitors of pendrin anion exchange identified in a small molecule screen increase airway surface liquid volume in cystic fibrosis

Chronic Rhinosinusitis with Nasal Polyps

Role of CFTR in epithelial physiology

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