Regulation of Basolateral Cl− Channels in Airway Epithelial Cells: The Role of Nitric Oxide

Duta, V.; Duta, Florentina; Puttagunta, Lakshmi; Befus, A. Dean; Duszyk, Marek

doi:10.1007/s00232-006-0062-x

Cited by 23 publications

(20 citation statements)

References 31 publications

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“…These experiments strongly suggest a direct association between bestrophin-3 expression and the cGMP-dependent I Cl(Ca) . The cGMP-dependence was previously also shown for human bestrophin-1 [184,196]. In contrast, the mouse bestrophin-3 variant expressed in the heart has no cGMP dependence [198].…”

Section: Bestrophins Are Strongly Associated With the Cgmp-dependent mentioning

confidence: 72%

“…Several other groups have recently used siRNA technique in cell culture and found an association between the bestrophin proteins and I Cl(Ca) [179,181,185,195,196,197]. We have found that downregulation of bestrophin-3 in mesenteric small artery VSMCs with siRNA suppressed the cGMP-dependent I Cl(Ca) without affecting the co-expressed classical I Cl(Ca) [112].…”

Section: Bestrophins Are Strongly Associated With the Cgmp-dependent mentioning

confidence: 89%

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Transport and Function of Chloride in Vascular Smooth Muscles

et al. 2012

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This review summarizes the current knowledge of Cl^– transport in vascular smooth muscle cells (VSMCs). VSMCs accumulate Cl^– intracellularly using two secondary-active transport mechanisms. The Cl^– equilibrium potential is more positive than the resting membrane potential enabling Cl^– to be a depolarizing ion upon activation of a Cl^– conductance. Cl^– currents are involved in different vascular responses suggesting a number of different Cl^– channels. All known Cl^– channel families, with the exception of the GABA-/glycine-receptor family, have been identified in VSMCs. At least one member of the voltage-activated ClC family – ClC-3 – has been suggested to be involved in myogenic constriction, in cell proliferation and to have an anti-apoptotic action. The cystic fibrosis transmembrane conductance regulator is also demonstrated in VSMCs. The molecular identity of the major anion conductance in VSMCs – a Ca²⁺-activated Cl^– current – is uncertain. Several candidates have been suggested with bestrophin and TMEM16 protein families the current favorites. Specific pharmacological tools are lacking for Cl^– channels but recent molecular biology developments have made selective gene manipulations possible. A continuing quest within the vascular research field is to explicitly demonstrate the coupling between a putative channel protein and an endogenous Cl^– current and the importance of these for specific functions.

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Section: Bestrophins Are Strongly Associated With the Cgmp-dependent mentioning

confidence: 72%

Section: Bestrophins Are Strongly Associated With the Cgmp-dependent mentioning

confidence: 89%

Transport and Function of Chloride in Vascular Smooth Muscles

et al. 2012

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“…Nitric oxide is generated from L-arginine by nitric oxide synthases and serves as a cell-signaling molecule in many physiologic processes (24). In the lungs, nitric oxide affects epithelial cell ciliary beat frequency (25) and transepithelial anion transport (26), which facilitate airway clearance. Nitric oxide affects parasympathetic nerve function, which controls bronchoconstriction (27).…”

Section: Discussionmentioning

confidence: 99%

Toll-like Receptor 7 Rapidly Relaxes Human Airways

Drake

Scott

Proskocil

et al. 2013

Am J Respir Crit Care Med

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Rationale: Toll-like receptors (TLRs) 7 and 8 detect respiratory virus single-stranded RNA and trigger an innate immune response. We recently described rapid TLR7-mediated bronchodilation in guinea pigs. Objectives: To characterize TLR7 expression and TLR7-induced airway relaxation in humans and in eosinophilic airway inflammation in guinea pigs. To evaluate the relaxant effects of other TLRs. Methods: Human airway smooth muscle strips were contracted with methacholine in vitro, and responses to TLR7 and TLR8 agonists were assessed. TLR7-mediated nitric oxide production was measured using a fluorescent indicator, and TLR7 expression was characterized using immunofluorescence. TLR7 signaling was also evaluated in ovalbumin-challenged guinea pigs. Measurements and Main Results: The TLR7 agonist imiquimod (R837) caused rapid dose-dependent relaxation of methacholine-contracted human airways in vitro. This was blocked by the TLR7 antagonist IRS661 and by inhibiting nitric oxide production but not by inhibiting prostaglandin production. TLR7 activation markedly increased fluorescence of a nitric oxide detector. TLR7 was expressed on airway nerves, but not airway smooth muscle, implicating airway nerves as the source of TLR7-induced nitric oxide production. TLR7-mediated relaxation persisted in inflamed guinea pigs airways in vivo. The TLR8 agonists polyuridylic acid and polyadenylic acid also relaxed human airways, and this was not blocked by the TLR7 antagonist or by blocking nitric oxide or prostaglandin production. No other TLRs relaxed the airways. Conclusions: TLR7 is expressed on airway nerves and mediates relaxation of human and animal airways through nitric oxide production. TLR7-mediated bronchodilation may be a new therapeutic strategy in asthma.Keywords: Toll-like receptor 7; imiquimod; nitric oxide; asthma; nerve Toll-like receptor (TLR) 7 is a pattern recognition receptor in the lungs (1-3) that detects single-stranded RNA genomes, common to many respiratory viruses (4). Respiratory viruses cause airway hyperreactivity (an abnormal tendency to contract) (5, 6) and asthma exacerbations (7). A role for TLR7 in the development of virus-induced airway hyperreactivity has been proposed, because TLR7 activation causes a proinflammatory type 1 T-helper cell (Th1) immune response (8) and because TLR7 polymorphisms have been associated with asthma (9). In patients with asthma, however, TLR7 responses were reduced (10). Furthermore, in mouse models of allergic airway inflammation, the TLR7 imidazoquinoline agonists imiquimod (R837) and resiquimod (R848) reduced airway hyperreactivity, airway eosinophilia, goblet cell hyperplasia, and smooth muscle hypertrophy (11-14), whereas TLR7 knockout mice were prone to the development of asthma-like airway pathology after pneumovirus infection (15). These studies suggest that TLR7 may be protective against the development of allergic type 2 T-helper cell airway inflammation, possibly by altering the Th1 versus Th2 immune balance (16). Similarly, a TLR7 agonist is currently i...

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“…Bestrophins (also known as BEST or VMD2) are members of a family of CaCC found in epithelial tissues that express Ca 2ϩ -activated Cl Ϫ currents (1)(2)(3). The recent discovery of the TMEM16 (also termed ANO) family of CaCC (4 -7) introduces additional questions regarding the molecular identity of the epithelial CaCC.…”

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confidence: 99%