New Insights into Upper Airway Innate Immunity

Hariri, Benjamin M.; Cohen, Noam A.

doi:10.2500/ajra.2016.30.4360

Cited by 66 publications

(70 citation statements)

References 83 publications

(111 reference statements)

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“…However, another important primary innate host defence mechanism in the airway epithelial cells is the production of antimicrobial peptides (AMPs). Indeed, epithelial cells synthesize and secrete AMPs either constitutively or inducibly upon viral and bacterial infections (Hariri and Cohen, 2016). Here we measured by ELISA assays the apical and basal secretion of defensins and cathelicidin, which represent the two main respiratory epithelium AMP classes, during different viral infections.…”

Section: Rhinoviruses and Influenza A(h1n1) Induce An Increase Of Antmentioning

confidence: 99%

Antiviral drug screening by assessing epithelial functions and innate immune responses in human 3D airway epithelium model

et al. 2018

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Respiratory viral infections cause mild to severe diseases, such as common cold, bronchiolitis and pneumonia and are associated with substantial burden for society. To test new molecules for shortening, alleviating the diseases or to develop new therapies, relevant human in vitro models are mandatory. MucilAir™, a human standardized air-liquid interface 3D airway epithelial culture holds in vitro specific mechanisms to counter invaders comparable to the in vivo situation, such as mucus production, mucociliary clearance, and secretion of defensive molecules. The objective of this study was to test the relevance of such a model for the discovery and validation of antiviral drugs. Fully differentiated 3D nasal epithelium cultures were inoculated with picornaviruses, a coronavirus and influenza A viruses in the absence or in the presence of reference antiviral drugs. Results showed that, rupintrivir efficiently inhibits the replication of respiratory picornaviruses in a dose dependent manner and prevents the impairment of the mucociliary clearance. Similarly, oseltamivir reduced the replication of influenza A viruses in a dose dependent manner and prevented the impairment of the epithelial barrier function and cytotoxicity until 4 days of infection. In addition we found that Rhinovirus B14, C15 and influenza A(H1N1) induce significant increase of β Defensins 2 and Cathelicidin release with different time course. These results reveal that a large panel of epithelial functions is modified upon viral infection and validate MucilAir™ as a pertinent tool for pre-clinical antiviral drug testing.

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Section: Rhinoviruses and Influenza A(h1n1) Induce An Increase Of Antmentioning

confidence: 99%

Antiviral drug screening by assessing epithelial functions and innate immune responses in human 3D airway epithelium model

et al. 2018

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“…Because PAR-2 is a GPCR tied to inositol trisphosphate production and intracellular Ca 2+ signaling (15), we examined whether PAR-2 activates acute Ca 2+ responses in primary sinonasal epithelial cells and the effect on motile cilia beating, which drives mucociliary clearance, the main physical defense of the airways (28). Ca 2+ generally increases ciliary beat frequency (CBF) (29), although some Ca 2+ agonists do not increase CBF, either because of insufficient magnitude or because of localization of the Ca 2+ response.…”

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confidence: 99%

Protease‐activated receptor 2 activates airway apical membrane chloride permeability and increases ciliary beating

et al. 2017

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Mucociliary clearance, driven by the engine of ciliary beating, is the primary physical airway defense against inhaled pathogens and irritants. A better understanding of the regulation of ciliary beating and mucociliary transport is necessary for identifying new receptor targets to stimulate improved clearance in airway diseases, such as cystic fibrosis and chronic rhinosinusitis. In this study, we examined the protease-activated receptor (PAR)-2, a GPCR previously shown to regulate airway cell cytokine and mucus secretion, and transepithelial Cl current. PAR-2 is activated by proteases secreted by airway neutrophils and pathogens. We cultured various airway cell lines, primary human and mouse sinonasal cells, and human bronchial cells at air-liquid interface and examined them using molecular biology, biochemistry, and live-cell imaging. We found that PAR-2 is expressed basolaterally, where it stimulates both intracellular Ca release and Ca influx, which activates low-level nitric oxide production, increases apical membrane Cl permeability ∼3-5-fold, and increases ciliary beating ∼20-50%. No molecular or functional evidence of PAR-4 was observed. These data suggest a novel and previously overlooked role of PAR-2 in airway physiology, adding to our understanding of the role of this receptor in airway Ca signaling and innate immunity.-McMahon, D. B., Workman, A. D., Kohanski, M. A., Carey, R. M., Freund, J. R., Hariri, B. M., Chen, B., Doghramji, L. J., Adappa, N. D., Palmer, J. N., Kennedy, D. W., Lee, R. J. Protease-activated receptor 2 activates airway apical membrane chloride permeability and increases ciliary beating.

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“…In healthy individuals, mucociliary clearance (MCC) is part of the innate defense mechanism and functions to protect the airways by trapping inhaled ambient pathogens within the mucus layer of epithelial surfaces and propelling it out of the airways through coordinated cilia movement . In fact, MCC is the primary mechanism by which particulate matter is removed from the airways . Normal functioning of MCC consists of 2 equally important components: mucus production and mucus transport, both of which depend on coordinated ciliary beating, adequate hydration of airway surface liquid (ASL), periciliary liquid (PCL), and mucus viscosity.…”

mentioning

confidence: 99%

“…In fact, MCC is the primary mechanism by which particulate matter is removed from the airways . Normal functioning of MCC consists of 2 equally important components: mucus production and mucus transport, both of which depend on coordinated ciliary beating, adequate hydration of airway surface liquid (ASL), periciliary liquid (PCL), and mucus viscosity. Ciliary beat frequency (CBF) is a quantifiable, highly regulated function of ciliated respiratory epithelium and an established indicator of well‐differentiated airway epithelium .…”

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confidence: 99%

Assessment of acquired mucociliary clearance defects using micro‐optical coherence tomography

Tipirneni

Grayson

Zhang

et al. 2017

Int Forum Allergy Rhinol

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Background Dehydration of airway surface liquid (ASL) disrupts normal mucociliary clearance (MCC) in sinonasal epithelium, which may lead to chronic rhinosinusitis (CRS). Abnormal chloride (Cl−) transport is one such mechanism that contributes to this disorder and can be acquired secondary to environmental perturbations, such as hypoxia at the tissue surface. The objective of this study was to assess the technological feasibility of the novel micro-optical coherence tomography (μOCT) imaging technique for investigating acquired MCC defects in cultured human sinonasal epithelial (HSNE) cells. Methods Primary HSNE cell cultures were subjected to a 1% oxygen environment for 12 hours to induce acquired cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction. Ion transport characteristics were assessed with pharmacologic manipulation in Ussing chambers. ASL, periciliary fluid (PCL), and ciliary beat frequency (CBF) were evaluated using μOCT. Results Amiloride-sensitive transport (ΔISC) was greater in cultures exposed to hypoxia (hypoxia: −13.2 ± 0.6 μA/cm2; control: −6.5 ± 0.1 μA/cm2; p < 0.01), whereas CFTR-mediated anion transport was significantly diminished (hypoxia: 28.6 ± 0.3 μA/cm2; control: 36.2 ± 1.6 μA/cm2; p < 0.01), consistent with acquired CFTR dysfunction and sodium hyperabsorption. Hypoxia diminished all markers of airway surface function microanatomy as observed with μOCT, including ASL (hypoxia: 5.0 ± 0.4 μm; control: 9.0 ± 0.9 μm; p < 0.01) and PCL depth (hypoxia: 2.5 ± 0.1 μm; control: 4.8 ± 0.3 μm; p < 0.01), and CBF (hypoxia: 8.7 ± 0.3 Hz; control: 10.2 ± 0.3 Hz; p < 0.01). Conclusion Hypoxia-induced defects in epithelial anion transport in HSNE led to predictable effects on markers of MCC measured with novel μOCT imaging. This imaging method represents a technological leap forward and is feasible for assessing acquired defects impacting the airway surface.

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New Insights into Upper Airway Innate Immunity

Abstract: Background: Protecting the upper airway from microbial infection is an important function of the immune system. Proper detection of these

Cited by 66 publications

References 83 publications

Antiviral drug screening by assessing epithelial functions and innate immune responses in human 3D airway epithelium model

Antiviral drug screening by assessing epithelial functions and innate immune responses in human 3D airway epithelium model

Protease‐activated receptor 2 activates airway apical membrane chloride permeability and increases ciliary beating

Assessment of acquired mucociliary clearance defects using micro‐optical coherence tomography

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