Air-Liquid interface cultures to model drug delivery through the mucociliary epithelial barrier

Re, Lee; Reidel, Boris; Nelson, Mark; Macdonald, Jeffrey M.; Kesımer, Mehmet; Randell, Scott H.

doi:10.1016/j.addr.2023.114866

Cited by 12 publications

(10 citation statements)

References 158 publications

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“…The development of physiologically relevant respiratory epithelium analogues is important for infection studies as these models more accurately reflect the in vivo situation. Growing Calu-3 cells on Transwell ® inserts [(two-dimensional (2D)] under ALI conditions allows the differentiation of cells into polarized monolayers and formation of pseudostratified layers and mucus production ( Kreft et al., 2015 ; Lee et al., 2023 ; Silva et al., 2023 ). However, even the use of 2D cultures on plastic surfaces and filter cultures cannot completely reproduce the microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Interaction of Neisseria meningitidis carrier and disease isolates of MenB cc32 and MenW cc22 with epithelial cells of the nasopharyngeal barrier

Peters,

Mohort,

Claus

et al. 2024

Front. Cell. Infect. Microbiol.

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Neisseria meningitidis (Nm, the meningococcus) is considered an asymptomatic colonizer of the upper respiratory tract and a transient member of its microbiome. It is assumed that the spread of N. meningitidis into the bloodstream occurs via transcytosis of the nasopharyngeal epithelial barrier without destroying the barrier layer. Here, we used Calu-3 respiratory epithelial cells that were grown under air-liquid-interface conditions to induce formation of pseudostratified layers and mucus production. The number of bacterial localizations in the outer mucus, as well as cellular adhesion, invasion and transmigration of different carrier and disease N. meningitidis isolates belonging to MenB:cc32 and MenW:cc22 lineages was assessed. In addition, the effect on barrier integrity and cytokine release was determined. Our findings showed that all strains tested resided primarily in the outer mucus layer after 24 h of infection (>80%). Nonetheless, both MenB:cc32 and MenW:cc22 carrier and disease isolates reached the surface of the epithelial cells and overcame the barrier. Interestingly, we observed a significant difference in the number of bacteria transmigrating the epithelial cell barrier, with the representative disease isolates being more efficient to transmigrate compared to carrier isolates. This could be attributed to the capacity of the disease isolates to invade, however could not be assigned to expression of the outer membrane protein Opc. Moreover, we found that the representative meningococcal isolates tested in this study did not damage the epithelial barrier, as shown by TEER measurement, FITC-dextran permeability assays, and expression of cell-junction components.

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Section: Discussionmentioning

confidence: 99%

Interaction of Neisseria meningitidis carrier and disease isolates of MenB cc32 and MenW cc22 with epithelial cells of the nasopharyngeal barrier

Peters,

Mohort,

Claus

et al. 2024

Front. Cell. Infect. Microbiol.

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“…The current gold standard pre-clinical CF model are human airway epithelial (HAE) cell cultures. 17,18 Primary CF HAE cells can be harvested from explanted tissue and differentiated at an air–liquid interface into a pseudostratified epithelium with characteristics similar to the airway in vivo . HAE cell culture models were pivotal in the development of CFTR modulator drugs, which can slow declining lung function and dramatically improve CF patient quality of life.…”

Section: Introductionmentioning

confidence: 99%

“…HAE cell culture models were pivotal in the development of CFTR modulator drugs, which can slow declining lung function and dramatically improve CF patient quality of life. 18–20 Despite this progress, CF remains an incurable disease and lung function still declines over time even with CFTR modulator treatment, partially due to chronic bacterial infections and persistent inflammation. 20 Inhaled therapeutics, including antimicrobial agents such as tobramycin and mucolytics such as DNase are commonly used in CF to treat infections and resolve airway obstruction, respectively.…”

Section: Introductionmentioning

confidence: 99%

“…17,21 Both ex vivo and in vitro models have been essential in testing new treatments and studying host-pathogen interactions in the CF airway microenvironment. 18,22–24 Despite our growing understanding of the importance of NET-mediated dysfunction in CF, traditional human in vitro models do not account for their presence.…”

Section: Introductionmentioning

confidence: 99%

“…27,28 HAE cells derived from CF donors produce minimal extracellular DNA and are unable to produce NETs without co-culture and stimulation of neutrophils. 18,29…”

Section: Introductionmentioning

confidence: 99%

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Engineering in vitro models of cystic fibrosis lung disease using neutrophil extracellular trap inspired biomaterials

Boboltz,

Yang,

Duncan

2023

J. Mater. Chem. B

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Akt activator SC79 stimulates antibacterial nitric oxide generation in human nasal epithelial cells in vitro

Lee,

Adappa,

Palmer

2024

Int Forum Allergy Rhinol

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BackgroundThe role of Akt in nasal immunity is unstudied. Akt phosphorylates and activates endothelial nitric oxide synthase (eNOS) expressed in epithelial ciliated cells. Nitric oxide (NO) production by ciliated cells can have antibacterial and antiviral effects. Increasing nasal NO may be a useful antipathogen strategy in chronic rhinosinusitis (CRS). We previously showed that small‐molecule Akt activator SC79 induces nasal cell NO production and suppresses IL‐8 via the transcription factor Nrf‐2. We hypothesized that SC79 NO production may additionally have antibacterial effects.MethodsNO production was measured using fluorescent dye DAF‐FM. We tested effects of SC79 during co‐culture of Pseudomonas aeruginosa with primary nasal epithelial cells, using CFU counting and live–dead staining to quantify bacterial killing. Pharmacology determined the mechanism of SC79‐induced NO production and tested dependence on Akt.ResultsSC79 induced dose‐dependent, Akt‐dependent NO production in nasal epithelial cells. The NO production required eNOS and Akt. The NO released into the airway surface liquid killed P. aeruginosa. No toxicity (LDH release) or inflammatory effects (IL8 transcription) were observed over 24 h.ConclusionsTogether, these data suggest multiple immune pathways are stimulated by SC79, with antipathogen effects. This in vitro pilot study suggests that a small‐molecule Akt activator may have clinical utility in CRS or respiratory other infection settings, warranting future in vivo studies.

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Air-Liquid interface cultures to model drug delivery through the mucociliary epithelial barrier

Cited by 12 publications

References 158 publications

Interaction of Neisseria meningitidis carrier and disease isolates of MenB cc32 and MenW cc22 with epithelial cells of the nasopharyngeal barrier

Interaction of Neisseria meningitidis carrier and disease isolates of MenB cc32 and MenW cc22 with epithelial cells of the nasopharyngeal barrier

Engineering in vitro models of cystic fibrosis lung disease using neutrophil extracellular trap inspired biomaterials

Akt activator SC79 stimulates antibacterial nitric oxide generation in human nasal epithelial cells in vitro

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