<i>Scnn1b</i>
            -Transgenic BALB/c Mice as a Model of Pseudomonas aeruginosa Infections of the Cystic Fibrosis Lung

Brao, Kristen; Wille, Brendan P.; Lieberman, Joshua A.; Ernst, Robert K.; Shirtliff, Mark E.; Harro, Janette M.

doi:10.1128/iai.00237-20

Cited by 12 publications

(7 citation statements)

References 67 publications

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“…The Tg+ mice are susceptible to spontaneous bacterial infection, a likely outcome of airway mucus obstruction, which is cleared significantly within four weeks of age ( 26 , 31 ). Based on a previous report that demonstrated a beneficial effect of HMGB1 inhibition on bacterial clearance in CFTR -/- mice ( 21 ), we anticipated that airway epithelial cell-specific HMGB1-deficient Tg+ mice will have a better bacterial clearance compared to HMGB1-sufficent Tg+ mice.…”

Section: Discussionmentioning

confidence: 99%

“…As a result, the Tg+ mice exhibit various features of mucoobstructive airway diseases including mucus obstruction, mucous cell metaplasia, lung inflammation, and bacterial infection (2,(25)(26)(27)(28)(29)(30). The Tg+ neonates are prone to early spontaneous bacterial infections that are cleared almost completely by the adulthood (26,31). HMGB1 levels are elevated in the BALF of Tg+ mice (18).…”

Section: Introductionmentioning

confidence: 99%

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Airway epithelial cell-specific deletion of HMGB1 exaggerates inflammatory responses in mice with muco-obstructive airway disease

Mao

Patial²,

Saini³

2023

Front. Immunol.

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High mobility group box 1 (HMGB1), a ubiquitous chromatin-binding protein required for gene transcription regulation, is released into the extracellular microenvironment by various structural and immune cells, where it is known to act as an alarmin. Here, we investigated the role of airway epithelium-specific HMGB1 in the pathogenesis of muco-obstructive lung disease in Scnn1b-transgenic (Tg+) mouse, a model of human cystic fibrosis (CF)-like lung disease. We hypothesized that airway epithelium-derived HMGB1 modulates muco-inflammatory lung responses in the Tg+ mice. The airway epithelium-specific HMGB1-deficient mice were generated and the effects of HMGB1 deletion on immune cell recruitment, airway epithelial cell composition, mucous cell metaplasia, and bacterial clearance were determined. The airway epithelium-specific deletion of HMGB1 in wild-type (WT) mice did not result in any morphological alterations in the airway epithelium. The deficiency of HMGB1 in airway epithelial cells in the Tg+ mice, however, resulted in significantly increased infiltration of macrophages, neutrophils, and eosinophils which was associated with significantly higher levels of inflammatory mediators, including G-CSF, KC, MIP-2, MCP-1, MIP-1α, MIP-1β, IP-10, and TNF-α in the airspaces. Furthermore, as compared to the HMGB1-sufficient Tg+ mice, the airway epithelial cell-specific HMGB1-deficient Tg+ mice exhibited poor resolution of spontaneous bacterial infection. The HMGB1 deficiency in the airway epithelial cells of Tg+ mice did not alter airway epithelial cell-specific responses including epithelial cell proliferation, mucous cell metaplasia, and mucus obstruction. Collectively, our findings provide novel insights into the role of airway epithelial cell-derived HMGB1 in the pathogenesis of CF-like lung disease in Tg+ mice.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Airway epithelial cell-specific deletion of HMGB1 exaggerates inflammatory responses in mice with muco-obstructive airway disease

Mao

Patial²,

Saini³

2023

Front. Immunol.

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“…These mice overexpress the β subunit of the epithelial sodium channel (β-ENaC) in the airway epithelium, resulting in increased sodium absorption similar to CF. In both studies these β-ENaC mice cleared the infections more slowly than the WT mice, indicating impaired clearance ( Mall et al, 2004 ; Brao et al, 2020 ). One of the studies further investigated the effect of PAO1 and non-mucoid or mucoid CF clinical isolates in cytokine responses and histological features ( Brao et al, 2020 ).…”

Section: Cystic Fibrosis Lung Diseasementioning

confidence: 94%

“…Multiple delivery methods exist for administering P. aeruginosa into the lungs of animals, and the chosen delivery technique is important as it determines the accuracy and precision of dosing, progression of infection, and has impacts on the animal’s health and welfare. Inoculation techniques include adding bacteria to the drinking water ( Coleman et al, 2003 ), intranasal application ( Schroeder et al, 2001 ; van Heeckeren et al, 2006 ; Brao et al, 2020 ), tracheostomy ( van Heeckeren et al, 2000 ; Hoffmann et al, 2005 ; Bayes et al, 2016 ) and non-surgical intratracheal delivery ( Schroeder et al, 2001 ; Munder et al, 2011 ) ( Table 1 ). Some factors that should be considered when deciding on which technique to use to deliver P. aeruginosa to the lungs include the target location and the number of bacteria to be delivered to that location, minimising contamination of non-target tissue, the reproducibility of the technique, and the physiological impact on the animal (e.g.…”

Section: Cystic Fibrosis Lung Diseasementioning

confidence: 99%

To bead or not to bead: A review of Pseudomonas aeruginosa lung infection models for cystic fibrosis

et al. 2023

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Cystic fibrosis (CF) lung disease is characterised by recurring bacterial infections resulting in inflammation, lung damage and ultimately respiratory failure. Pseudomonas aeruginosa is considered one of the most important lung pathogens in those with cystic fibrosis. While multiple cystic fibrosis animal models have been developed, many fail to mirror the cystic fibrosis lung disease of humans, including the colonisation by opportunistic environmental pathogens. Delivering bacteria to the lungs of animals in different forms is a way to model cystic fibrosis bacterial lung infections and disease. This review presents an overview of previous models, and factors to consider when generating a new P. aeruginosa lung infection model. The future development and application of lung infection models that more accurately reflect human cystic fibrosis lung disease has the potential to assist in understanding the pathophysiology of cystic fibrosis lung disease and for developing treatments.

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“…Studies of these mice (βENaC-Tg) demonstrated that increased airway sodium absorption causes airway surface liquid depletion, reduced mucus transport, and spontaneous CF-like lung disease with airway mucus obstruction, impaired mucociliary clearance, emphysema, and chronic inflammation including airway neutrophilia, similar to human CF lung disease [19,[21][22][23]. P. aeruginosa can infect the airways of βENaC-Tg mice, both in planktonic and biofilm forms, and form bacterial aggregates [23,24], a well-described feature of P. aeruginosa in CF patients with chronic infection [25][26][27][28]. The goal of this work was to characterize NETs and further details of the neutrophil-mediated inflammation in the airways of βENaC-Tg mice, as the best murine CF lung disease model, in the absence of bacterial infections.…”

Section: Introductionmentioning

confidence: 99%

Neutrophil extracellular traps are present in the airways of ENaC-overexpressing mice with cystic fibrosis-like lung disease

2021

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Background Neutrophils are key components of the exacerbated inflammation and tissue damage in cystic fibrosis (CF) airways. Neutrophil extracellular traps (NETs) trap and kill extracellular pathogens. While NETs are abundant in the airways of CF patients and have been hypothesized to contribute to lung damage in CF, the in vivo role of NETs remains controversial, partially due to lack of appropriate animal models. The goal of this study was to detect NETs and to further characterize neutrophil-mediated inflammation in the airways of mice overexpressing the epithelial sodium channel (βENaC-Tg mice on C57BL/6 background) in their lung with CF-like airway disease, in the absence of any apparent bacterial infections. Methods Histology scoring of lung tissues, flow cytometry, multiplex ELISA, immunohistochemistry and immunofluorescence were used to characterize NETs and the airway environment in uninfected, βENaC-Tg mice at 6 and 8 weeks of age, the most chronic time points so far studied in this model. Results Excessive neutrophilic infiltration characterized the lungs of uninfected, βENaC-Tg mice at 6 and 8 weeks of age. The bronchoalveolar lavage fluid (BALF) of βENaC-Tg mice contains increased levels of CF-associated cytokines and chemokines: KC, MIP-1α/β, MCP-1, G-CSF, IL-5, and IL-6. The BALF of βENaC-Tg mice contain MPO-DNA complexes, indicative of the presence of NETs. Immunofluorescence and flow cytometry of BALF neutrophils and lung tissues demonstrated increased histone citrullination, a NET-specific marker, in βENaC-Tg mice. Conclusions NETs are detected in the airways of βENaC-Tg mice, in the absence of bacterial infections. These data demonstrate the usefulness of the βENaC-Tg mouse to serve as a model for studying the role of NETs in chronic CF airway inflammation.

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Scnn1b -Transgenic BALB/c Mice as a Model of Pseudomonas aeruginosa Infections of the Cystic Fibrosis Lung

Cited by 12 publications

References 67 publications

Airway epithelial cell-specific deletion of HMGB1 exaggerates inflammatory responses in mice with muco-obstructive airway disease

Airway epithelial cell-specific deletion of HMGB1 exaggerates inflammatory responses in mice with muco-obstructive airway disease

To bead or not to bead: A review of Pseudomonas aeruginosa lung infection models for cystic fibrosis

Neutrophil extracellular traps are present in the airways of ENaC-overexpressing mice with cystic fibrosis-like lung disease

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