Intra-tracheal Administration of &lt;em&gt;Haemophilus influenzae&lt;/em&gt; in Mouse Models to Study Airway Inflammation

Venuprasad, K.; Theivanthiran, Balamayooran; Cantarel, Brandi L.

doi:10.3791/53964

Cited by 2 publications

(4 citation statements)

References 16 publications

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“…Subsequently, increased MUC5AC mRNA was maintained via EGFR signaling through increased metalloproteinase and EGFR ligand production. Consistent with previous studies in mice, [ 16–19 ] intratracheal NTHi exposure in our study induced pulmonary inflammation, particularly neutrophil influx, which phloretin inhibited. Moreover, phloretin inhibited the increase in MUC5AC induced by NTHi in mouse lung and human airway epithelial cells.…”

Section: Discussionsupporting

confidence: 93%

“…In mice, intratracheal and intranasal instillation of NTHi induces pulmonary histopathological changes including bronchial, bronchiolar, and alveolar epithelial injury and inflammatory cell infiltration. [ 16–19 ] In this study, intratracheal NTHi also induced inflammatory cell influx into the airways, particularly neutrophils, which a phloretin‐enriched diet inhibited (Figure S1, Supporting Information). Previously, phloretin was found to protect against ovalbumin [ 20 ] and cigarette smoke‐induced [ 15 ] MUC5AC production in mice.…”

Section: Resultsmentioning

confidence: 62%

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Phloretin, an Apple Polyphenol, Inhibits Pathogen‐Induced Mucin Overproduction

Birru

Bein

Wells

et al. 2020

Molecular Nutrition Food Res

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Scope Bacterial infection induces mucus overproduction, contributing to acute exacerbations and lung function decline in chronic respiratory diseases. A diet enriched in apples may provide protection from pulmonary disease development and progression. This study examined whether phloretin, an apple polyphenol, inhibits mucus synthesis and secretion induced by the predominant bacteria associated with chronic respiratory diseases. Methods and Results The expression of mucus constituent mucin 5AC (MUC5AC) in FVB/NJ mice and NCI‐H292 epithelial cells is analyzed. Nontypeable Haemophilus influenzae (NTHi)‐infected mice developed increased MUC5AC mRNA, which a diet containing phloretin inhibited. In NCI‐H292 cells, NTHi, Moraxella catarrhalis, Streptococcus pneumoniae, and Pseudomonas aeruginosa increased MUC5AC mRNA, which phloretin inhibited. Phloretin also diminished NTHi‐induced MUC5AC protein secretion. NTHi‐induced increased MUC5AC required toll‐like receptor 4 (TLR4) and NADH oxidase 4 (NOX4) signaling and subsequent activation of the epidermal growth factor receptor (EGFR)/mitogen‐activated protein kinase (MAPK) pathway. Phloretin inhibited NTHi‐induced TLR4/NOX4 and EGFR/MAPK signaling, thereby preventing increased MUC5AC mRNA. EGFR activation can also result from increased EGFR ligand synthesis and subsequent ligand activation by matrix metalloproteinases (MMPs). In NCI‐H292 cells, NTHi increased EGFR ligand and MMP1 and MMP13 mRNA, which phloretin inhibited. Conclusions In summary, phloretin is a promising therapeutic candidate for preventing bacterial‐induced mucus overproduction.

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Section: Discussionsupporting

confidence: 93%

Section: Resultsmentioning

confidence: 62%

Phloretin, an Apple Polyphenol, Inhibits Pathogen‐Induced Mucin Overproduction

Birru

Bein

Wells

et al. 2020

Molecular Nutrition Food Res

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“…Mice were randomly divided into six groups (five mice per group): bacteria only, MYY9 therapy, HX1 therapy, MYY9 only, HX1 only, and the normal control. To establish the acute infection models, P. aeruginosa PAO1 and W 19 strains were used to set up acute pneumonia by the intratracheal administration of approximately 1 Â 10 8 and 2 Â 10 7 CFU in 50 ml, respectively, under anesthetized conditions (58). After 2 h of bacterial infection, the phages were administered to achieve therapeutic aims by tail vein injection (system delivery) and intratracheal instillation (topical application) in mice (47,48).…”

Section: Methodsmentioning

confidence: 99%

“…The trachea was excised and intubated with a catheter. The lavage fluid was collected via instilling and aspirating 1 ml of sterile PBS repeatedly (58). Concentrations of the inflammatory biomarkers interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-a) were measured via an ELISA kit (Neobioscreen, China) according to the recommendations of the manufacturer.…”

Section: Methodsmentioning

confidence: 99%

Novel Lytic Phages Protect Cells and Mice against Pseudomonas aeruginosa Infection

Chen

Cheng

et al. 2021

J Virol

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With the fast emergence of serious antibiotic resistance and the lagged discovery of novel antibacterial drugs, phage therapy for pathogenic bacterial infections has acquired great attention in the clinics. However, development of therapeutic phages also faces tough challenges, such as laborious screening and time to generate effective phage drugs since each phage may only lyse a narrow scope of bacterial strains. Identifying highly effective phages with broad host ranges is crucial for improving phage therapy. Here, we isolated and characterized several lytic phages from various environments specific for Pseudomonas aeruginosa by testing their growth, invasion, host ranges, and potential for killing targeted bacteria. Importantly, we identified several therapeutic phages (HX1, PPY9, and TH15) with broad host ranges to lyse laboratory strains and clinical isolates of P. aeruginosa with multi-drug resistance (MDR) both in vitro and in mouse models. In addition, we analyzed critical genetic traits related to the high-level broad host coverages by genome sequencing and subsequent computational analysis against known phages. Collectively, our findings establish that these novel phages may have potential for further development as therapeutic options for patients who fail to respond to conventional treatments. IMPORTANCE Novel lytic phages isolated from various environmental settings were systematically characterized for their critical genetic traits, morphology structures, host ranges against laboratory strains and clinical multi-drug resistant (MDR) Pseudomonas aeruginosa, and antibacterial capacity both in vitro and in mouse models. First, we characterized the genetic traits and compared with other existing phages. Furthermore, we utilized acute pneumonia induced by laboratorial strain PAO1, and W19, an MDR clinical isolate and chronic pneumonia by agar beads laden with FDR1, a mucoid phenotype strain isolated from the sputum of a cystic fibrosis (CF) patient. Consequently, we found that these phages not only suppress bacteria in vitro but also significantly reduce the infection symptom and disease progression in vivo, including lowered bug burdens, inflammatory responses and lung injury in mice, suggesting that they may be further developed as therapeutic agents against MDR P. aeruginosa.

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Intra-tracheal Administration of <em>Haemophilus influenzae</em> in Mouse Models to Study Airway Inflammation

Cited by 2 publications

References 16 publications

Phloretin, an Apple Polyphenol, Inhibits Pathogen‐Induced Mucin Overproduction

Phloretin, an Apple Polyphenol, Inhibits Pathogen‐Induced Mucin Overproduction

Novel Lytic Phages Protect Cells and Mice against Pseudomonas aeruginosa Infection

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