<scp>MUC5B</scp> induces in vitro neutrophil extracellular trap formation: Implication in otitis media

Val, Stéphanie; Krueger, Anna; Hussain, A.; Tomney, Amarel; Chen, Yajun; Lazarski, Christopher A.; Preciado, Diego

doi:10.1002/lio2.396

Cited by 6 publications

(5 citation statements)

References 29 publications

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“…32,[37][38][39] with viscous, difficult to clear effusion, biofilm formation, disease recurrence, and chronicity. 22,35,[40][41][42][43] Consistent with the pattern previously observed in pediatric primary cultures relative to HMEEC-1, 28 baseline expressions of OM-relevant cytokines and mucins was higher in the immortalized pediatric MEE lines (including non-OM derived PCI) relative to adultderived HMEEC-1, with the exception of IL6. This finding is in agreement with differences in innate immunity observed in adults relative to children predisposing the latter toward excessive inflammation.…”

Section: Discussionsupporting

confidence: 84%

“…These cytokines are thought to be responsible for many of the inflammatory changes induced by pathogenic organisms during OM as well as delayed recovery, recurrence, and persistence or chronicity of OME 32,37–39 . MUC5AC and MUC5B encode mucin 5AC and 5B, large secreted mucins which are hypersecreted during OM and associated with viscous, difficult to clear effusion, biofilm formation, disease recurrence, and chronicity 22,35,40–43 …”

Section: Discussionmentioning

confidence: 99%

“… 32 , 37 , 38 , 39 MUC5AC and MUC5B encode mucin 5AC and 5B, large secreted mucins which are hypersecreted during OM and associated with viscous, difficult to clear effusion, biofilm formation, disease recurrence, and chronicity. 22 , 35 , 40 , 41 , 42 , 43 …”

Section: Discussionmentioning

confidence: 99%

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Establishment of novel immortalized middle ear cell lines as models for otitis media

Blaine‐Sauer,

Samuels,

Khampang

et al. 2023

Laryngoscope Investig Oto

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ObjectiveOtitis media (OM) is among the most frequently diagnosed pediatric diseases in the US. Despite the significant public health burden of OM and the contribution research in culture models has made to understanding its pathobiology, a singular immortalized human middle ear epithelial (MEE) cell line exists (HMEEC‐1, adult‐derived). We previously developed MEE cultures from pediatric patients with non‐inflamed MEE (PCI), recurrent OM (ROM), or OM with effusion (OME) and demonstrated differences in their baseline inflammatory cytokine expression and response to stimulation with an OM‐relevant pathogen lysate and cytokines. Herein, we sought to immortalize these cultures and assess retention of their phenotypes.MethodsMEE cultures were immortalized via lentivirus encoding temperature‐sensitive SV40 T antigen. Immortalized MEE lines and HMEEC‐1 grown in monolayer were stimulated with non‐typeable Haemophilus influenzae (NTHi) lysate. Gene expression (TNFA, IL1B, IL6, IL8, MUC5AC, and MUC5B) was assessed by qPCR.ResultsSimilar to parental cultures, baseline cytokine expressions were higher in pediatric OM lines than in HMEEC‐1 and PCI, and HMEEC‐1 cells were less responsive to stimulation than pediatric lines.ConclusionImmortalized MEE lines retained the inflammatory expression and responsiveness of their tissues of origin and differences between non‐OM versus OM and pediatric versus adult cultures, supporting their value as novel in vitro culture models for OM.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Establishment of novel immortalized middle ear cell lines as models for otitis media

Blaine‐Sauer,

Samuels,

Khampang

et al. 2023

Laryngoscope Investig Oto

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“…Tobacco smoke and in vitro neutrophil stimulation by purified MUC5B induces neutrophils to undergo NETosis, and smoking and genetic variants associated with increased MUC5B production are known risk factors for IPF [20][21][22][23][24]. Additionally, in mouse models, inhibition of NETosis reduces bleomycin-induced lung injury [25].…”

Section: Discussionmentioning

confidence: 99%

Neutrophil extracellular traps linked to idiopathic pulmonary fibrosis severity and survival

Matson,

Ngo,

Sugawara

et al. 2024

Preprint

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Rationale: Neutrophil counts in bronchoalveolar lavage fluid in idiopathic pulmonary fibrosis are associated with worse outcomes; however, the underlying mechanisms are unknown. Neutrophil extracellular trap formation is associated with worse outcomes in several chronic lung diseases however, there is an unknown role in idiopathic pulmonary fibrosis. Objectives: To determine the relationship between neutrophil extracellular trap formation in the lungs of idiopathic pulmonary fibrosis patients and clinical outcomes. Methods: In a discovery cohort of 156 patients with idiopathic pulmonary fibrosis, we measured neutrophil extracellular trap markers in bronchoalveolar lavage fluid, including extracellular DNA, DNA-myeloperoxidase complexes, calprotectin, and neutrophil elastase. We assessed the correlation of these markers with baseline pulmonary function and survival. In a subset of 50 patients, label-free quantitative proteomics was performed to identify the source of extracellular DNA. A validation cohort of 52 patients was similarly assessed. Measurements and Main Results: Neutrophil extracellular trap markers in the discovery cohort were significantly correlated with worse pulmonary function (p<0.03). Higher levels of these markers predicted worse survival after adjusting for gender, age, and baseline physiologic severity (hazard ratio range: 1.79 − 2.19). Proteomics revealed a significant correlation between extracellular DNA levels and proteins related to neutrophil extracellular trap formation. The validation cohort showed that extracellular DNA levels were associated with reduced pulmonary function (p=0.04) and trend towards worse survival (hazard ratio=2.16). Conclusions: Neutrophil extracellular trap formation markers were associated with disease severity and worse survival in idiopathic pulmonary fibrosis. These findings suggest neutrophil extracellular trap formation contributes to lung injury and decreased survival and may represent a potential therapeutic target.

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“…MUC5B, a particularly large and viscous mucin, is one of the most abundant proteins in mucoid effusion and major determinant of viscosity 61 . MUC5B promotes NETosis 66,67 and complexes with NETs in MEF 36 forming the basis of ME biofilms, which provide a nutrient‐rich niche for bacteria that protects against mucociliary clearance and antibiotic penetrance 68 …”

Section: Discussionmentioning

confidence: 99%

Association of Pepsin With Inflammatory Signaling and Effusion Viscosity in Pediatric Otitis Media

et al. 2021

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Objective: Otitis media (OM) is a common inflammatory disease spectrum. Cytokine signaling, neutrophil activity, and mucin hypersecretion during recurrent and chronic OM contribute to persistent, viscous middle ear (ME) effusions, hearing loss, and potential for developmental delay. Extraesophageal reflux (EER), specifically pepsin, triggers inflammatory signaling in respiratory mucosa and is associated with OM. The objective of this study was to investigate the association of pepsin with ME inflammatory signaling and the outcomes and examine causality in vitro.Study Design: Cross-sectional study. Methods: ME fluid (MEF) and preoperative audiometric data were collected from 30 pediatric subjects undergoing tympanostomy tube placement for recurrent OM or OM with effusion. MEF viscosity was characterized by the surgeon. Pepsin, inflammatory molecules, and mucin were assayed by enzyme-linked immunosorbent assay (ELISA). ME epithelial primary culture was exposed to 0.1 to 1 mg/ml pepsin at pH 5, 6, and 7 for 30 minutes, and cytokine expression was assayed via qPCR.Results: Pepsin was observed in the MEF of 77% of patients (range 71-2,734 ng/ml). Pepsin correlated with effusion viscosity, interleukins À6 and À8, neutrophil elastase, and mucin 5B (P < .05). Pepsin-negative MEF was more frequently absent of interleukin 8 or mucin 5B (P < .05). Weak acid was generally insufficient to elicit cytokine expression in ME cells in vitro, however, pepsin induced IL6, IL8, and TNF at pH 7 (P < .05) and weak acid (pH 6) facilitated a response at lower pepsin concentration.Conclusions: Pepsin may contribute to inflammatory signaling, persistent viscous effusion, and poorer OM outcomes.

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MUC5B induces in vitro neutrophil extracellular trap formation: Implication in otitis media

Cited by 6 publications

References 29 publications

Establishment of novel immortalized middle ear cell lines as models for otitis media

Establishment of novel immortalized middle ear cell lines as models for otitis media

Neutrophil extracellular traps linked to idiopathic pulmonary fibrosis severity and survival

Association of Pepsin With Inflammatory Signaling and Effusion Viscosity in Pediatric Otitis Media

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