Loss of Cystic Fibrosis Transmembrane Conductance Regulator Function Produces Abnormalities in Tracheal Development in Neonatal Pigs and Young Children

Meyerholz, David K.; Stoltz, David A.; Namati, Eman; Ramachandran, Shyam; Pezzulo, Alejandro A.; Smith, Amanda R.; Rector, Michael V.; Suter, Melissa J.; Kao, Simon C.; McLennan, Geoffrey; Tearney, Guillermo J.; Zabner, Joseph; McCray, Paul B.; Welsh, Michael J.

doi:10.1164/rccm.201004-0643oc

Cited by 182 publications

(238 citation statements)

References 56 publications

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“…Despite substantial variability at different locations within individual airways, these data suggest that MUC5AC is the predominant mucin produced by goblet cells. These results are consistent with earlier studies in porcine and human airways (1,4,5,28). In addition, WGA labeling did not colocalize with anti-MUC5AC antibody, and JAC labeling did not colocalize with anti-MUC5B antibody ( Fig.…”

Section: Resultssupporting

confidence: 93%

“…1A). The presence of MUC5B but not MUC5AC in submucosal glands is consistent with previous studies in humans and pigs (1,4,5,28).…”

Section: Resultssupporting

confidence: 92%

“…However, MUC5B and MUC5AC transcripts, Western blotting of mucin protein, goblet cell numbers, and mucus glycosylation did not differ by genotype (28,29). In addition, controlling the solution volume and maintaining pH at 7.35 on the apical surface did not prevent the mucus abnormality or impaired MCT (21).…”

Section: Strands Of Muc5b Mucus Emerge From Submucosal Glands Andmentioning

confidence: 82%

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Gel-forming mucins form distinct morphologic structures in airways

Ostedgaard

Moninger

McMenimen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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144

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Gel-forming mucins, the primary macromolecular components of airway mucus, facilitate airway clearance by mucociliary transport. In cystic fibrosis (CF) altered mucus properties impair mucociliary transport. Airways primarily secrete two closely related gel-forming mucins, MUC5B and MUC5AC. However, their morphologic structures and associations in airways that contain abundant submucosal glands and goblet cells are uncertain. Moreover, there is limited knowledge about mucins in airways not affected by inflammation, infection, or remodeling or in CF airways. Therefore, we examined airways freshly excised from newborn non-CF pigs and CF pigs before secondary manifestations develop. We found that porcine submucosal glands produce MUC5B, whereas goblet cells produce predominantly MUC5AC plus some MUC5B. We found that MUC5B emerged from submucosal gland ducts in the form of strands composed of multiple MUC5B filaments. In contrast, MUC5AC emerged from goblet cells as wispy threads and sometimes formed mucin sheets. In addition, MUC5AC often partially coated the MUC5B strands. Compared with non-CF, MUC5B more often filled CF submucosal gland ducts. MUC5AC sheets also accumulated in CF airways overlying MUC5B strands. These results reveal distinct morphology and interactions for MUC5B and MUC5AC and suggest that the two mucins make distinct contributions to mucociliary transport. Thus, they provide a framework for understanding abnormalities in disease.mucus | cystic fibrosis | lung | asthma | COPD

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Section: Resultssupporting

confidence: 93%

“…1A). The presence of MUC5B but not MUC5AC in submucosal glands is consistent with previous studies in humans and pigs (1,4,5,28).…”

Section: Resultssupporting

confidence: 92%

Section: Strands Of Muc5b Mucus Emerge From Submucosal Glands Andmentioning

confidence: 82%

See 1 more Smart Citation

Gel-forming mucins form distinct morphologic structures in airways

Ostedgaard

Moninger

McMenimen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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144

178

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“…A limitation of this study is that loss of CFTR may influence the function of other cell types and structures, including submucosal glands (31,55), airway smooth muscle (56), cartilage (57,58), and myeloid-derived cells (59). Impairment of their function might also contribute to the pathogenesis of CF airway disease.…”

Section: As Hcomentioning

confidence: 99%

Relationships among CFTR expression, HCO ₃ ⁻ secretion, and host defense may inform gene- and cell-based cystic fibrosis therapies

Shah

Ernst

Tang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. Airway disease is the major source of morbidity and mortality. Successful implementation of gene- and cell-based therapies for CF airway disease requires knowledge of relationships among percentages of targeted cells, levels of CFTR expression, correction of electrolyte transport, and rescue of host defense defects. Previous studies suggested that, when ∼10–50% of airway epithelial cells expressed CFTR, they generated nearly wild-type levels of Cl− secretion; overexpressing CFTR offered no advantage compared with endogenous expression levels. However, recent discoveries focused attention on CFTR-mediated HCO3− secretion and airway surface liquid (ASL) pH as critical for host defense and CF pathogenesis. Therefore, we generated porcine airway epithelia with varying ratios of CF and wild-type cells. Epithelia with a 50:50 mix secreted HCO3− at half the rate of wild-type epithelia. Likewise, heterozygous epithelia (CFTR+/− or CFTR+/∆F508) expressed CFTR and secreted HCO3− at ∼50% of wild-type values. ASL pH, antimicrobial activity, and viscosity showed similar relationships to the amount of CFTR. Overexpressing CFTR increased HCO3− secretion to rates greater than wild type, but ASL pH did not exceed wild-type values. Thus, in contrast to Cl− secretion, the amount of CFTR is rate-limiting for HCO3− secretion and for correcting host defense abnormalities. In addition, overexpressing CFTR might produce a greater benefit than expressing CFTR at wild-type levels when targeting small fractions of cells. These findings may also explain the risk of airway disease in CF carriers.

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“…All analyses in this paragraph were done with HE stained tissues unless otherwise stated. Mean tissue thickness for the molecular layer (ML), IGL and EGL was evaluated by defining the total area of each layer and dividing by length of the layer being evaluated for an average thickness as previously described (76). The EGL was also evaluated for retention or altered migration into the ML by measuring the maximum EGL thickness in each tissue section, avoiding areas of sectioning artifact.…”

Section: Histopathology and Morphometric Analysismentioning

confidence: 99%

A novel porcine model of ataxia telangiectasia reproduces neurological features and motor deficits of human disease

et al. 2015

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Ataxia telangiectasia (AT) is a progressive multisystem disorder caused by mutations in the AT-mutated (ATM) gene. AT is a neurodegenerative disease primarily characterized by cerebellar degeneration in children leading to motor impairment. The disease progresses with other clinical manifestations including oculocutaneous telangiectasia, immune disorders, increased susceptibly to cancer and respiratory infections. Although genetic investigations and physiological models have established the linkage of ATM with AT onset, the mechanisms linking ATM to neurodegeneration remain undetermined, hindering therapeutic development. Several murine models of AT have been successfully generated showing some of the clinical manifestations of the disease, however they do not fully recapitulate the hallmark neurological phenotype, thus highlighting the need for a more suitable animal model. We engineered a novel porcine model of AT to better phenocopy the disease and bridge the gap between human and current animal models. The initial characterization of AT pigs revealed early cerebellar lesions including loss of Purkinje cells (PCs) and altered cytoarchitecture suggesting a developmental etiology for AT and could advocate for early therapies for AT patients. In addition, similar to patients, AT pigs show growth retardation and develop motor deficit phenotypes. By using the porcine system to model human AT, we established the first animal model showing PC loss and motor features of the human disease. The novel AT pig provides new opportunities to unmask functions and roles of ATM in AT disease and in physiological conditions. † These authors contributed equally.

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Loss of Cystic Fibrosis Transmembrane Conductance Regulator Function Produces Abnormalities in Tracheal Development in Neonatal Pigs and Young Children

Abstract: Our findings in newborn CF pigs and young patients with CF suggest that airway changes begin during fetal life and may contribute to CF pathogenesis and clinical disease during postnatal life.

Cited by 182 publications

References 56 publications

Gel-forming mucins form distinct morphologic structures in airways

Gel-forming mucins form distinct morphologic structures in airways

Relationships among CFTR expression, HCO ₃ ⁻ secretion, and host defense may inform gene- and cell-based cystic fibrosis therapies

A novel porcine model of ataxia telangiectasia reproduces neurological features and motor deficits of human disease

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Loss of Cystic Fibrosis Transmembrane Conductance Regulator Function Produces Abnormalities in Tracheal Development in Neonatal Pigs and Young Children

Abstract: Our findings in newborn CF pigs and young patients with CF suggest that airway changes begin during fetal life and may contribute to CF pathogenesis and clinical disease during postnatal life.

Cited by 182 publications

References 56 publications

Gel-forming mucins form distinct morphologic structures in airways

Gel-forming mucins form distinct morphologic structures in airways

Relationships among CFTR expression, HCO 3 − secretion, and host defense may inform gene- and cell-based cystic fibrosis therapies

A novel porcine model of ataxia telangiectasia reproduces neurological features and motor deficits of human disease

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Relationships among CFTR expression, HCO ₃ ⁻ secretion, and host defense may inform gene- and cell-based cystic fibrosis therapies