Development of an airway mucus defect in the cystic fibrosis rat

Birket, Susan E.; Davis, Julia; Fernandez, Courtney M.; Tuggle, Katherine L.; Oden, Ashley M; Chu, Kengyeh K.; Tearney, Guillermo J.; Fanucchi, Michelle V.; Sorscher, Eric J.; Rowe, Steven M.

doi:10.1172/jci.insight.97199

Cited by 95 publications

(134 citation statements)

References 67 publications

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“…Similarly, Hoegger and colleagues found a failure of mucus detachment from airway submucosal glands in newborn pigs with CF, resulting in impaired mucociliary transport (6). Likewise, rats with CF displayed submucosal gland duct plugging prior to onset of airway infection (7), whereas ferrets with CF showed excessive mucus accumulation even in a sterile airway environment (8). Combined, these studies highlight the submucosal gland as a key node in CF pathogenesis (9), and suggest that abnormal mucus might precede infection and inflammation.…”

Section: Introductionmentioning

confidence: 95%

“…CF airways are distinguished by impaired mucociliary transport (6,7,28,29). Thus, to determine whether intra-airway induced mucociliary transport defects, we utilized freshly excised tracheal segments stimulated with methacholine under diminished bicarbonate and chloride transport conditions.…”

Section: Mucociliary Transport Is Impaired In Acid-challenged Airwaysmentioning

confidence: 99%

“…The lack of bicarbonate transport and an acidic airway pH hypothesis has received scrutiny as studies describing acidification find that it occurs early in disease. For example, decreased airway pH has been found in CF pigs (18) and CF rats (7) prior to the onset of infection and inflammation, whereas in humans, decreased airway surface pH has been described in neonates with CF (19), but not children (20,21).…”

Section: Introductionmentioning

confidence: 99%

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Acid exposure impairs mucus secretion and disrupts mucus transport in neonatal piglet airways

Liao

Kuan

Guevara

et al. 2019

Preprint

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# equal contribution % equal contribution ABSTRACT Tenacious mucus produced by tracheal and bronchial submucosal glands is a defining feature of cystic fibrosis (CF). Although airway acidification occurs early in CF, whether transient acidification is sufficient to initiate mucus abnormalities is unknown. We studied mucus secretion and mucus transport in piglets forty-eight hours following an intra-airway acid challenge. Acid-challenged piglet airways were distinguished by increased mucin 5B (MUC5B) in the submucosal gland but decreased lung lavage fluid MUC5B, following in vivo cholinergic stimulation, suggesting a failure in submucosal gland secretion. Concomitantly, intrapulmonary airways were obstructed with glycoprotein rich material under both basal and methacholinestimulated conditions. To mimic a CF-like environment, we also studied mucus secretion and transport under diminished bicarbonate and chloride transport conditions ex vivo. Cholinergic stimulation in acid-challenged piglet airways induced extensive mucus films, greater mucus strand formation, increased dilation of submucosal gland duct openings and decreased mucociliary transport. Finally, to elucidate potential mediators of acid-induced mucus defects, we investigated diminazene aceturate, a small molecule that inhibits the acid-sensing ion channel (ASIC). Diminazene aceturate restored surface MUC5B in acid-challenged piglet airways under basal conditions, mitigated acid-induced airway obstruction, and magnified the number of dilated submucosal gland duct openings. These findings suggest that even transient airway acidification early in life might have profound impacts on mucus secretion and transport properties. Further they highlight diminazene aceturate as an agent that might be beneficial in alleviating certain mucus defects in CF airway disease.

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Section: Introductionmentioning

confidence: 95%

Section: Mucociliary Transport Is Impaired In Acid-challenged Airwaysmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Acid exposure impairs mucus secretion and disrupts mucus transport in neonatal piglet airways

Liao

Kuan

Guevara

et al. 2019

Preprint

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“…Impaired PGE2‐stimulated chloride and bicarbonate secretion in submucosal glands also contribute to cystic fibrosis airway disease . The importance of bicarbonate is further manifest by a recent report of data from the CF rat, in which correction of low pH and bicarbonate transport is a specific target for restoring mucus clearance . Further regarding oxygen detection in mucin‐blocked airways, neurosecretory cells at bronchial bifurcations signal to the brain through their vagal nerve innervation that CO 2 levels are high and O 2 levels are low.…”

Section: What Symptoms Must Be Suppressed By a Durable Therapy In Thementioning

confidence: 99%

“…27 The importance of bicarbonate is further manifest by a recent report of data from the CF rat, in which correction of low pH and bicarbonate transport is a specific target for restoring mucus clearance. 28 Further regarding oxygen detection in mucin-blocked airways, neurosecretory cells at bronchial bifurcations signal to the brain through their vagal nerve innervation that CO 2 levels are high and O 2 levels are low. Vagal innervation which contributes to the cough reflex in humans, 29 may be very important to the CF patient for helping clear blocked airways.…”

Section: Thick Sticky Mucusmentioning

confidence: 99%

Induced pluripotent stem cells for treating cystic fibrosis: State of the science

Pollard¹,

Pollard

2018

Pediatric Pulmonology

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Induced pluripotent stem cells (iPSCs) are a recently developed technology in which fully differentiated cells such as fibroblasts from individual CF patients can be repaired with [wildtype] CFTR, and reprogrammed to differentiate into fully differentiated cells characteristic of the proximal and distal airways. Here, we review properties of different epithelial cells in the airway, and the in vitro genetic roadmap which iPSCs follow as they are step-wise differentiated into either basal stem cells, for the proximal airway, or into Type II Alveolar cells for the distal airways. The central theme is that iPSC-derived basal stem cells, are penultimately dependent on NOTCH signaling for differentiation into club cells, goblet cells, ciliated cells, and neuroendocrine cells. Furthermore, given the proper matrix, these cellular progenies are also able to self-assemble into a fully functional pseudostratified squamous proximal airway epithelium. By contrast, club cells are reserve stem cells which are able to either differentiate into goblet or ciliated cells, but also to de-differentiate into basal stem cells. Variant club cells, located at the transition between airway and alveoli, may also be responsible for differentiation into Type II Alveolar cells, which then differentiate into Type I Alveolar cells for gas exchange in the distal airway. Using gene editing, the mutant CFTR gene in iPSCs from CF patients can be repaired, and fully functional epithelial cells can thus be generated through directed differentiation. However, there is a limitation in that the lung has other CFTR-dependent cells besides epithelial cells. Another limitation is that there are CFTR-dependent cells in other organs which would continue to contribute to CF disease. Furthermore, there are also bystander or modifier genes which affect disease outcome, not only in the lung, but specifically in other CF-affected organs. Finally, we discuss future personalized applications of the iPSC technology, many of which have already survived the "proof-of-principle" test. These include (i) patient-derived iPSCs used as a "lung-on-a-chip" tool for personalized drug discovery; (ii) replacement of mutant lung cells by wildtype lung cells in the living lung; and (iii) development of bio-artificial lungs. It is hoped that this review will give the reader a roadmap through the most complicated of the obstacles, and foster a guardedly optimistic view of how some of the remaining obstacles might one day be overcome.

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Cystic Fibrosis

Ong

Ramsey

2023

JAMA

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ImportanceCystic fibrosis, a genetic disorder defined by variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, affects more than 30 000 individuals in the US and approximately 89 000 worldwide. Absent or decreased function of the CFTR protein is associated with multiorgan dysfunction and shortened life expectancy.ObservationsCFTR is an anion channel in the apical membrane of epithelial cells. Loss of function leads to obstructed exocrine glands. Of people with cystic fibrosis in the US, approximately 85.5% have the gene variant F508del. Manifestations of cystic fibrosis in patients with the F508del gene variant begin in infancy with steatorrhea, poor weight gain, and respiratory symptoms (coughing, wheezing). As people with cystic fibrosis age, chronic respiratory bacterial infections cause loss of lung function and bronchiectasis. With the availability of universal newborn screening in multiple countries including the US, many people with cystic fibrosis are asymptomatic at diagnosis. With multidisciplinary care teams that included dietitians, respiratory therapists, and social workers, treatment of cystic fibrosis can slow disease progression. Median survival has improved from 36.3 years (95% CI, 35.1-37.9) in 2006 to 53.1 years (95% CI, 51.6-54.7) in 2021. Pulmonary therapies for patients with cystic fibrosis consist of mucolytics (eg, dornase alfa), anti-inflammatories (eg, azithromycin), and antibiotics (such as tobramycin delivered by a nebulizer). Four small molecular therapies, termed CFTR modulators, that facilitate CFTR production and/or function have received regulatory approval. Examples are ivacaftor and elexacaftor-tezacaftor-ivacaftor. For example, in patients with 1 F508del variant, the combination of ivacaftor, tezacaftor, and elexacaftor improved lung function from −0.2% in the placebo group to 13.6% (difference, 13.8%; 95% CI, 12.1%-15.4%) and decreased the annualized estimated rate of pulmonary exacerbations from 0.98 to 0.37 (rate ratio, 0.37; 95% CI, 0.25-0.55). Improved respiratory function and symptoms have lasted up to 144 weeks in postapproval observational studies. An additional 177 variants are eligible for treatment with the elexacaftor-tezacaftor-ivacaftor combination.ConclusionCystic fibrosis affects approximately 89 000 people worldwide and is associated with a spectrum of disease related to exocrine dysfunction, including chronic respiratory bacterial infections and reduced life expectancy. First-line pulmonary therapies consist of mucolytics, anti-inflammatories, and antibiotics, and approximately 90% of people with cystic fibrosis who are 2 years or older may benefit from a combination of ivacaftor, tezacaftor, and elexacaftor.

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Development of an airway mucus defect in the cystic fibrosis rat

Cited by 95 publications

References 67 publications

Acid exposure impairs mucus secretion and disrupts mucus transport in neonatal piglet airways

Acid exposure impairs mucus secretion and disrupts mucus transport in neonatal piglet airways

Induced pluripotent stem cells for treating cystic fibrosis: State of the science

Cystic Fibrosis

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