Submucosal gland dysfunction as a primary defect in cystic fibrosis

Salinas, Danieli; Haggie, Peter M.; Thiagarajah, Jay R.; Song, Yuanlin; Rosbe, Kristina W.; Finkbeiner, Walter E.; Nielson, Dennis W.; Verkman, A. S.

doi:10.1096/fj.04-2879fje

Cited by 76 publications

(92 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the properties of CF gland mucus produced in response to carbachol are altered (5), and their responses appear to be reduced when corrected for the hypertrophied state of CF glands. 3 These results have been independently confirmed (6,7). The direct explanation for these results is that CFTR-mediated fluid secretion is lost in CF glands.…”

mentioning

confidence: 68%

Hyposecretion, Not Hyperabsorption, Is the Basic Defect of Cystic Fibrosis Airway Glands

Joo

Irokawa

Robbins

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

Human airways and glands express the anion channel cystic fibrosis transmembrane conductance regulator, CFTR, and the epithelial Na ؉ channel, ENaC. Cystic fibrosis (CF) airway glands fail to secrete mucus in response to vasoactive intestinal peptide or forskolin; the failure was attributed to loss of CFTR-mediated anion and fluid secretion. Alternatively, CF glands might secrete acinar fluid via CFTR-independent pathways, but the exit of mucus from the glands could be blocked by hyperabsorption of fluid in the gland ducts. This could occur because CFTR loss can disinhibit ENaC, and ENaC activity can drive absorption. To test these two hypotheses, we measured single gland mucus secretion optically and applied ENaC inhibitors to determine whether they augmented secretion. Human CF glands were pretreated with benzamil and then stimulated with forskolin in the continued presence of benzamil. Benzamil did not rescue the lack of secretion to forskolin (50 glands, 6 CF subjects) nor did it increase the rate of cholinergically mediated mucus secretion from CF glands. Finally, neither benzamil nor amiloride increased forskolin-stimulated mucus secretion from porcine submucosal glands (75 glands, 7 pigs). One possible explanation for these results is that ENaC within the gland ducts was not active in our experiments. Consistent with that possibility, we discovered that human airway glands express Kunitz-type and nonKunitz serine protease inhibitors, which might prevent proteolytic activation of ENaC. Our results suggest that CF glands do not display excessive, ENaC-mediated fluid absorption, leaving defective, anion-mediated fluid secretion as the most likely mechanism for defective mucus secretion from CF glands.

show abstract

mentioning

confidence: 68%

Hyposecretion, Not Hyperabsorption, Is the Basic Defect of Cystic Fibrosis Airway Glands

Joo

Irokawa

Robbins

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…A wealth of information has been gained by these experiments, leading us to a deeper appreciation of host-pathogen interactions. Although never tested directly, it is estimated that targeting as few as 6% of epithelial cells could correct CF pulmonary disease (45), although evidence suggests that correction of specific structures such as the submucosal glands may also be required (46). Early clinical trials with adenovirus yielded short-term localized expression of CFTR, but a strong immune response to the adenoviral vectors was observed (47)(48)(49).…”

Section: Discussionmentioning

confidence: 99%

Directed evolution of adeno-associated virus to an infectious respiratory virus

Excoffon

Koerber²,

Dickey

et al. 2009

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

160

180

View full text Add to dashboard Cite

Respiratory viruses evolve to maintain infectivity levels that permit spread yet prevent host and virus extinction, resulting in surprisingly low infection rates. Respiratory viruses harnessed as gene therapy vectors have illustrated this limitation. We used directed evolution in an organotypic human airway model to generate a highly infectious adeno-associated virus. This virus mediated gene transfer more than 100-fold better than parental strains and corrected the cystic fibrosis epithelial Cl ؊ transport defect. Thus, under appropriate selective pressures, viruses can evolve to be more infectious than observed in nature, a finding that holds significant implications for designing vectors for gene therapy and for understanding emerging pathogens.

show abstract

“…Thus, secretion by glands to saturating levels of VIP or forskolin (Joo, Irokawa et al 2002), as well as the synergistic increase of gland secretion to combinations of VIP + carbachol, are lost in cystic fibrosis . In contrast, secretion to cholinergic agonists remains robust, although the level of secretion is reduced and the composition is altered Thiagarajah, Song et al 2004;Salinas, Haggie et al 2005;Song, Salinas et al 2006).…”

Section: Airway Submucosal Glandsmentioning

confidence: 99%

“…This method doesn't work well with sheep, pigs or humans, which have mucus that is much thicker than that of the cat (unpublished observations). However, the bubbles of mucus that form under oil in these species can be quantified optically, and single gland secretion rates for these species have been determined for a variety of mediators and conditions, and their pharmacology further studied Joo, Irokawa et al 2002;Joo, Saenz et al 2002;Verkman, Song et al 2003;Thiagarajah, Song et al 2004;Salinas, Haggie et al 2005;Joo, Irokawa et al 2006;Song, Salinas et al 2006). Among the findings of such studies are that vasoactive intestinal peptide (VIP), usually considered to be a muscle relaxant, is a good secretagogue for fluid secretion from pig and human airway glands, as was first suggested based on measures of lactoferrin release (Baraniuk, Lundgren et al 1990).…”

Section: Airway Submucosal Glandsmentioning

confidence: 99%

Parasympathetic control of airway submucosal glands: Central reflexes and the airway intrinsic nervous system

Wine

2007

Autonomic Neuroscience

103

View full text Add to dashboard Cite

Airway submucosal glands produce the mucus that lines the upper airways to protect them against insults. This review summarizes evidence for two forms of gland secretion, and hypothesizes that each is mediated by different but partially overlapping neural pathways. Airway innate defense comprises low level gland secretion, mucociliary clearance and surveillance by airway-resident phagocytes to keep the airways sterile in spite of nearly continuous inhalation of low levels of pathogens. Gland secretion serving innate defense is hypothesized to be under the control of intrinsic (peripheral) airway neurons and local reflexes, and these may depend disproportionately on noncholinergic mechanisms, with most secretion being produced by VIP and tachykinins. In the genetic disease cystic fibrosis, airway glands no longer secrete in response to VIP alone and fail to show the synergy between VIP, tachykinins and ACh that is observed in normal glands. The consequent crippling of the submucosal gland contribution to innate defense may be one reason that cystic fibrosis airways are infected by mucus-resident bacteria and fungi that are routinely cleared from normal airways. By contrast, the acute (emergency) airway defense reflex is centrally mediated by vagal pathways, is primarily cholinergic, and stimulates copious volumes of gland mucus in response to acute, intense challenges to the airways, such as those produced by very vigorous exercise or aspiration of foreign material. In cystic fibrosis, the acute airway defense reflex can still stimulate the glands to secrete large amounts of mucus, although its properties are altered. Importantly, treatments that recruit components of the acute reflex, such as inhalation of hypertonic saline, are beneficial in treating cystic fibrosis airway disease. The situation for recipients of lung transplants is the reverse; transplanted airways retain the airway intrinsic nervous system but lose centrally mediated reflexes. The consequences of this for gland secretion and airway defense are poorly understood, but it is possible that interventions to modify submucosal gland secretion in transplanted lungs might have therapeutic consequences.

show abstract

Submucosal gland dysfunction as a primary defect in cystic fibrosis

Cited by 76 publications

References 25 publications

Hyposecretion, Not Hyperabsorption, Is the Basic Defect of Cystic Fibrosis Airway Glands

Hyposecretion, Not Hyperabsorption, Is the Basic Defect of Cystic Fibrosis Airway Glands

Directed evolution of adeno-associated virus to an infectious respiratory virus

Parasympathetic control of airway submucosal glands: Central reflexes and the airway intrinsic nervous system

Contact Info

Product

Resources

About