New concepts of the pathogenesis of cystic fibrosis lung disease

Rc, Boucher

doi:10.1183/09031936.03.00057003

Cited by 575 publications

(438 citation statements)

References 107 publications

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“…This is a necessary but not sufficient component of the pathogenesis of P. aeruginosa in CF that is well documented and supported by the work of Boucher and colleagues [13]. But this abnormal physiology does not provide an explanation for why P. aeruginosa is so clearly the predominant pathogen in CF, as other pathogens could probably take advantage of this niche to cause lung infection.…”

Section: Pseudomonas Aeruginosa In Cystic Fibrosismentioning

confidence: 98%

“…The alterations in pH, ion concentration and ASL hydration are all potential factors contributing to P. aeruginosa infecting a high proportion of CF patients. Although it has been proposed that there is an elevated salt concentration in CF ASL that inhibits the activities of antibacterial substances, including lysozyme, lactoferrin and β-defensins [26], most studies [13] have not confirmed the early observation. Better established are findings pointing to a high viscosity of the ASL that then hinders the normal beat of the ciliated airway epithelial cells, which in turn compromises mechanical clearance of P. aeruginosa from the airway, allowing for retention of organisms within the airway lumen [7] (Box 1).…”

mentioning

confidence: 99%

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Airway epithelial control of Pseudomonas aeruginosa infection in cystic fibrosis

Campodónico

Gadjeva

Paradis-Bleau

et al. 2008

Trends in Molecular Medicine

100

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Defective expression or function of the cystic fibrosis transmembrane conductance regulator (CFTR) underlies the hypersusceptibility of cystic fibrosis (CF) patients to chronic airway infections, particularly with Pseudomonas aeruginosa. CFTR is involved in the specific recognition of P. aeruginosa, thereby contributing to effective innate immunity and proper hydration of the airway surface layer (ASL). In CF, the airway epithelium fails to initiate an appropriate innate immune response, allowing the microbe to bind to mucus plugs that are then not properly cleared because of the dehydrated ASL. Recent studies have identified numerous CFTR-dependent factors that are recruited to the epithelial plasma membrane in response to infection and that are needed for bacterial clearance, a process that is defective in CF patients hypersusceptible to infection with this organism. Pseudomonas aeruginosa in cystic fibrosisCystic fibrosis (CF) is unique among human genetic disorders in that mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a protein whose primary function described to date has been to regulate conductance of ions in and out of cells and intracellular vacuoles, lead to hypersusceptibility to chronic lung infection. Human diseases wherein individuals homozygous for mutant genes are predisposed to infections serve as a firm foundation for understanding the molecular, cellular, physiologic and immunologic aspects of normal and compromised resistance to infection. CF is not just a prime example of how we can learn about normal and pathologic states; it could, in fact, be the only known human genetically determined disease wherein infection with a single pathogen -Pseudomonas aeruginosa -drives the vast majority of morbidity, clinical deterioration and ultimately life-shortening mortality encountered in this disease. In humans with significant compromises to their immune system, such as advanced AIDS, we would normally expect to see a plethora of pathogens take advantage of this debilitated state, but this is not the case in CF.CF is characterized by the emergence and persistence of (and, ultimately, the inability to clear) chronic infection with a variant of P. aeruginosa (mucoid P. aeruginosa) that overproduces a surface polysaccharide known as alginate. The organism undergoes other significant genetic adaptations and selections within the CF lung, and it is the emergence of mucoid P. aeruginosa that is the primary determinant of the clinical course of this disease [1,2]. In those individuals with either an uncommon but fortuitous protective immune response to specific P. aeruginosa antigens [3,4] Histopathologic basis for defining relevant interactions between P.aeruginosa and the CF airway epitheliumAlthough CF is a multisystem disease characterized by GI and nutritional abnormalities, salt loss syndromes and male urogenital abnormalities, the major clinical problem for CF patients is chronic sinopulmonary disease. Therefore, relying on observations made fr...

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Section: Pseudomonas Aeruginosa In Cystic Fibrosismentioning

confidence: 98%

mentioning

confidence: 99%

Airway epithelial control of Pseudomonas aeruginosa infection in cystic fibrosis

Campodónico

Gadjeva

Paradis-Bleau

et al. 2008

Trends in Molecular Medicine

100

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“…12 As an alternative, we and others have begun to investigate the use of endogenous, cell-type specific promoters to target the expression of CFTR to the airway epithelium where the CFTR protein is a critical regulator of the volume of airway surface liquid. 13 For example, Hu and co-workers 14 have developed an expression cassette using the promoter from the keratin 18 gene. Previously, we have demonstrated that a small fragment of the human FOXJ1 promoter is sufficient to target the expression of a reporter (enhanced green fluorescent protein (EGFP)) to the ciliated cells of the respiratory tract in a transgenic mouse model.…”

Section: Introductionmentioning

confidence: 99%

Expression of CFTR from a ciliated cell-specific promoter is ineffective at correcting nasal potential difference in CF mice

et al. 2007

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“…Chronic obstructive pulmonary diseases (COPDs) are essentially observed in cigarette smokers and share many clinical features with CF (cystic fibrosis) (2), a disease caused by mutations of the cAMP-activated cystic fibrosis transmembrane conductance regulator (CFTR) Cl − channel. In COPD and patients with cystic fibrosis (CF), the lack of functional CFTR in the airways results in altered ion transport at the apical membrane, mucus dehydration and hyperviscosity, reduced mucus transport, the inability to prevent bacterial infections, and the progressive decline of lung function (2)(3)(4). In addition, cigarette smoke decreases cAMPdependent Cl − secretion in vivo (5,6) and in vitro (7), a process possibly related to smoke oxidants (8).…”

mentioning

confidence: 99%

Contribution of α7 nicotinic receptor to airway epithelium dysfunction under nicotine exposure

Maouche

Medjber

Zahm

et al. 2013

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

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Loss or dysfunction of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) leads to impairment of airway mucus transport and to chronic lung diseases resulting in progressive respiratory failure. Nicotinic acetylcholine receptors (nAChRs) bind nicotine and nicotine-derived nitrosamines and thus mediate many of the tobacco-related deleterious effects in the lung. Here we identify α7 nAChR as a key regulator of CFTR in the airways. The airway epithelium in α7 knockout mice is characterized by a higher transepithelial potential difference, an increase of amiloride-sensitive apical Na + absorption, a defective cAMP-dependent Cl − conductance, higher concentrations of Na + , Cl − , K + , and Ca 2+ in secretions, and a decreased mucus transport, all relevant to a deficient CFTR activity. Moreover, prolonged nicotine exposure mimics the absence of α7 nAChR in mice or its inactivation in vitro in human airway epithelial cell cultures. The functional coupling of α7 nAChR to CFTR occurs through Ca 2+ entry and activation of adenylyl cyclases, protein kinase A, and PKC. α7 nAChR, CFTR, and adenylyl cyclase-1 are physically and functionally associated in a macromolecular complex within lipid rafts at the apical membrane of surface and glandular airway epithelium. This study establishes the potential role of α7 nAChR in the regulation of CFTR function and in the pathogenesis of smoking-related chronic lung diseases.chloride efflux | ciliated cell | mouse | mucociliary clearance | submucosal gland

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New concepts of the pathogenesis of cystic fibrosis lung disease

Cited by 575 publications

References 107 publications

Airway epithelial control of Pseudomonas aeruginosa infection in cystic fibrosis

Airway epithelial control of Pseudomonas aeruginosa infection in cystic fibrosis

Expression of CFTR from a ciliated cell-specific promoter is ineffective at correcting nasal potential difference in CF mice

Contribution of α7 nicotinic receptor to airway epithelium dysfunction under nicotine exposure

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