Cystic fibrosis: the mechanisms of pathogenesis of an inherited lung disorder

Clunes, Mark T.; Boucher, Richard C.

doi:10.1016/j.ddmec.2007.09.001

Cited by 91 publications

(62 citation statements)

References 56 publications

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“…The CFTR glycoprotein regulates salt and water transport across epithelial cells (8,9). Accumulation of the chloride ion inside the cells carrying defective CFTR protein results in dehydration of the epithelial lining fluid and overproduction of thick and sticky mucus (10). The condition, in part, provides a suitable environment for microbial growth, including bacteria, such as Staphylococcus aureus, Haemophilus influenzae, Burkholderia cepacia, and Pseudomonas aeruginosa (11).…”

mentioning

confidence: 99%

Efficacy and Safety of Liposomal Clarithromycin and Its Effect on Pseudomonas aeruginosa Virulence Factors

Alhajlan

Alhariri

Omri

2013

Antimicrob Agents Chemother

116

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We investigated the efficacy and safety of liposomal clarithromycin formulations with different surface charges against clinical isolates of Pseudomonas aeruginosa from the lungs of cystic fibrosis (CF) patients. The liposomal clarithromycin formulations were prepared by the dehydration-rehydration method, and their sizes were measured using the dynamic-light-scattering technique. Encapsulation efficiency was determined by microbiological assay, and the stabilities of the formulations in biological fluid were evaluated for a period of 48 h. The MICs and minimum bactericidal concentrations (MBCs) of free and liposomal formulations were determined with P. aeruginosa strains isolated from CF patients. Liposomal clarithromycin activity against biofilm-forming P. aeruginosa was compared to that of free antibiotic using the Calgary Biofilm Device (CBD). The effects of subinhibitory concentrations of free and liposomal clarithromycin on bacterial virulence factors and motility on agar were investigated on clinical isolates of P. aeruginosa. The cytotoxicities of the liposome preparations and free drug were evaluated on a pulmonary epithelial cell line (A549). The average diameter of the formulations was >222 nm, with encapsulation efficiencies ranging from 5.7% to 30.4%. The liposomes retained more than 70% of their drug content during the 48-h time period. The highly resistant strains of P. aeruginosa became susceptible to liposome-encapsulated clarithromycin (MIC, 256 mg/liter versus 8 mg/liter; P < 0.001). Liposomal clarithromycin reduced the bacterial growth within the biofilm by 3 to 4 log units (P < 0.001), significantly attenuated virulence factor production, and reduced bacterial twitching, swarming, and swimming motilities. The clarithromycin-entrapped liposomes were less cytotoxic than the free drug (P < 0.001). These data indicate that our novel formulations could be a useful strategy to enhance the efficacy of clarithromycin against resistant P. aeruginosa strains that commonly affect individuals with cystic fibrosis.

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mentioning

confidence: 99%

Efficacy and Safety of Liposomal Clarithromycin and Its Effect on Pseudomonas aeruginosa Virulence Factors

Alhajlan

Alhariri

Omri

2013

Antimicrob Agents Chemother

116

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“…Other proteins, DNA, and cellular debris also are present. Continual secretion and shedding of mucins maintain a protective mucus layer from 10-700 μm thick depending on species and body location (19)(20)(21)(22).…”

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confidence: 99%

Bacteriophage adhering to mucus provide a non–host-derived immunity

Barr

Auro

Furlan

et al. 2013

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

770

708

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Mucosal surfaces are a main entry point for pathogens and the principal sites of defense against infection. Both bacteria and phage are associated with this mucus. Here we show that phageto-bacteria ratios were increased, relative to the adjacent environment, on all mucosal surfaces sampled, ranging from cnidarians to humans. In vitro studies of tissue culture cells with and without surface mucus demonstrated that this increase in phage abundance is mucus dependent and protects the underlying epithelium from bacterial infection. Enrichment of phage in mucus occurs via binding interactions between mucin glycoproteins and Ig-like protein domains exposed on phage capsids. In particular, phage Ig-like domains bind variable glycan residues that coat the mucin glycoprotein component of mucus. Metagenomic analysis found these Ig-like proteins present in the phages sampled from many environments, particularly from locations adjacent to mucosal surfaces. Based on these observations, we present the bacteriophage adherence to mucus model that provides a ubiquitous, but non-host-derived, immunity applicable to mucosal surfaces. The model suggests that metazoan mucosal surfaces and phage coevolve to maintain phage adherence. This benefits the metazoan host by limiting mucosal bacteria, and benefits the phage through more frequent interactions with bacterial hosts. The relationships shown here suggest a symbiotic relationship between phage and metazoan hosts that provides a previously unrecognized antimicrobial defense that actively protects mucosal surfaces.symbiosis | host-pathogen | virus | immunoglobulin | immune system

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“…5 It is caused by loss-of-function mutations in both copies of the CFTR gene, which is located on human chromosome 7 (in 7q31.2). The CFTR protein belongs to the ATP-Binding Cassette subfamily B (member 7).…”

Section: Pathogenesis Of Cf Geneticsmentioning

confidence: 99%

Matrix metalloproteinases in cystic fibrosis: pathophysiologic and therapeutic perspectives

Owen

Jojas-Quintero²

2016

MNM

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Cystic fibrosis (CF) is the most common inherited disease in the Caucasian population. CF is caused by loss-of-function mutations in the CFTR gene leading to an altered electrolyte and water movement into the airway surface liquid, dehydration of the mucus layer, defective mucociliary clearance, and increased susceptibility to airway bacterial infections. CF is characterized by airway neutrophilic inflammation and activation of airway epithelial cells leading to increased airway levels of various matrix metalloproteinases (MMPs). Herein, we review MMP structure, regulation, and activity, along with the literature on MMPs expression in CF and the contributions of MMPs to CF pathogenesis. Numerous studies report elevated levels of MMPs (especially MMP-8, MMP-7, and MMP-9) in blood and/or lung samples from CF patients and have correlated MMP levels with measures of lung inflammation and injury and/or clinical parameters. No study has yet investigated the contributions of MMPs to the pathogenesis of CF using MMP gene-targeted murine of CF. Based upon the known activities of MMPs in animal models of other lung diseases, we hypothesize that some MMPs (such as MMP-8 and MMP-9) may amplify airway inflammation, and promote airway injury and airway-remodeling processes, or inhibit chloride epithelial transport by inhibiting activation of the CFTR (MMP-2). Other MMPs (such as MMP-7 and MMP-12) may limit the severity of CF by activating host defense proteins to enhance pathogen clearance from the airways, directly killing pathogens that colonize the airways of CF patients and/or promoting epithelial repair. We discuss potential approaches to selectively target MMPs to develop novel therapies that limit the high morbidity and mortality associated with CF.

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Cystic fibrosis: the mechanisms of pathogenesis of an inherited lung disorder

Cited by 91 publications

References 56 publications

Efficacy and Safety of Liposomal Clarithromycin and Its Effect on Pseudomonas aeruginosa Virulence Factors

Efficacy and Safety of Liposomal Clarithromycin and Its Effect on Pseudomonas aeruginosa Virulence Factors

Bacteriophage adhering to mucus provide a non–host-derived immunity

Matrix metalloproteinases in cystic fibrosis: pathophysiologic and therapeutic perspectives

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