A novel survival strategy of Pseudomonas aeruginosa: using exopolysaccharides to sequester and store iron to stimulate Psl-dependent biofilm formation.

Appl Environ Microbiol. 2016 Aug 26;

Authors: Yu S, Wei Q, Zhao T, Guo Y, Ma LZ

Abstract
Exopolysaccharide Psl is a critical biofilm matrix component in Pseudomonas aeruginosa, which forms a fiber-like matrix to enmesh bacteria communities. Iron is important for P. aeruginosa biofilm development, yet it is not clearly understood about how iron contributes to biofilm development. Here we showed that iron promoted biofilm formation via elevating Psl production in P. aeruginosa The high level of iron stimulated the synthesis of Psl by reducing the rhamnolipids biosynthesis and inhibiting the expression of AmrZ, a repressor of psl genes. Iron-stimulated Psl biosynthesis and biofilm formation held true in mucoid P. aeruginosa strains. Subsequent experiments indicated that iron bound with Psl in vitro and in biofilms, which suggested that Psl fibers functioned as an iron storage channel in P. aeruginosa biofilms. Moreover, among three matrix exopolysaccharides of P. aeruginosa, Psl is the only exopolysaccharide that can bind with both ferrous and ferric ion, yet with higher affinity for ferrous iron. Our data suggest a survival strategy of P. aeruginosa that uses exopolysaccharide to sequester and store iron to stimulate Psl-dependent biofilm formation.
IMPORTANCE: Pseudomonas aeruginosa is an environmental microorganism, which is also an opportunistic pathogen that can cause severe infections in immunocompromised individuals. It is the predominant airway pathogen causing morbidity and mortality in individuals affected by the genetic disease cystic fibrosis (CF). Increased airway iron and biofilm formation have been proposed to be the potential factors involved in the persistence of P. aeruginosa in CF patients. Here we showed that high level of iron enhanced the production of the key biofilm matrix exopolysaccharide Psl to stimulate Psl-dependent biofilm formation. Our results not only make the link between biofilm formation and iron concentration in CF, but also could guide the administration or use of iron-chelators to interfere with biofilm formation of P. aeruginosa in CF patients. Furthermore, our data also imply a survival strategy of P. aeruginosa at high iron environmental condition.

PMID: 27565622 [PubMed - as supplied by publisher]

Transitions in Health Care: What Can We Learn from Our Experience with Cystic Fibrosis.

Pediatr Clin North Am. 2016 Oct;63(5):887-97

Authors: West NE, Mogayzel PJ

Abstract
Numerous individuals with chronic disease age into adulthood each year, necessitating transition from a pediatric to an adult medical care team. Transition should start early in adolescence and occur gradually over years, preparing the individual for the transfer to the adult team. Cystic fibrosis (CF) has a growing population of adults, as survival over the past several decades has increased. The CF Foundation has implemented guidelines for the transition process. The transition process for individuals with CF provides an example that could be adapted into other chronic disease populations, to provide a successful and meaningful transition into adult care.

PMID: 27565366 [PubMed - in process]

Delivery of Alpha-1 Antitrypsin to Airways.

Ann Am Thorac Soc. 2016 Aug;13(Supplement_4):S346-S351

Authors: Griese M, Scheuch G

Abstract
Treatment with exogenous alpha-1 antitrypsin (AAT), a potent serine protease inhibitor, was developed originally for chronic obstructive pulmonary disease associated with AAT deficiency; however, other lung conditions involving neutrophilic inflammation and proteolytic tissue injury related to neutrophil elastase and other serine proteases may also be considered for AAT therapy. These conditions include bronchiectasis caused by primary ciliary dyskinesia, cystic fibrosis, and other diseases associated with an increased free elastase activity in the airways. Inhaled AAT may be a viable option to counteract proteolytic tissue damage. This form of treatment requires efficient drug delivery to the targeted pulmonary compartment. Aerosol technology meeting this requirement is currently available and offers an alternative therapeutic approach to systemic AAT administration. To date, early studies in humans have shown biochemical efficacy and have established the safety of inhaled AAT. However, to bring aerosol AAT therapy to patients, large phase 3 protocols in carefully selected patient populations (i.e., subgroups of patients with AAT deficiency, cystic fibrosis, or other lung diseases with bronchiectasis) will be needed with clinical end points in addition to the measurement of proteolytic activity in the airway. The outcomes likely will have to include lung function, lung structure assessed by computed tomography imaging, disease exacerbations, health status, and mortality.

PMID: 27564672 [PubMed - as supplied by publisher]

The Advantages of Adding Hyaluronic Acid or Mannitol to Hypertonic Saline Inhalation Treatment in Cystic Fibrosis.

J Aerosol Med Pulm Drug Deliv. 2016 Aug 26;

Authors: Cazzarolli C, Tartali C, Pradal U

PMID: 27563742 [PubMed - as supplied by publisher]

Targeting the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Protein for the Treatment of Cystic Fibrosis.

ACS Med Chem Lett. 2016 Aug 11;7(8):725-7

Authors: Abdel-Magid AF

PMID: 27563392 [PubMed]

Characterization of Staphylococcus aureus isolates from pediatric patients with cystic fibrosis.

World J Microbiol Biotechnol. 2016 Oct;32(10):162

Authors: Liu Y, Zhang J, Zhong D, Ji L, Yang J, Phillips J, Ji Y

Abstract
Staphylococcus aureus is one of the major respiratory pathogens associated with cystic fibrosis (CF) patients. In this study, we collected sputum and isolated fifty S. aureus isolates from CF patients with the median age of 9.5 years old. Then we determined the profiles of these isolates by antibiotic susceptibility testing, examining their cytotoxicity and ability to internalize into an epithelial cell line (A549), as well as multiple loci sequencing typing. Predominant CF S. aureus isolates were resistant to penicillin; however, these isolates were sensitive to various antibiotics, such as vancomycin and minocycline. Different CF S. aureus isolates showed distinct cytotoxic activities, and 90 % of CF S. aureus isolates possessed the enterotoxin genes, sea and hlg. Moreover, we found that multiple different CF S. aureus isolates appeared to have the distinct capacity of invading A549 cells. ST5 (14 %), ST30 (14 %), and ST8 (10 %) were prevalent ST types in these isolates. Further analysis revealed that ST5 and ST30 isolates were less toxic than ST8 and ST15 isolates, and that the ST5, ST15, ST59, and ST87 types of CF S. aureus were less capable of invading A549 cells. Our results suggest that the ST typing method may be useful in predicting cytotoxicity and the invading capacity of S. aureus isolates from patients with CF.

PMID: 27562596 [PubMed - in process]

Nano-based rescue of dysfunctional autophagy in chronic obstructive lung diseases.

Expert Opin Drug Deliv. 2016 Aug 26;:1-7

Authors: Vij N

Abstract
INTRODUCTION: ΔF508-CFTR (cystic fibrosis transmembrane conductance regulator) is a common CF-mutation that is known to induce oxidative-inflammatory stress through activation of reactive oxygen species (ROS), which induces autophagy-impairment resulting in accumulation of CFTR in aggresome-bodies. Cysteamine, the reduced form of cystamine, is a FDA-approved drug that has anti-oxidant, anti-bacterial, and mucolytic properties. This drug has been shown in a recent clinical trial to decrease lung inflammation and improve lung function in CF patients by potentially restoring autophagy and allowing CFTR to be trafficked to the cell membrane.
AREAS COVERED: The delivery of cysteamine to airway epithelia of chronic subjects prerequisite the need for a delivery system to allow rescue of dysfunctional autophagy.
EXPERT OPINION: We anticipate based on our ongoing studies that PLGA-PEG- or Dendrimer-mediated cysteamine delivery could allow sustained airway delivery over standard cysteamine tablets or delay release capsules that are currently used for systemic treatment. In addition, proposed nano-based autophagy induction strategy can also allow rescue of cigarette smoke (CS) induced acquired-CFTR dysfunction seen in chronic obstructive pulmonary disease (COPD)-emphysema subjects. The CS induced acquired-CFTR dysfunction involves CFTR-accumulation in aggresome-bodies that can be rescued by an autophagy-inducing antioxidant drug, cysteamine. Moreover, chronic CS-exposure generates ROS that induces overall protein-misfolding and aggregation of ubiquitinated-proteins as aggresome-bodies via autophagy-impairment that can be also be resolved by treatment with autophagy-inducing antioxidant drug, cysteamine.

PMID: 27561233 [PubMed - as supplied by publisher]

Microbiome in the pathogenesis of cystic fibrosis and lung transplant-related disease.

Transl Res. 2016 Aug 4;

Authors: Cribbs SK, Beck JM

Abstract
Significant advances in culture-independent methods have expanded our knowledge about the diversity of the lung microbial environment. Complex microorganisms and microbial communities can now be identified in the distal airways in a variety of respiratory diseases, including cystic fibrosis (CF) and the posttransplantation lung. Although there are significant methodologic concerns about sampling the lung microbiome, several studies have now shown that the microbiome of the lower respiratory tract is distinct from the upper airway. CF is a disease characterized by chronic airway infections that lead to significant morbidity and mortality. Traditional culture-dependent methods have identified a select group of pathogens that cause exacerbations in CF, but studies using bacterial 16S rRNA gene-based microarrays have shown that the CF microbiome is an intricate and dynamic bacterial ecosystem, which influences both host immune health and disease pathogenesis. These microbial communities can shift with external influences, including antibiotic exposure. In addition, there have been a number of studies suggesting a link between the gut microbiome and respiratory health in CF. Compared with CF, there is significantly less knowledge about the microbiome of the transplanted lung. Risk factors for bronchiolitis obliterans syndrome, one of the leading causes of death, include microbial infections. Lung transplant patients have a unique lung microbiome that is different than the pretransplanted microbiome and changes with time. Understanding the host-pathogen interactions in these diseases may suggest targeted therapies and improve long-term survival in these patients.

PMID: 27559681 [PubMed - as supplied by publisher]

Chronic electronic cigarette exposure in mice induces features of COPD in a nicotine-dependent manner.

Thorax. 2016 Aug 24;

Authors: Garcia-Arcos I, Geraghty P, Baumlin N, Campos M, Dabo AJ, Jundi B, Cummins N, Eden E, Grosche A, Salathe M, Foronjy R

Abstract
BACKGROUND: The use of electronic (e)-cigarettes is increasing rapidly, but their lung health effects are not established. Clinical studies examining the potential long-term impact of e-cigarette use on lung health will take decades. To address this gap in knowledge, this study investigated the effects of exposure to aerosolised nicotine-free and nicotine-containing e-cigarette fluid on mouse lungs and normal human airway epithelial cells.
METHODS: Mice were exposed to aerosolised phosphate-buffered saline, nicotine-free or nicotine-containing e-cigarette solution, 1-hour daily for 4 months. Normal human bronchial epithelial (NHBE) cells cultured at an air-liquid interface were exposed to e-cigarette vapours or nicotine solutions using a Vitrocell smoke exposure robot.
RESULTS: Inhalation of nicotine-containing e-cigarettes increased airway hyper-reactivity, distal airspace enlargement, mucin production, cytokine and protease expression. Exposure to nicotine-free e-cigarettes did not affect these lung parameters. NHBE cells exposed to nicotine-containing e-cigarette vapour showed impaired ciliary beat frequency, airway surface liquid volume, cystic fibrosis transmembrane regulator and ATP-stimulated K+ ion conductance and decreased expression of FOXJ1 and KCNMA1. Exposure of NHBE cells to nicotine for 5 days increased interleukin (IL)-6 and IL-8 secretion.
CONCLUSIONS: Exposure to inhaled nicotine-containing e-cigarette fluids triggered effects normally associated with the development of COPD including cytokine expression, airway hyper-reactivity and lung tissue destruction. These effects were nicotine-dependent both in the mouse lung and in human airway cells, suggesting that inhaled nicotine contributes to airway and lung disease in addition to its addictive properties. Thus, these findings highlight the potential dangers of nicotine inhalation during e-cigarette use.

PMID: 27558745 [PubMed - as supplied by publisher]

Chenodeoxycholic Acid Requires Activation of EGFR, EPAC and Ca2+ to Stimulate CFTR-dependent Cl- Secretion in Human Colonic T84 Cells.

Am J Physiol Cell Physiol. 2016 Aug 24;:ajpcell.00168.2016

Authors: Domingue JC, Ao M, Sarathy J, Rao MC

Abstract
Bile acids are known to initiate intricate signaling events in a variety of tissues, primarily in the liver and gastrointestinal tract. Of the known bile acids, only the dihydroxy species, deoxycholic acid and chenodeoxycholic acid (CDCA), and their conjugates, activate processes that stimulate epithelial Cl(-) secretion. We have previously published that CDCA acts in a rapid manner to stimulate colonic ion secretion via protein kinase A (PKA)-mediated activation of the dominant Cl(-) channel, the cystic fibrosis transmembrane conductance regulator (CFTR) (AJP 305:C447-56, 2013); however, PKA signaling did not account for the entire CDCA response. Here we show that in human colonic T84 cells, CDCA's induction of CFTR activity, measured as changes in short-circuit current (Isc), is dependent on epidermal growth factor receptor (EGFR) activation, and does not involve the bile acid receptors TGR5 or FXR. CDCA activation of Cl(-) secretion does not require Src, mitogen activated protein kinases, or phosphoinositide-3 kinase downstream of EGFR, but does require an increase in cytosolic Ca(2+) In addition to PKA signaling, we found that the CDCA response requires a novel involvement of the exchange protein directly activated by cAMP (EPAC). EPAC is a known hub for cAMP and Ca(2+) cross talk. Downstream of EPAC, CDCA activates Rap2, and changes in [Ca(2+)]i were dependent on both EPAC and EGFR activation. This study establishes the complexity of CDCA signaling in the colonic epithelium, and shows the contribution of EGFR, EPAC and Ca(2+) in CDCA-induced activation of CFTR-dependent Cl(-) secretion.

PMID: 27558159 [PubMed - as supplied by publisher]

From Genesis To Revelation: The Role Of Inflammatory Mediators In Chronic Respiratory Diseases And Their Control By Nucleic Acid-Based Drugs.

Curr Drug Deliv. 2016 Aug 24;

Authors: Di Gioia S, Sardo C, Castellani S, Porsio B, Belgiovine G, Carbone A, Giammona G, Cavallaro G

Abstract
Asthma, chronic obstructive pulmonary disease, cystic fibrosis, and idiopathic pulmonary fibrosis, are among the most common chronic diseases and their prevalence is increasing. Each of these diseases is characterized by the secretion of cytokines and pro-inflammatory molecules which are thought to play a critical role in their pathogenesis. Moreover, immune cells, particularly neutrophils, macrophages and dendritic cells as well structural cells such as epithelial and airway smooth muscle cells are also involved in the pathogenic cycle of these diseases. There is a pressing need for the development of new therapies for these pulmonary diseases, particularly as no existing treatment has been shown to reduce disease progression. HMGB1 (high-mobility group box 1), originally identified as a nuclear non histone protein with DNA-binding domains can be secreted by living and dying cells and it is now regarded as an important endogenous danger signaling molecule. Besides as a signal of tissue injury, HMGB1 is considered a powerful mediator of inflammation and high levels of HMGB1 are found in chronic lung diseases. The role of HMGB1 in respiratory diseases is still elusive nevertheless these studies suggest an involvement of this cytokine in their pathogenesis. Nucleic acid-based drugs (NABDs) are a novel class of pharmaceuticals including antisense oligonucleotides, DNA-zymes, and RNA interference as mediated by small interfering RNA (siRNA), which are used to dampen the expression of disease-causing genes having therapeutic potential for controlling chronic airway diseases. Due to their inherent difficulties, such as for example sensitivity to endonucleases, their delivery in vivo should be assured by vectors. Non-viral lipid- and polymer-based nanosystems have acquired much importance in this context. In this review, we will discuss these emerging tools in gene therapy of chronic lung diseases, particularly the use of siRNA in the down-regulation of critical molecules in the pathogenesis of chronic lung diseases, with particular emphasis on HMGB1 as therapeutic target.

PMID: 27557670 [PubMed - as supplied by publisher]

12 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Cystic Fibrosis"

These pubmed results were generated on 2016/08/25

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

8 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Cystic Fibrosis"

These pubmed results were generated on 2016/08/24

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Cystic Fibrosis"

These pubmed results were generated on 2016/08/23

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Surfactant protein A recognizes outer membrane protein OprH on Pseudomonas aeruginosa chronic infection isolates.

J Infect Dis. 2016 Aug 19;

Authors: Qadi M, Lopez-Causapé C, Izquierdo-Rabassa S, Mateu Borrás M, Goldberg JB, Oliver A, Albertí S

Abstract
Surfactant protein A (SP-A) plays a critical role in the clearance of Pseudomonas aeruginosa from the lung. However, there is limited information about the interaction of this protein with P. aeruginosa cystic fibrosis (CF) isolates. We characterized the interplay between SP-A and a collection of isogenic sequential isolates from seven CF patients. We identified outer membrane protein OprH as a novel ligand for SP-A on P. aeruginosa CF late isolates bound significantly less SP-A than their respective early isolates. This difference could be associated with a reduction in the expression of OprH. Binding of SP-A to OprH promoted phagocityc killing, thus late CF isolates were at least two-fold more resistant to SP-A mediated killing by human macrophages than their respective early isolates. We postulate that reduction of OprH expression is a previously unrecognized adaptation of P. aeruginosa to CF lung that facilitates the escape of the microorganism from SP-A-mediated phagocytic killing.

PMID: 27543671 [PubMed - as supplied by publisher]

PATHOPHYSIOLOGIC EVALUATION OF THE TRANSGENIC CFTR "GUT-CORRECTED" PORCINE MODEL OF CYSTIC FIBROSIS.

Am J Physiol Lung Cell Mol Physiol. 2016 Aug 19;:ajplung.00242.2016

Authors: Ballard ST, Evans JW, Drag HS, Schuler M

Abstract
This study evaluated the pulmonary pathophysiology of the transgenic CFTR "gut-corrected" cystic fibrosis (CF) pigs. Four sows produced 18 piglets of which 11 were stillborn with only 2 animals surviving beyond 2 weeks. Failure to survive beyond the neonatal period by 5 piglets was judged to result from metabolic dysfunction related to genetic manipulation for CFTR gut expression or due to cloning artifact. Plasma analysis showed very low plasma proteins, highly elevated liver enzymes, and severe acidosis. All surviving offspring received furosemide for systemic edema. Physiologic evaluation was performed with lung tissues from the two surviving pigs. Both acetylcholine and forskolin induced mucous liquid secretion that was significantly lower in CF bronchi than non-CF bronchi. The percent non-volatile solids in mucus secreted from CF bronchi was elevated following acetylcholine or forskolin. Mucociliary transport in excised tracheas was reduced in the CF tracheas relative to nonCF tracheas. The diameter of CF tracheas was less than that of non-CF pigs in spite of their greater body weight. Despite exhibiting severe metabolic dysfunction during the neonatal period, this CF animal model appears to express important characteristics of human CF pulmonary disease.

PMID: 27542808 [PubMed - as supplied by publisher]

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Cystic Fibrosis"

These pubmed results were generated on 2016/08/20

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Cystic Fibrosis"

These pubmed results were generated on 2016/08/19

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

7 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Cystic Fibrosis"

These pubmed results were generated on 2016/08/18

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Regulation of the Coxsackie and Adenovirus Receptor Expression is Dependent on CFTR in Airway Epithelial Cells.

Cell Microbiol. 2016 Aug 16;

Authors: Sharma A, Xu Y, Sung B, Vincent TC, Worgall T, Worgall S

Abstract
The coxsackievirus and adenovirus receptor (CAR), in addition to serving as viral receptor, is a component of tight junctions and plays an important role in tissue homeostasis. Defects in the cystic fibrosis transmembrane regulator (CFTR) in lung epithelial cells are linked to inflammation and susceptibility for respiratory tract infections. Here we demonstrate that CAR expression and infectivity with adenovirus (Ad) are increased in cystic fibrosis (CF) airway epithelial cells. Inhibition of CFTR or histone deacetylase (HDAC) enhanced CAR expression while CFTR overexpression or restoration of the diminished HDAC activity in CF cells reduced CAR expression. This connects the CFTR to CAR expression and infectivity with Ad through HDAC.

PMID: 27527752 [PubMed - as supplied by publisher]