Lung Transplantation in Cystic Fibrosis Patients in Israel: The Importance of Ethnicity and Nutritional status.

Clin Transplant. 2017 Sep 08;:

Authors: Levine H, Prais D, Raviv Y, Rusanov V, Rosengarten D, Saute M, Hoshen M, Mussaffi H, Blau H, Kramer MR

Abstract
OBJECTIVES: To assess the characteristics that correlate with better outcomes after lung transplantation for patients with cystic fibrosis (CF).
METHODS: We retrospectively reviewed the charts of all patients with CF who underwent lung transplantation between 1996-2014 at Rabin Medical Center, Israel.
RESULTS: Fifty patients with CF underwent 55 lung transplantations. Eighteen patients (36%) died during the study period. Actuarial survival was 83%, 68%, 62% and 39% at 1, 3, 5 and 10 years, respectively. Better survival correlated with: BMI at 6-months and 1-year after transplantation (p=0.002 and p=0.003, respectively), ischemic time of less than 300 minutes (p=0.023), absence of liver disease (p=0.012) and Jewish compared to Arab ethnicity (p=0.007). Freedom from bronchiolitis obliterans syndrome (BOS) was 87%, 75% and 72% at 1, 3 and 5 years, respectively. BOS was more common and appeared earlier in the Arab than in the Jewish population (p=0.012, p=0.007). Additionally, prolonged time free of BOS correlated with male gender (p=0.039), older age (p<0.001), absence of liver disease (p=0.012) and higher BMI 1-year after transplantation (p<0.001).
CONCLUSIONS: Clinically important determinants for survival include BMI pre and 1-year post transplantation and improved freedom from BOS. Arab ethnicity correlated with higher incidence and earlier onset of BOS compared to Jewish ethnicity in Israel. This article is protected by copyright. All rights reserved.

PMID: 28886227 [PubMed - as supplied by publisher]

Compassionate Nitric Oxide Adjuvant Treatment of Persistent Mycobacterium Infection in Cystic Fibrosis Patients.

Pediatr Infect Dis J. 2017 Sep 06;:

Authors: Yaacoby-Bianu K, Gur M, Toukan Y, Nir V, Hakim F, Geffen Y, Bentur L

Abstract
BACKGROUND: Mycobacterium abscessus is one of the most antibiotic-resistant pathogens in Cystic Fibrosis (CF) patients. Nitric Oxide (NO) has broad-spectrum antimicrobial activity. Clinical studies indicated that it is safe and tolerable when given as 160 ppm intermittent inhalations.
METHODS: A prospective compassionate adjunctive inhaled NO therapy in two CF patients with persistent Mycobacterium abscessus infection.
RESULTS: No adverse events were reported. Both subjects showed significant reduction in quantitative PCR results for Mycobacterium abscessus load in sputum during treatment; estimated colony forming unit (CFU) decreased from 7000 to 550 and from 3000 to 0 for patient 1 and patient 2, respectively.
CONCLUSIONS: Intermittent inhalations with 160 ppm NO are well tolerated, safe and result in significant reduction of Mycobacterium abscessus load. It may constitute an adjuvant therapeutic approach for CF patients with Mycobacterium abscessus lung disease. Further studies are needed to define dosing, duration and long-term clinical outcome.

PMID: 28885458 [PubMed - as supplied by publisher]

Procalcitonin, Erythrocyte Sedimentation Rate, and C-Reactive Protein in Acute Pulmonary Exacerbations of Cystic Fibrosis.

Clin Respir J. 2017 Sep 07;:

Authors: Loh G, Ryaboy IV, French A, Skabelund A

Abstract
INTRODUCTION: Acute pulmonary exacerbations of cystic fibrosis (APECF) are a leading cause of morbidity and mortality among patients with CF. APECF require frequent administration of antibiotics and subsequently lead to development of resistant organisms.
OBJECTIVES: Identify inflammatory markers that may be help identify need for antibiotics and exacerbation as well as predict risk of exacerbations.
METHODS: 17 patients were enrolled and baseline ESR, CRP, and procalcitonin levels were obtained in addition to obtaining these levels during admissions for Acute Pulmonary Exacerbations of Cystic Fibrosis (APECF).
RESULTS: 28 APECF were recorded. ESR and CRP both significantly increased during exacerbation (p < 0.01 for both). Procalcitonin did not increase during exacerbations. Baseline elevations in ESR and CRP increased risk of an exacerbation (RR = 2.3 and RR 4.5, respectively).
CONCLUSION: ESR and CRP are both useful markers for cystic fibrosis exacerbations, as levels rise with exacerbations. Baseline elevations in ESR and CRP were noted to show an increased risk for cystic fibrosis exacerbations. Procalcitonin, in contrast, is not a useful inflammatory marker. This article is protected by copyright. All rights reserved.

PMID: 28884501 [PubMed - as supplied by publisher]

Electronic Cigarette Use in US Adults at Risk for or with COPD: Analysis from Two Observational Cohorts.

J Gen Intern Med. 2017 Sep 07;:

Authors: Bowler RP, Hansel NN, Jacobson S, Graham Barr R, Make BJ, Han MK, O'Neal WK, Oelsner EC, Casaburi R, Barjaktarevic I, Cooper C, Foreman M, Wise RA, DeMeo DL, Silverman EK, Bailey W, Harrington KF, Woodruff PG, Drummond MB, for COPDGene and SPIROMICS Investigators

Abstract
BACKGROUND: Electronic cigarettes (e-cigarettes) are battery-operated nicotine-delivery devices used by some smokers as a cessation tool as well as by never smokers.
OBJECTIVE: To determine the usage of e-cigarettes in older adults at risk for or with chronic obstructive pulmonary disease (COPD).
DESIGN: Prospective cohorts.
PARTICIPANTS: COPDGene (N = 3536) and SPIROMICS (N = 1060) subjects who were current or former smokers aged 45-80.
MAIN MEASURES: Participants were surveyed to determine whether e-cigarette use was associated with longitudinal changes in COPD progression or smoking habits.
KEY RESULTS: From 2010 to 2016, participants who had ever used e-cigarettes steadily increased to 12-16%, but from 2014 to 2016 current use was stable at ~5%. E-cigarette use in African-Americans (AA) and whites was similar; however, AA were 1.8-2.9 times as likely to use menthol-flavored e-cigarettes. Current e-cigarette and conventional cigarette users had higher nicotine dependence and consumed more nicotine than those who smoked only conventional cigarettes. E-cigarette users had a heavier conventional cigarette smoking history and worse respiratory health, were less likely to reduce or quit conventional cigarette smoking, had higher nicotine dependence, and were more likely to report chronic bronchitis and exacerbations. Ever e-cigarette users had more rapid decline in lung function, but this trend did not persist after adjustment for persistent conventional cigarette smoking.
CONCLUSIONS: E-cigarette use, which is common in adults with or at risk for COPD, was associated with worse pulmonary-related health outcomes, but not with cessation of smoking conventional cigarettes. Although this was an observational study, we find no evidence supporting the use of e-cigarettes as a harm reduction strategy among current smokers with or at risk for COPD.

PMID: 28884423 [PubMed - as supplied by publisher]

Ezrin links CFTR to TLR4 signaling to orchestrate anti-bacterial immune response in macrophages.

Sci Rep. 2017 Sep 07;7(1):10882

Authors: Di Pietro C, Zhang PX, O'Rourke TK, Murray TS, Wang L, Britto CJ, Koff JL, Krause DS, Egan ME, Bruscia EM

Abstract
Macrophages (MΦs) with mutations in cystic fibrosis transmembrane conductance regulator (CFTR) have blunted induction of PI3K/AKT signaling in response to TLR4 activation, leading to hyperinflammation, a hallmark of cystic fibrosis (CF) disease. Here, we show that Ezrin links CFTR and TLR4 signaling, and is necessary for PI3K/AKT signaling induction in response to MΦ activation. Because PI3K/AKT signaling is critical for immune regulation, Ezrin-deficient MΦs are hyperinflammatory and have impaired Pseudomonas aeruginosa phagocytosis, phenocopying CF MΦs. Importantly, we show that activated CF MΦs have reduced protein levels and altered localization of the remaining Ezrin to filopodia that form during activation. In summary, we have described a direct link from CFTR to Ezrin to PI3K/AKT signaling that is disrupted in CF, and thus promotes hyper-inflammation and weakens phagocytosis.

PMID: 28883468 [PubMed - in process]

Enhanced efficacy of the engineered antimicrobial peptide WLBU2 via direct airway delivery in a murine model of P. aeruginosa pneumonia.

Clin Microbiol Infect. 2017 Sep 04;:

Authors: Chen C, Deslouches B, Montelaro RC, Di YP

Abstract
OBJECTIVES: P. aeruginosa is a common cause of pneumonia in cystic fibrosis patients with the property to generate multidrug resistance against clinically used antibiotics. Antimicrobial peptides (AMPs) are a diverse group of effector molecules of the innate immunity that protect the host against pathogens. However, the lack of activity in common biological matrices has hampered efforts towards clinical development. In this study, we evaluated the therapeutic potential of engineered antimicrobial peptide WLBU2 via direct airway delivery in a murine model of P. aeruginosa infection.
METHODS: The human AMP LL37 and WLBU2 were compared for (1) antibiofilm activity using P. aeruginosa on polarized human bronchial epithelial cells; (2) efficacy in P. aeruginosa pneumonia in mice using intra-tracheal (i.t.) instillation of bacteria and AMPs.
RESULTS: WLBU2 (16μM) prevents biofilm formation by up to 3-log compared to 1-log reduction by LL37. With a single dose of 1μg (0.05mg/kg) delivered i.t., the initial effect of LL37 was moderate and transitory, as bacterial load and inflammatory cytokines increased at 24h with observed signs of disease such as lethargy and hypothermia (L&H), consistent with moribund state requiring euthanasia. In sharp contrast, WLBU2 reduced bacterial burden (by 2 logs) and bacteria-induced inflammation (leucocytic infiltrates, cytokine and chemokine gene expression) at 6h and 24h post-exposure, with no observed signs of disease or host toxicity.
CONCLUSION: These promising results now establish a much lower minimum therapeutic dose (mTd) of WLBU2 (a net gain of 80-fold) compared to the previously reported 4mg/kg systemic mTd, with significant implications for clinical development.

PMID: 28882728 [PubMed - as supplied by publisher]

In cystic fibrosis, lung clearance index is sensitive to detecting abnormalities appearing at exercise in children with normal spirometry.

Respir Physiol Neurobiol. 2017 Sep 04;:

Authors: Chelabi R, Soumagne T, Guillien A, Puyraveau M, Degano B

Abstract
Symptom-limited incremental cardiopulmonary exercise test was performed in school-age children with clinically stable cystic fibrosis (CF), all with normal spirometry. Physiological parameters were compared between patients with normal lung clearance index (LCI; n=6) and patients with elevated LCI (n=6). Dyspnoea ratings during exercise were similar in both groups. Although no patient had significant dynamic hyperinflation, end-expiratory lung volumes were higher throughout exercise in patients with elevated LCI. In addition, alveolar-arterial oxygen gradient at peak exercise was higher, and SpO2 was lower in patients with elevated LCI. LCI can thus be regarded as a test performed at rest that predicts some abnormalities appearing at exercise in CF children with normal spirometry. (KEYWORDS).

PMID: 28882651 [PubMed - as supplied by publisher]

Cystic fibrosis complicated by cor pulmonale: The first case report in Taiwan.

Pediatr Neonatol. 2017 Aug 18;:

Authors: Chen IH, Shyur SD, Lin YC

PMID: 28882398 [PubMed - as supplied by publisher]

P2Y6 Receptor Activation Promotes Inflammation and Tissue Remodeling in Pulmonary Fibrosis.

Front Immunol. 2017;8:1028

Authors: Müller T, Fay S, Vieira RP, Karmouty-Quintana H, Cicko S, Ayata CK, Zissel G, Goldmann T, Lungarella G, Ferrari D, Di Virgilio F, Robaye B, Boeynaems JM, Lazarowski ER, Blackburn MR, Idzko M

Abstract
Idiopathic pulmonary fibrosis (IPF) is a disease with a poor prognosis and very few available treatment options. The involvement of the purinergic receptor subtypes P2Y2 and P2X7 in fibrotic lung disease has been demonstrated recently. In this study, we investigated the role of P2Y6 receptors in the pathogenesis of IPF in humans and in the animal model of bleomycin-induced lung injury. P2Y6R expression was upregulated in lung structural cells but not in bronchoalveolar lavage (BAL) cells derived from IPF patients as well as in animals following bleomycin administration. Furthermore, BAL fluid levels of the P2Y6R agonist uridine-5'-diphosphate were elevated in animals with bleomycin-induced pulmonary fibrosis. Inflammation and fibrosis following bleomycin administration were reduced in P2Y6R-deficient compared to wild-type animals confirming the pathophysiological relevance of P2Y6R subtypes for fibrotic lung diseases. Experiments with bone marrow chimeras revealed the importance of P2Y6R expression on lung structural cells for pulmonary inflammation and fibrosis. Similar effects were obtained when animals were treated with the P2Y6R antagonist MRS2578. In vitro studies demonstrated that proliferation and secretion of the pro-inflammatory/pro-fibrotic cytokine IL-6 by lung fibroblasts are P2Y6R-mediated processes. In summary, our results clearly demonstrate the involvement of P2Y6R subtypes in the pathogenesis of pulmonary fibrosis. Thus, blocking pulmonary P2Y6 receptors might be a new target for the treatment of IPF.

PMID: 28878780 [PubMed]

Quantitative assessment of airway dimensions in young children with cystic fibrosis lung disease using chest computed tomography.

Pediatr Pulmonol. 2017 Sep 07;:

Authors: Kuo W, Soffers T, Andrinopoulou ER, Rosenow T, Ranganathan S, Turkovic L, Stick SM, Tiddens HAWM, AREST CF

Abstract
OBJECTIVE: To evaluate lung disease progression using airway and artery (AA) dimensions on chest CT over 2-year interval in young CF patients longitudinally and compare to disease controls cross-sectionally.
METHODS: Retrospective analysis of pressure controlled end-inspiratory CTs, 12 routine baseline (CT1 ) and follow up (CT2 ) from AREST CF cohort; 12 disease controls with normal CT. All visible AA-pairs were measured perpendicular to the airway axis. Inner and outer airway diameters and wall (outer-inner radius) thickness were divided by adjacent arteries to compute Ain A-, Aout A-, and AWT A-ratios, respectively. Differences between CF and control data were assessed using mixed effects models predicting AA-ratios per segmental generation (SG). Power calculations were performed with 80% power and ɑ = 0.05.
RESULTS: CF, median age CT1 2 years; CT2 3.9 years, 5 males. Controls, median age 2.9 years, 10 males. Total of 4798 AA-pairs measured. Cross-sectionally: Ain A-ratio showed no difference between controls and CF CT1 or CT2 . Aout A-ratio was significantly higher in CF CT1 (SG 2-4) and CT2 (SG 2-5) compared to controls. AWT A-ratio was increased for CF CT1 (SG 1-5) and CT2 (SG 2-6) compared to controls. CF longitudinally: Ain A-ratio was significantly higher at CT2 compared to CT1 . Increase in Aout A-ratio at CT2 compared to CT1 was visible in SG ≥4. Sample sizes of 21 and 58 would be necessary for 50% and 30% Aout A-ratio reductions, respectively, between CF CT2 and controls.
CONCLUSION: AA-ratio differences were present in young CF patients relative to disease controls. Aout A-ratio as an objective parameter for bronchiectasis could reduce sample sizes for clinical trials.

PMID: 28881106 [PubMed - as supplied by publisher]

Toward inclusive therapy with CFTR modulators: Progress and challenges.

Pediatr Pulmonol. 2017 Sep 07;:

Authors: Guimbellot J, Sharma J, Rowe SM

Abstract
Cystic fibrosis is caused by gene mutations that result in an abnormal Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein on the surface of cells. CFTR modulators are a novel class of drugs that directly target the molecular defect. CFTR modulators include potentiators that result in improved activity of the channel; correctors that help the protein traffic to the cell surface properly; and readthrough agents that restore full-length CFTR by suppression of premature termination codons, among other novel classes more recently established. While some of these drugs, CFTR potentiators in particular, have provided remarkable improvements for CF patients, others have yet to achieve profoundly improved outcomes, and many CF patients are not yet impacted by CFTR modulators due to lack of knowledge regarding susceptibility of their mutations to treatment. One limitation to expanding these types of therapies to the maximum number of patients with CF is the lack of rigorously validated clinical biomarkers that can determine efficacy on an individual basis, as well as few pre-clinical tools that can predict whether an individual with a rare combination of mutant alleles will respond to a particular CFTR modulator regimen. In this review, we discuss the various groups of CFTR modulators and their status in clinical development, as well as address the current literature on biomarkers, pre-clinical cell-based tools, and the role of pharmacometrics in creating therapeutic strategies to improve the lives of all patients with cystic fibrosis, regardless of their specific mutation.

PMID: 28881097 [PubMed - as supplied by publisher]

Nontuberculous mycobacteria in cystic fibrosis: Updates and the path forward.

Pediatr Pulmonol. 2017 Sep 07;:

Authors: Martiniano SL, Davidson RM, Nick JA

Abstract
Nontuberculous mycobacteria (NTM) are troublesome pathogens that can cause significant pulmonary disease in patients with cystic fibrosis (CF). Diagnosis can be difficult in the setting of underlying CF and treatment regimens are burdensome on both patients and providers. Recent consensus guidelines for treatment of NTM in CF have provided a guide for the CF community, however research is lagging regarding accuracy of our diagnostic abilities and treatment efficacy. In this review, we provide new insights into the complexity of NTM from emerging whole genome sequencing data, a summary of current NTM diagnosis and treatment guidelines, highlight new treatment options, and discuss future research projects which aim to better define which patients to treat and timing and duration of treatment.

PMID: 28881094 [PubMed - as supplied by publisher]

Poor recovery from cystic fibrosis pulmonary exacerbations is associated with poor long-term outcomes.

Pediatr Pulmonol. 2017 Sep 07;:

Authors: Sanders DB, Zhao Q, Li Z, Farrell PM

Abstract
RATIONALE: People with CF treated with IV antibiotics for a pulmonary exacerbation (PEx) frequently fail to recover to baseline FEV1 . The long-term impact of these events has not been studied.
OBJECTIVES: To determine if a patient's spirometric recovery after a PEx is associated with time to next PEx within 1 year, the spirometric recovery after the next PEx, and/or the number of PEx episodes in the next 3 years.
METHODS: We used data from the CF Foundation Patient Registry from 2004 to 2011. We randomly selected one PEx per patient that met inclusion/exclusion criteria. Patients were defined as Non-Responders if their best FEV1 (in liters) recorded in the 3 months after the PEx was <90% of the best FEV1 (in liters) in the 6 months before the PEx. We compared Responders and Non-Responders using multivariable regression models.
RESULTS: We randomly chose 13 954 PEx episodes that met inclusion/exclusion criteria. A total of 2 762 (19.8%) patients were classified as Non-Responders. Non-Responders had a shorter median time to the next PEx, 235 (95%CI 218, 252) days, versus >365 days for Responders. Thirty-four percent of Non-Responders at the initial PEx were also Non-Reponders at the next PEx, versus 20% of Responders at the initial PEx. Non-Responders had more PEx episodes over the next 3 years, 4.99 (95%CI 4.84, 5.13), than Responders, 3.46 (95%CI 3.41, 3.51).
CONCLUSIONS: Poor recovery after a PEx is associated with a shorter time to the next PEx, increased risk of poor recovery at a second PEx, and more frequent subsequent PEx treatments.

PMID: 28881091 [PubMed - as supplied by publisher]

Novel GP64 envelope variants for improved delivery to human airway epithelial cells.

Gene Ther. 2017 Sep 07;:

Authors: Sinn PL, Hwang BY, Li N, Ortiz JLS, Shirazi E, Parekh KR, Cooney AL, Schaffer DV, McCray PB

Abstract
Lentiviral vectors pseudotyped with the baculovirus envelope protein GP64 transduce primary cultures of human airway epithelia (HAE) at their apical surface. Our goal in this study was to harness a directed evolution approach to develop a novel envelope glycoprotein with increased transduction properties for HAE. Using error-prone PCR, a library of GP64 mutants was generated and used to prepare a diverse pool of lentiviral virions pseudotyped with GP64 variants. The library was serially passaged on HAE and three GP64 mutations were recovered. Single-, double- and the triple-combination mutant envelope glycoproteins were compared with wild-type GP64 for their ability to transduce HAE. Our results suggest that lentiviral vectors pseudotyped with evolved GP64 transduced HAE with greater efficiency than wild-type GP64. This effect was not observed in primary cultures of porcine airway epithelial cells, suggesting that the directed evolution protocol was species specific. In summary, our studies indicate that serial passage of a GP64 mutant library yielded specific variants with improved HAE cell tropism, yielding tools with the potential to improve the success of gene therapy for airway diseases.Gene Therapy advance online publication, 7 September 2017; doi:10.1038/gt.2017.78.

PMID: 28880020 [PubMed - as supplied by publisher]

Cholesterol-modified Hydroxychloroquine-loaded Nanocarriers in Bleomycin-induced Pulmonary Fibrosis.

Sci Rep. 2017 Sep 06;7(1):10737

Authors: Liu L, Ren J, He Z, Men K, Mao Y, Ye T, Chen H, Li L, Xu B, Wei Y, Wei X

Abstract
An increasing number of reports have suggested the use of hydroxychloroquine (HCQ) as an adjunct anti-cancer treatment to enhance the chemotherapeutic response, as well as for the treatment of several fibrotic skin diseases and cystic fibrosis. In this study, we synthesized a cholesterol-modified HCQ (Chol-HCQ) and hypothesized that a systemic delivery system with Chol-HCQ nanocarriers could be effective for the treatment of bleomycin-induced pulmonary fibrosis. Chol-HCQ significantly inhibits the proliferation of rat lung fibroblasts, regulates inflammation and ameliorates bleomycin-induced pulmonary fibrosis in rats. It regulates the expression of pro-inflammatory cytokines, such as TNF-α; reduces the infiltration of inflammatory neutrophils; and inhibits the phosphorylation of NF-κB. Chol-HCQ also reduces the expression of connective tissue growth factor (CTGF) and phosphorylation of extracellular regulated protein kinase (p-ERK) in rats with bleomycin-induced pulmonary fibrosis. Chol-HCQ nanocarriers reduce early pulmonary inflammation and inhibit the CTGF/ERK signalling pathway in bleomycin-induced pulmonary fibrosis. These results demonstrate that Chol-HCQ liposomes suppress pulmonary inflammation and reduce pulmonary fibrosis induced by bleomycin. The systemic administration safety of Chol-HCQ liposomes was confirmed after intravenous administration for 28 days in rats. The present study provides evidence that Chol-HCQ liposomes may be a potential therapeutic agent for inflammation associated with pulmonary fibrosis.

PMID: 28878315 [PubMed - in process]

CF airway smooth muscle transcriptome reveals a role for PYK2.

JCI Insight. 2017 Sep 07;2(17):

Authors: Cook DP, Adam RJ, Zarei K, Deonovic B, Stroik MR, Gansemer ND, Meyerholz DK, Au KF, Stoltz DA

Abstract
Abnormal airway smooth muscle function can contribute to cystic fibrosis (CF) airway disease. We previously found that airway smooth muscle from newborn CF pigs had increased basal tone, an increased bronchodilator response, and abnormal calcium handling. Since CF pigs lack airway infection and inflammation at birth, these findings suggest intrinsic airway smooth muscle dysfunction in CF. In this study, we tested the hypothesis that CFTR loss in airway smooth muscle would produce a distinct set of changes in the airway smooth muscle transcriptome that we could use to develop novel therapeutic targets. Total RNA sequencing of newborn wild-type and CF airway smooth muscle revealed changes in muscle contraction-related genes, ontologies, and pathways. Using connectivity mapping, we identified several small molecules that elicit transcriptional signatures opposite of CF airway smooth muscle, including NVP-TAE684, an inhibitor of proline-rich tyrosine kinase 2 (PYK2). In CF airway smooth muscle tissue, PYK2 phosphorylation was increased and PYK2 inhibition decreased smooth muscle contraction. In vivo NVP-TAE684 treatment of wild-type mice reduced methacholine-induced airway smooth muscle contraction. These findings suggest that studies in the newborn CF pig may provide an important approach to enhance our understanding of airway smooth muscle biology and for discovery of novel airway smooth muscle therapeutics for CF and other diseases of airway hyperreactivity.

PMID: 28878137 [PubMed - as supplied by publisher]

Not All Is CFTR - Neutrophils and Cholesterol in Cystic Fibrosis.

EBioMedicine. 2017 Sep 01;:

Authors: Castellani S, Conese M

PMID: 28877849 [PubMed - as supplied by publisher]

[A new toolbox for genome editing].

Med Sci (Paris). 2017 Jan;33(1):105-108

Authors: Jordan B

Abstract
A new approach, based on the use of peptide nucleic acid molecules to form triple helices and promote locus-specific recombination, demonstrates potential for in vivo gene correction at clinically significant levels and may provide a promising avenue for gene therapy.

PMID: 28120767 [PubMed - indexed for MEDLINE]

CFTR supports cell death through ROS-dependent activation of TMEM16F (anoctamin 6).

Pflugers Arch. 2017 Sep 05;:

Authors: Simões F, Ousingsawat J, Wanitchakool P, Fonseca A, Cabrita I, Benedetto R, Schreiber R, Kunzelmann K

Abstract
Cystic fibrosis transmembrane conductance regulator (CFTR) is the essential chloride and bicarbonate channel in the apical membrane of epithelial cells. CFTR was also proposed earlier to conduct glutathione (GSH) out of airway epithelial cells to be enriched in the apical airway surface liquid to neutralize reactive oxygen species (ROS). Although earlier studies suggested that release of GSH by wild type (wt) CFTR may lead to an increase in cytosolic ROS, we did not detect different ROS levels in cells expressing wt-CFTR and mutant F508del-CFTR, independent of CFTR-activation or exposure to the ROS donor tert-butyl hydroperoxide. The Ca(2+)-activated phospholipid scramblase and ion channel TMEM16F (anoctamin 6, ANO6) is also expressed in airway cells. ANO6 produced outwardly rectifying Cl(-) currents (ORCC) and scrambled plasma membrane phospholipids when activated by increase in cytosolic ROS and consecutive peroxidation of plasma membrane lipids. ANO6 activity is enhanced by CFTR, probably through translocation of signaling proteins to the plasma membrane. The present data suggest that enhanced cell death in CFTR-expressing cells is due to upregulation of ANO6-activity. In ANO6 knockout mice, the number of apoptotic cells in the intestinal epithelium was strongly reduced, supporting the role of ANO6 for cell death. Thus, ANO6 and CFTR act cooperatively on ROS-mediated cell death, which is not further augmented by cAMP-dependent stimulation. We propose that ANO6 supports cell death correlated with expression of CFTR, possibly by inducing ferroptosis.

PMID: 28875346 [PubMed - as supplied by publisher]

Role of Smad3 and p38 Signalling in Cigarette Smoke-induced CFTR and BK dysfunction in Primary Human Bronchial Airway Epithelial Cells.

Sci Rep. 2017 Sep 05;7(1):10506

Authors: Sailland J, Grosche A, Baumlin N, Dennis JS, Schmid A, Krick S, Salathe M

Abstract
Mucociliary clearance (MCC) is a major airway host defence system that is impaired in patients with smoking-associated chronic bronchitis. This dysfunction is partially related to a decrease of airway surface liquid (ASL) volume that is in part regulated by apically expressed cystic fibrosis transmembrane conductance regulator (CFTR) and large-conductance, Ca(2+)-activated, and voltage dependent K(+) (BK) channels. Here, data from human bronchial epithelial cells (HBEC) confirm that cigarette smoke not only downregulates CFTR activity but also inhibits BK channel function, thereby causing ASL depletion. Inhibition of signalling pathways involved in cigarette smoke-induced channel dysfunction reveals that CFTR activity is downregulated via Smad3 signalling whereas BK activity is decreased via the p38 cascade. In addition, pre-treatment with pirfenidone, a drug presently used to inhibit TGF-β signalling in idiopathic pulmonary fibrosis, ameliorated BK dysfunction and ASL volume loss. Taken together, our results highlight the importance of not only CFTR but also BK channel function in maintaining ASL homeostasis and emphasize the possibility that pirfenidone could be employed as a novel therapeutic regimen to help improve MCC in smoking-related chronic bronchitis.

PMID: 28874823 [PubMed - in process]