Help, hinder, hide and harm: what can we learn from the interactions between Pseudomonas aeruginosa and Staphylococcus aureus during respiratory infections?

Thorax. 2019 Feb 18;:

Authors: Limoli DH, Hoffman LR

Abstract
Recent studies of human respiratory secretions using culture-independent techniques have found a surprisingly diverse array of microbes. Interactions among these community members can profoundly impact microbial survival, persistence and antibiotic susceptibility and, consequently, disease progression. Studies of polymicrobial interactions in the human microbiota have shown that the taxonomic and structural compositions, and resulting behaviours, of microbial communities differ substantially from those of the individual constituent species and in ways of clinical importance. These studies primarily involved oral and gastrointestinal microbiomes. While the field of polymicrobial respiratory disease is relatively young, early findings suggest that respiratory tract microbiota members also compete and cooperate in ways that may influence disease outcomes. Ongoing efforts therefore focus on how these findings can inform more 'enlightened', rational approaches to combat respiratory infections. Among the most common respiratory diseases involving polymicrobial infections are cystic fibrosis (CF), non-CF bronchiectasis, COPD and ventilator-associated pneumonia. While respiratory microbiota can be diverse, two of the most common and best-studied members are Staphylococcus aureus and Pseudomonas aeruginosa, which exhibit a range of competitive and cooperative interactions. Here, we review the state of research on pulmonary coinfection with these pathogens, including their prevalence, combined and independent associations with patient outcomes, and mechanisms of those interactions that could influence lung health. Because P. aeruginosa-S. aureus coinfection is common and well studied in CF, this disease serves as the paradigm for our discussions on these two organisms and inform our recommendations for future studies of polymicrobial interactions in pulmonary disease.

PMID: 30777898 [PubMed - as supplied by publisher]

Adapting Proteostasis and Autophagy for Controlling the Pathogenesis of Cystic Fibrosis Lung Disease.

Front Pharmacol. 2019;10:20

Authors: Bodas M, Vij N

Abstract
Cystic fibrosis (CF), a fatal genetic disorder predominant in the Caucasian population, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (Cftr) gene. The most common mutation is the deletion of phenylalanine from the position-508 (F508del-CFTR), resulting in a misfolded-CFTR protein, which is unable to fold, traffic and retain its plasma membrane (PM) localization. The resulting CFTR dysfunction, dysregulates variety of key cellular mechanisms such as chloride ion transport, airway surface liquid (ASL) homeostasis, mucociliary-clearance, inflammatory-oxidative signaling, and proteostasis that includes ubiquitin-proteasome system (UPS) and autophagy. A collective dysregulation of these key homoeostatic mechanisms contributes to the development of chronic obstructive cystic fibrosis lung disease, instead of the classical belief focused exclusively on ion-transport defect. Hence, therapeutic intervention(s) aimed at rescuing chronic CF lung disease needs to correct underlying defect that mediates homeostatic dysfunctions and not just chloride ion transport. Since targeting all the myriad defects individually could be quite challenging, it will be prudent to identify a process which controls almost all disease-promoting processes in the CF airways including underlying CFTR dysfunction. There is emerging experimental and clinical evidence that supports the notion that impaired cellular proteostasis and autophagy plays a central role in regulating pathogenesis of chronic CF lung disease. Thus, correcting the underlying proteostasis and autophagy defect in controlling CF pulmonary disease, primarily via correcting the protein processing defect of F508del-CFTR protein has emerged as a novel intervention strategy. Hence, we discuss here both the rationale and significant therapeutic utility of emerging proteostasis and autophagy modulating drugs/compounds in controlling chronic CF lung disease, where targeted delivery is a critical factor-influencing efficacy.

PMID: 30774592 [PubMed]

Peripheral muscle strength is associated with lung function and functional capacity in patients with cystic fibrosis.

Physiother Res Int. 2019 Feb 18;:e1771

Authors: Rovedder PME, Borba GC, Anderle M, Flores J, Ziegler B, Barreto SSM, Roth Dalcin PT

PMID: 30776177 [PubMed - as supplied by publisher]

Unraveling the host's immune response to infection: Seeing is believing.

J Leukoc Biol. 2019 Feb 18;:

Authors: Scott BNV, Sarkar T, Kratofil RM, Kubes P, Thanabalasuriar A

Abstract
It has long been appreciated that understanding the interactions between the host and the pathogens that make us sick is critical for the prevention and treatment of disease. As antibiotics become increasingly ineffective, targeting the host and specific bacterial evasion mechanisms are becoming novel therapeutic approaches. The technology used to understand host-pathogen interactions has dramatically advanced over the last century. We have moved away from using simple in vitro assays focused on single-cell events to technologies that allow us to observe complex multicellular interactions in real time in live animals. Specifically, intravital microscopy (IVM) has improved our understanding of infection, from viral to bacterial to parasitic, and how the host immune system responds to these infections. Yet, at the same time it has allowed us to appreciate just how complex these interactions are and that current experimental models still have a number of limitations. In this review, we will discuss the advances in vivo IVM has brought to the study of host-pathogen interactions, focusing primarily on bacterial infections and innate immunity.

PMID: 30776153 [PubMed - as supplied by publisher]

Population genomic screening of all young adults in a health-care system: a cost-effectiveness analysis.

Genet Med. 2019 Feb 18;:

Authors: Zhang L, Bao Y, Riaz M, Tiller J, Liew D, Zhuang X, Amor DJ, Huq A, Petelin L, Nelson M, James PA, Winship I, McNeil JJ, Lacaze P

Abstract
PURPOSE: To consider the impact and cost-effectiveness of offering preventive population genomic screening to all young adults in a single-payer health-care system.
METHODS: We modeled screening of 2,688,192 individuals, all adults aged 18-25 years in Australia, for pathogenic variants in BRCA1/BRCA2/MLH1/MSH2 genes, and carrier screening for cystic fibrosis (CF), spinal muscular atrophy (SMA), and fragile X syndrome (FXS), at 71% testing uptake using per-test costs ranging from AUD$200 to $1200 (~USD$140 to $850). Investment costs included genetic counseling, surveillance, and interventions (reimbursed only) for at-risk individuals/couples. Cost-effectiveness was defined below AUD$50,000/DALY (disability-adjusted life year) prevented, using an incremental cost-effectiveness ratio (ICER), compared with current targeted testing. Outcomes were cancer incidence/mortality, disease cases, and treatment costs reduced.
RESULTS: Population screening would reduce variant-attributable cancers by 28.8%, cancer deaths by 31.2%, and CF/SMA/FXS cases by 24.8%, compared with targeted testing. Assuming AUD$400 per test, investment required would be between 4 and 5 times higher than current expenditure. However, screening would lead to substantial savings in medical costs and DALYs prevented, at a highly cost-effective ICER of AUD$4038/DALY. At AUD$200 per test, screening would approach cost-saving for the health system (ICER = AUD$22/DALY).
CONCLUSION: Preventive genomic screening in early adulthood would be highly cost-effective in a single-payer health-care system, but ethical issues must be considered.

PMID: 30773532 [PubMed - as supplied by publisher]

Compensatory changes in physical activity and sedentary time in children and adolescents with cystic fibrosis.

J Sports Sci. 2019 Feb 16;:1-6

Authors: Mackintosh KA, Ridgers ND, McNarry MA

Abstract
Physical activity (PA) is a key element in Cystic Fibrosis (CF) treatment strategies, yet little is known as to whether activity compensation occurs. This study examined whether PA and/or sedentary time on one day were temporally associated with time spent in these intensities the following day in youth with CF. Time spent sedentary and in different PA intensities were objectively-measured for seven consecutive days in 50 youth (22 boys; 12.0 ± 2.7 years); 25 with mild-to-moderate CF and 25 age- and sex-matched controls. Multilevel analyses (day and child) were conducted using generalised linear latent and mixed models. On any given day, every additional 10 minutes spent in sedentary time or moderate-to-vigorous physical activity (MVPA) were associated with 1.9 (95%CI: -3.6 to -1.2) and 12.4 (95%CI: -22.1 to -2.9) minutes less sedentary time the following day, respectively. These temporal associations were also observed when split by group (3.1 vs. 1.9 minutes for healthy and CF, respectively). These findings indicate that youth do not compensate their PA, irrespective of disease status, between days, but may compensate their sedentary time between days. Experimental studies are warranted to fully elucidate whether compensatory responses to PA and sedentary time occur, which is fundamental for informing PA promotion strategies.

PMID: 30773099 [PubMed - as supplied by publisher]

Successful treatment with omalizumab of allergic bronchopulmonary aspergillosis in patients with cystic fibrosis: case reports and literature review.

J Allergy Clin Immunol Pract. 2019 Feb 14;:

Authors: Parisi GF, Portale A, Papale M, Tardino L, Rotolo N, Licari A, Leonardi S

PMID: 30772479 [PubMed - as supplied by publisher]

Cystic fibrosis - How we reach adult life.

Pulmonology. 2019 Feb 13;:

Authors: Serras I, Oliveira JA, Pereira L, Barreto C

PMID: 30772263 [PubMed - as supplied by publisher]

Social support is associated with fewer reported symptoms and decreased treatment burden in adults with cystic fibrosis.

J Cyst Fibros. 2019 Feb 13;:

Authors: Flewelling KD, Sellers DE, Sawicki GS, Robinson WM, Dill EJ

Abstract
BACKGROUND: Although social support has been linked to a variety of health outcomes in those with and without chronic illness, this construct has rarely been studied in adults with cystic fibrosis (CF), who may face a unique set of clinical and psychosocial barriers. The current study explored the relationships between social support, mental health, physical health, treatment activity, and disease-specific quality of life in a sample of adults with CF.
METHODS: Participants in the study included 250 adults with CF who took part in a larger longitudinal study. Participants were administered a battery of measures including a social support evaluation (Interpersonal Support Evaluation List, ISEL), a health assessment (Memorial Symptom Assessment Scale, MSAS), a health-related quality of life measure (Cystic Fibrosis Questionnaire - Revised, CFQ-R), and treatment activity questionnaires (Tool for Adherence Behaviour Screening, TABS and other surveys).
RESULTS: Linear regression analyses indicated that greater social support was associated with fewer self-reported mental and physical health symptoms, digestive symptoms, and eating disturbances over time. Social support also was associated with elevated emotional, social, and role functioning as well as vitality and improved body image. Those who reported more support perceived less treatment burden and better overall perceptions of their health.
CONCLUSIONS: Social support has been shown to be associated with health outcomes in other chronic illnesses, and the same is true for adults with CF. This study fills gaps in the literature by examining outcomes of social support in this emerging adult population and providing a potential area for intervention.

PMID: 30772245 [PubMed - as supplied by publisher]

Do patients with cystic fibrosis participating in clinical trials demonstrate placebo response? A meta-analysis.

J Cyst Fibros. 2019 Feb 13;:

Authors: Coton J, Le HH, Veuillet V, Janiaud P, Cucherat M, Kassai-Koupai B, Gueyffier F, Reix P

Abstract
BACKGROUND: Patients' and families' expectation that a cure for cystic fibrosis (CF) will be found is high. In other debilitating conditions, high expectation has been shown to drive a strong placebo response (PR). Therefore, our goal was to evaluate PR on objective continuous outcomes (FEV1, BMI) and the CF Questionnaire Revised-Respiratory Domain (CFQR-RD) monitored during randomised clinical trials (RCTs) for CF.
METHODS: We conducted a meta-analysis after a systematic review of the literature carried out to identify RCTs with FEV1, CFQR-RD and BMI as outcome measures. The standardised mean difference (SMD) was calculated to estimate the PR. A meta-regression analysis was conducted to assess other contributing factors on PR such as study design, trial duration, patient age and disease severity.
RESULTS: Out of 289 RCTs found in the search, we identified 61 articles (published from 1987 to 2017) with respectively 59, 17 and 9 reporting FEV1, CFQR-RD and BMI at the start and at the end of the RCTs. No significant PR was found on FEV1 or CFQR-RD. However, a small but significant PR was found on BMI SMD, 0.09 (95% CI (0.01; 0.17); p = 0.03).
CONCLUSION: The PR seems higher when measuring BMI. However, it is not clear whether this improvement can be explained by a PR alone.

PMID: 30772244 [PubMed - as supplied by publisher]

Disruption of quorum sensing and virulence in Burkholderia cenocepacia by a structural analogue of the cis-2-dodecenoic acid signal.

Appl Environ Microbiol. 2019 Feb 15;:

Authors: Cui C, Song S, Yang C, Sun X, Huang Y, Li K, Zhao S, Zhang Y, Deng Y

Abstract
Quorum sensing (QS) signals are widely used by bacterial pathogens to control biological functions and virulence in response to changes in cell population densities. Burkholderia cenocepacia employs a molecular mechanism in which the cis-2-dodecenoic acid (named B urkholderia d iffusible s ignal f actor, abbreviated as BDSF) QS system regulates N-acyl homoserine lactone (AHL) signal production and virulence by modulating intracellular levels of cyclic diguanosine monophosphate (c-di-GMP). Thus, inhibition of BDSF signaling may offer a non-antibiotic-based therapeutic strategy against BDSF-regulated bacterial infections. In this study, we report the synthesis of small molecule mimics of the BDSF signal and evaluate their ability to inhibit BDSF QS signaling in B. cenocepacia A novel structural analogue of BDSF, 14-Me-C16:Δ2 (cis-14-methylpentadec-2-enoic acid), was observed to inhibit BDSF production and impair BDSF-regulated phenotypes in B. cenocepacia, including motility, biofilm formation and virulence, while it did not inhibit the growth rate of this pathogen. 14-Me-C16:Δ2 also reduced AHL signal production. Genetic and biochemical analyses showed that 14-Me-C16:Δ2 inhibited the production of the BDSF and AHL signals by decreasing the expression of their synthase-encoding genes. Notably, 14-Me-C16:Δ2 attenuated BDSF-regulated phenotypes in various Burkholderia species. These findings suggest that 14-Me-C16:Δ2 could potentially be developed as a new therapeutic agent against pathogenic Burkholderia species by interfering with their QS signaling.IMPORTANCE Burkholderia cenocepacia is an important opportunistic pathogen which can cause life-threatening infections in susceptible individuals, particularly in cystic fibrosis and immunocompromised patients. It usually employs two type quorum sensing (QS) systems, including the cis-2-dodecenoic acid (BDSF) system and N-acyl homoserine lactone (AHL) system, to regulate virulence. In this study, we have designed and identified an unsaturated fatty acid compound (cis-14-methylpentadec-2-enoic acid, named as 14-Me-C16:Δ2) that is capable of interfering with B. cenocepacia QS signaling and virulence. We demonstrate that 14-Me-C16:Δ2 reduced BDSF and AHL signal production in B. cenocepacia It also impaired QS-regulated phenotypes in various Burkholderia species. These results suggest that 14-Me-C16:Δ2 could interfere with QS signaling in many Burkholderia species and might be developed as a new antibacterial agent.

PMID: 30770405 [PubMed - as supplied by publisher]

Flexible Electronics toward Wearable Sensing.

Acc Chem Res. 2019 Feb 15;:

Authors: Gao W, Ota H, Kiriya D, Takei K, Javey A

Abstract
Wearable sensors play a crucial role in realizing personalized medicine, as they can continuously collect data from the human body to capture meaningful health status changes in time for preventive intervention. However, motion artifacts and mechanical mismatches between conventional rigid electronic materials and soft skin often lead to substantial sensor errors during epidermal measurement. Because of its unique properties such as high flexibility and conformability, flexible electronics enables a natural interaction between electronics and the human body. In this Account, we summarize our recent studies on the design of flexible electronic devices and systems for physical and chemical monitoring. Material innovation, sensor design, device fabrication, system integration, and human studies employed toward continuous and noninvasive wearable sensing are discussed. A flexible electronic device typically contains several key components, including the substrate, the active layer, and the interface layer. The inorganic-nanomaterials-based active layer (prepared by a physical transfer or solution process) is shown to have good physicochemical properties, electron/hole mobility, and mechanical strength. Flexible electronics based on the printed and transferred active materials has shown great promise for physical sensing. For example, integrating a nanowire transistor array for the active matrix and a conductive pressure-sensitive rubber enables tactile pressure mapping; tactile-pressure-sensitive e-skin and organic light-emitting diodes can be integrated for instantaneous pressure visualization. Such printed sensors have been applied as wearable patches to monitor skin temperature, electrocardiograms, and human activities. In addition, liquid metals could serve as an attractive candidate for flexible electronics because of their excellent conductivity, flexibility, and stretchability. Liquid-metal-enabled electronics (based on liquid-liquid heterojunctions and embedded microchannels) have been utilized to monitor a wide range of physiological parameters (e.g., pulse and temperature). Despite the rapid growth in wearable sensing technologies, there is an urgent need for the development of flexible devices that can capture molecular data from the human body to retrieve more insightful health information. We have developed a wearable and flexible sweat-sensing platform toward real-time multiplexed perspiration analysis. An integrated iontophoresis module on a wearable sweat sensor could enable autonomous and programmed sweat extraction. A microfluidics-based sensing system was demonstrated for sweat sampling, sensing, and sweat rate analysis. Roll-to-roll gravure printing allows for mass production of high-performance flexible chemical sensors at low cost. These wearable and flexible sweat sensors have shown great promise in dehydration monitoring, cystic fibrosis diagnosis, drug monitoring, and noninvasive glucose monitoring. Future work in this field should focus on designing robust wearable sensing systems to accurately collect data from the human body and on large-scale human studies to determine how the measured physical and chemical information relates to the individual's specific health conditions. Further research in these directions, along with the large sets of data collected via these wearable and flexible sensing technologies, will have a significant impact on future personalized healthcare.

PMID: 30767497 [PubMed - as supplied by publisher]

Exercise capacity and muscle fatiguability alterations following a progressive maximal exercise of lower extremities in children with cystic fibrosis.

Afr Health Sci. 2018 Dec;18(4):1236-1242

Authors: Abdelbasset WK, Soliman GS, Elshehawy AA, Alrawaili SM

Abstract
Background: Impairment of peripheral skeletal muscle function is a common phenomenon in patients with cystic fibrosis (CF) in addition to great clinical connotations, such as lack of exercise tolerance and decrease of health-related quality of life. There is very limited data on the effects of maximal exercise on muscle fatiguability and exercise capacity in children with cystic fibrosis.
Objectives: The aim of this study was to evaluate the effect of progressive maximal exercise training of the lower extremities on exercise capacity and muscle fatiguability in children with cystic fibrosis.
Study design: Between June and September 2017, eighteen children aged 8-12 years were recruited in this study. This study had two groups of children; the CF group consisted of nine children (6 males and 3 females) with cystic fibrosis and the control group consisted of nine healthy age matched children (6 males and 3 females). The children underwent a progressive maximal cardiopulmonary exercise cycling test (CPET), muscle fatigue test, and magnetic resonance imaging (MRI) to measure a muscle cross-section area (CSA). Also, pulmonary functions were assessed.
Results: The findings of this study showed that the CF children had less pulmonary functions, had a less exercise capacity, and had a higher breathing reserve index and oxygen desaturation when compared with healthy children (p<0.05). On the other hand, there was a non-significant difference in muscle fatiguability, muscle cross-section area, and maximal voluntary contraction between the CF and healthy children (p>0.05).
Conclusion: This study indicates that progressive maximal exercise doesn't affect muscle fatiguability, muscle cross-section area, and maximal voluntary contraction in CF children with moderate respiratory diseases but includes lower exercise capacity. CF children and healthy age matched children have similar responses to maximal exercise in muscle fatiguability, muscle cross-section area, and maximal voluntary contractions but lower exercise capacity in the CF group.

PMID: 30766590 [PubMed - in process]

The chloride channel CFTR controls cellular quiescence by hyperpolarizing the cell membrane during diapause in the crustacean Artemia.

J Biol Chem. 2019 Feb 14;:

Authors: Li AQ, Sun ZP, Liu X, Yang JS, Jin F, Zhu L, Jia WH, Vos S, Stappen GV, Bossier P, Yang WJ

Abstract
Cellular quiescence, a reversible state in which growth, proliferation, and other cellular activities are arrested, is important for self-renewal, differentiation, development, re-generation, and stress resistance. However, the physiological mechanisms underlying cellular quiescence remain largely unknown. In the present study, we used embryos of the crustacean Artemia in the diapause stage, in which these embryos remain quiescent for prolonged periods, as a model to explore the relationship between cell membrane potential (Vmem) and quiescence. We found that Vmem is hyperpolarized and that the intracellular chloride concentration is high in diapause embryos, while Vmem is depolarized and intracellular chloride concentration reduced in post-diapause embryos and during further embryonic development. We identified and characterized the chloride ion channel protein cystic fibrosis transmembrane conductance regulator (CFTR) of Artemia (Ar-CFTR) and found that its expression is silenced in quiescent cells of Artemia diapause embryos, but remains constant in all other embryonic stages. Ar-CFTR knockdown and GlyH-101-mediated chemical inhibition of Ar-CFTR produced diapause embryos having a high Vmem and intracellular chloride concentration, whereas control Artemia embryos released free-swimming nauplius larvae. Transcriptome analysis of embryos at different developmental stages revealed that proliferation, differentiation, and metabolism are suppressed in diapause embryos and restored in post-diapause embryos. Combined with RNA-Seq of GlyH-101-treated MCF-7 breast cancer cells, these analyses revealed that CFTR inhibition down-regulates the Wnt and AURKA signaling pathways and up-regulates the p53 signaling pathway. Our findings provide insight into CFTR-mediated regulation of cellular quiescence and Vmem in the Artemia model.

PMID: 30765604 [PubMed - as supplied by publisher]

Subacute invasive aspergillosis in a patient with cystic fibrosis.

Pulmonology. 2019 Feb 11;:

Authors: Padrão E, Amorim A

PMID: 30765333 [PubMed - as supplied by publisher]

CT evaluation of hyperattenuating mucus to diagnose allergic bronchopulmonary aspergillosis in the special condition of cystic fibrosis.

J Cyst Fibros. 2019 Feb 12;:

Authors: Refait J, Macey J, Bui S, Fayon M, Berger P, Delhaes L, Laurent F, Dournes G

Abstract
BACKGROUND: Mucus plugging (MP), central bronchiectasis (CB), and consolidation/atelectasia (CA) are conventional CT signs to diagnose allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis (CF). Hyperattenuating mucus (HAM) has recently been described and may improve diagnostic accuracy. The goal of our study was to compare HAM versus conventional CT signs to diagnose ABPA in CF. Secondary objectives were to determine the optimal threshold of HAM quantitatively and to assess the diagnostic value of HAM using chest radiograph (CXR).
METHODS: The study was retrospective and included 137 patients with CF, aged >6-year-old. The presence of HAM, CB, MP and CA were determined by two radiologists in consensus. HAM was quantified using an absolute mean density value (AMD) and a ratio between mucus and paraspinal muscle (DRM). Sensitivity (Se), Specificity (Sp) and Youden's J-index were calculated. The Cystic Fibrosis Conference Consensus criteria were chosen as Gold Standard.
RESULTS: 23 out of 137 CF patients had ABPA. Using CT, the most sensitive structural alteration was MP (Se = 91%), followed by CB (Se = 87%) and CA (Se = 70%) whereas specificities were 28%, 19% and 58%, respectively. Conversely, HAM had the highest specificity (Sp = 100%) whereas Se was 69%. HAM had the highest Youden's J-index (p < 0.001) Quantitative optimal thresholds were AMD > 78 HU (Se/Sp = 71%/98%) and DRM > 1.3 (Se/Sp = 82%/97%). HAM was unseen using CXR (Se = 0%).
CONCLUSION: HAM is the most specific CT biomarker of ABPA in CF, with good sensitivity. Our study suggests that characterization of mucus density may improve the accuracy of imaging criteria to diagnose ABPA early.

PMID: 30765182 [PubMed - as supplied by publisher]

Is cellular senescence involved in cystic fibrosis?

Respir Res. 2019 Feb 14;20(1):32

Authors: Bezzerri V, Piacenza F, Caporelli N, Malavolta M, Provinciali M, Cipolli M

Abstract
Pulmonary disease is the main cause of the morbidity and mortality of patients affected by cystic fibrosis (CF). The lung pathology is dominated by excessive recruitment of neutrophils followed by an exaggerated inflammatory process that has also been reported to occur in the absence of apparent pathogenic infections. Airway surface dehydration and mucus accumulation are the driving forces of this process. The continuous release of reactive oxygen species and proteases by neutrophils contributes to tissue damage, which eventually leads to respiratory insufficiency. CF has been considered a paediatric problem for several decades. Nevertheless, during the last 40 years, therapeutic options for CF have been greatly improved, turning CF into a chronic disease and extending the life expectancy of patients. Unfortunately, chronic inflammatory processes, which are characterized by a substantial release of cytokines and chemokines, along with ROS and proteases, can accelerate cellular senescence, leading to further complications in adulthood. The alterations and mechanisms downstream of CFTR functional defects that can stimulate cellular senescence remain unclear. However, while there are correlative data suggesting that cellular senescence may be implicated in CF, a causal or consequential relationship between cellular senescence and CF is still far from being established. Senescence can be both beneficial and detrimental. Senescence may suppress bacterial infections and cooperate with tissue repair. Additionally, it may act as an effective anticancer mechanism. However, it may also promote a pro-inflammatory environment, thereby damaging tissues and leading to chronic age-related diseases. In this review, we present the most current knowledge on cellular senescence and contextualize its possible involvement in CF.

PMID: 30764828 [PubMed - in process]

Targeting microRNAs using nanotechnology in pulmonary diseases.

Panminerva Med. 2018 Dec;60(4):230-231

Authors: Dua K, Chellappan DK, Singhvi G, de Jesus Andreoli Pinto T, Gupta G, Hansbro PM

Abstract

PMID: 30563304 [PubMed - indexed for MEDLINE]

TMEM16A in Cystic Fibrosis: Activating or Inhibiting?

Front Pharmacol. 2019;10:3

Authors: Kunzelmann K, Ousingsawat J, Cabrita I, Doušová T, Bähr A, Janda M, Schreiber R, Benedetto R

Abstract
The inflammatory airway disease cystic fibrosis (CF) is characterized by airway obstruction due to mucus hypersecretion, airway plugging, and bronchoconstriction. The cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel is dysfunctional in CF, leading to defects in epithelial transport. Although CF pathogenesis is still disputed, activation of alternative Cl- channels is assumed to improve lung function in CF. Two suitable non-CFTR Cl- channels are present in the airway epithelium, the Ca2+ activated channel TMEM16A and SLC26A9. Activation of these channels is thought to be feasible to improve hydration of the airway mucus and to increase mucociliary clearance. Interestingly, both channels are upregulated during inflammatory lung disease. They are assumed to support fluid secretion, necessary to hydrate excess mucus and to maintain mucus clearance. During inflammation, however, TMEM16A is upregulated particularly in mucus producing cells, with only little expression in ciliated cells. Recently it was shown that knockout of TMEM16A in ciliated cells strongly compromises Cl- conductance and attenuated mucus secretion, but does not lead to a CF-like lung disease and airway plugging. Along this line, activation of TMEM16A by denufosol, a stable purinergic ligand, failed to demonstrate any benefit to CF patients in earlier studies. It rather induced adverse effects such as cough. A number of studies suggest that TMEM16A is essential for mucus secretion and possibly also for mucus production. Evidence is now provided for a crucial role of TMEM16A in fusion of mucus-filled granules with the apical plasma membrane and cellular exocytosis. This is probably due to local Ca2+ signals facilitated by TMEM16A. Taken together, TMEM16A supports fluid secretion by ciliated airway epithelial cells, but also maintains excessive mucus secretion during inflammatory airway disease. Because TMEM16A also supports airway smooth muscle contraction, inhibition rather than activation of TMEM16A might be the appropriate treatment for CF lung disease, asthma and COPD. As a number of FDA-approved and well-tolerated drugs have been shown to inhibit TMEM16A, evaluation in clinical trials appears timely.

PMID: 30761000 [PubMed]

Mutational analysis of CFTR in the Ecuadorian population using next-generation sequencing.

Gene. 2019 Feb 11;:

Authors: Ruiz-Cabezas JC, Barros F, Sobrino B, García G, Burgos R, Farhat C, Castro A, Muñoz L, Zambrano AK, Martínez M, Montalván M, Paz-Y-Miño C

Abstract
The frequency distributions of cystic fibrosis variants are heterogeneous in Ecuador because of the genetic admixture of its population. The aim of this study was to identify disease-causing variants among Ecuadorian cystic fibrosis (CF) patients by next-generation sequencing (NGS) of the entire cystic fibrosis transmembrane conductance regulator (CFTR) gene. The results showed an approximation of the frequencies of pathogenic variants in the population under study and an optimal mutation panel for routine first-line CF molecular diagnosis. One hundred and forty-one patients with suspected CF from the 3 largest Ecuadorian cities (Guayaquil, Quito, and Cuenca) were studied. One hundred and seventy mutated alleles were detected in eighty-five individuals. Twenty-eight disease-causing variants were identified, with p.Phe508del and p.His609Arg being the most frequent (both 24.7%) followed by p.Gly85Glu (11.1%), p.Leu15Pro (9.4%), p.Asn1303Lys (4.1%), and p.Gly542* (2.3%). Together, these variants constituted 76.44% of the detected disease-causing variants. The following six novel potentially disease-associated variants were detected: 3 deletions (CFTR_dele10, CFTR_dele12, and c.2672delA), 1 nonsense variant (p.Cys491*), 1 missense variant (p.Trp496Arg), and 1 complex allele (p.[Gly253Arg;Gly451Val]). The remaining mutations occurred in isolation and were present in the databases.

PMID: 30763667 [PubMed - as supplied by publisher]