TMEM16A Ca2+-activated Cl- channel inhibition ameliorates acute pancreatitis via the IP3R/Ca2+/NFκB/IL-6 signaling pathway.

J Adv Res. 2020 May;23:25-35

Authors: Wang Q, Bai L, Luo S, Wang T, Yang F, Xia J, Wang H, Ma K, Liu M, Wu S, Wang H, Guo S, Sun X, Xiao Q

Abstract
TMEM16A Ca2+-activated Cl- channels are expressed in pancreatic acinar cells and participate in inflammation-associated diseases. Whether TMEM16A contributes to the pathogenesis of acute pancreatitis (AP) remains unknown. Here, we found that increased TMEM16A expression in the pancreatic tissue was correlated with the interleukin-6 (IL-6) level in the pancreatic tissue and in the serum of a cerulein-induced AP mouse model. IL-6 treatment promoted TMEM16A expression in AR42J pancreatic acinar cells via the IL-6 receptor (IL-6R)/signal transducers and activators of transcription 3 (STAT3) signaling pathway. In addition, TMEM16A was co-immunoprecipitated with the inositol 1,4,5-trisphosphate receptor (IP3R) and was activated by IP3R-mediated Ca2+ release. TMEM16A inhibition reduced the IP3R-mediated Ca2+ release induced by cerulein. Furthermore, TMEM16A overexpression activated nuclear factor-κB (NFκB) and increased IL-6 release by increasing intracellular Ca2+. TMEM16A knockdown by shRNAs reduced the cerulein-induced NFκB activation by Ca2+. TMEM16A inhibitors inhibited NFκB activation by decreasing channel activity and reducing TMEM16A protein levels in AR42J cells, and it ameliorated pancreatic damage in cerulein-induced AP mice. This study identifies a novel mechanism underlying the pathogenesis of AP by which IL-6 promotes TMEM16A expression via IL-6R/STAT3 signaling activation, and TMEM16A overexpression increases IL-6 secretion via IP3R/Ca2+/NFκB signaling activation in pancreatic acinar cells. TMEM16A inhibition may be a new potential strategy for treating AP.

PMID: 32071789 [PubMed]

Hypermutator Pseudomonas aeruginosa exploits multiple genetic pathways to develop multidrug resistance during long-term infections in the airways of cystic fibrosis patients.

Antimicrob Agents Chemother. 2020 Feb 18;:

Authors: Colque CA, Albarracín Orio AG, Feliziani S, Marvig RL, Tobares AR, Johansen HK, Molin S, Smania AM

Abstract
Pseudomonas aeruginosa exploits intrinsic and acquired resistance mechanisms to resist almost every antibiotic used in chemotherapy. Antimicrobial resistance in P. aeruginosa isolated from cystic fibrosis (CF) patients is further enhanced by the occurrence of hypermutator strains, a hallmark of chronic CF infections. However, the within-patient genetic diversity of P. aeruginosa populations related to antibiotic resistance remains unexplored. Here, we show the evolution of the mutational resistome profile of a P. aeruginosa hypermutator lineage by performing longitudinal and transversal analyses of isolates collected from a CF patient throughout 20 years of chronic infection. Our results show the accumulation of thousands of mutations with an overall evolutionary history characterized by purifying selection. However, mutations in antibiotic resistance genes appear to be positively selected, driven by antibiotic treatment. Antibiotic resistance increased as infection progressed towards the establishment of a population constituted by genotypically diversified coexisting sub-lineages, all of which converged to multi-drug resistance. These sub-lineages emerged by parallel evolution through distinct evolutionary pathways, which affected genes of the same functional categories. Interestingly, ampC and fstI, encoding the β-lactamase and penicillin-binding protein 3, respectively, were found among the most frequently mutated genes. In fact, both genes were targeted by multiple independent mutational events, which led to a wide diversity of coexisting alleles underlying β-lactam resistance. Our findings indicate that hypermutators, apart from boosting antibiotic resistance evolution by simultaneously targeting several genes, favor the emergence of adaptive innovative alleles by clustering beneficial/compensatory mutations in the same gene, hence expanding P. aeruginosa strategies for persistence.

PMID: 32071060 [PubMed - as supplied by publisher]

Antibacterial activity of iron oxide, iron nitride, and tobramycin conjugated nanoparticles against Pseudomonas aeruginosa biofilms.

J Nanobiotechnology. 2020 Feb 18;18(1):35

Authors: Armijo LM, Wawrzyniec SJ, Kopciuch M, Brandt YI, Rivera AC, Withers NJ, Cook NC, Huber DL, Monson TC, Smyth HDC, Osiński M

Abstract
BACKGROUND: Novel methods are necessary to reduce morbidity and mortality of patients suffering from infections with Pseudomonas aeruginosa. Being the most common infectious species of the Pseudomonas genus, P. aeruginosa is the primary Gram-negative etiology responsible for nosocomial infections. Due to the ubiquity and high adaptability of this species, an effective universal treatment method for P. aeruginosa infection still eludes investigators, despite the extensive research in this area.
RESULTS: We report bacterial inhibition by iron-oxide (nominally magnetite) nanoparticles (NPs) alone, having a mean hydrodynamic diameter of ~ 16 nm, as well as alginate-capped iron-oxide NPs. Alginate capping increased the average hydrodynamic diameter to ~ 230 nm. We also investigated alginate-capped iron-oxide NP-drug conjugates, with a practically unchanged hydrodynamic diameter of ~ 232 nm. Susceptibility and minimum inhibitory concentration (MIC) of the NPs, NP-tobramycin conjugates, and tobramycin alone were determined in the PAO1 bacterial colonies. Investigations into susceptibility using the disk diffusion method were done after 3 days of biofilm growth and after 60 days of growth. MIC of all compounds of interest was determined after 60-days of growth, to ensure thorough establishment of biofilm colonies.
CONCLUSIONS: Positive inhibition is reported for uncapped and alginate-capped iron-oxide NPs, and the corresponding MICs are presented. We report zero susceptibility to iron-oxide NPs capped with polyethylene glycol, suggesting that the capping agent plays a major role in enabling bactericidal ability in of the nanocomposite. Our findings suggest that the alginate-coated nanocomposites investigated in this study have the potential to overcome the bacterial biofilm barrier. Magnetic field application increases the action, likely via enhanced diffusion of the iron-oxide NPs and NP-drug conjugates through mucin and alginate barriers, which are characteristic of cystic-fibrosis respiratory infections. We demonstrate that iron-oxide NPs coated with alginate, as well as alginate-coated magnetite-tobramycin conjugates inhibit P. aeruginosa growth and biofilm formation in established colonies. We have also determined that susceptibility to tobramycin decreases for longer culture times. However, susceptibility to the iron-oxide NP compounds did not demonstrate any comparable decrease with increasing culture time. These findings imply that iron-oxide NPs are promising lower-cost alternatives to silver NPs in antibacterial coatings, solutions, and drugs, as well as other applications in which microbial abolition or infestation prevention is sought.

PMID: 32070354 [PubMed - in process]

Etiology and characteristics of patients with bronchiectasis in Taiwan: a cohort study from 2002 to 2016.

BMC Pulm Med. 2020 Feb 18;20(1):45

Authors: Huang HY, Chung FT, Lo CY, Lin HC, Huang YT, Yeh CH, Lin CW, Huang YC, Wang CH

Abstract
BACKGROUND: Bronchiectasis is a chronic infectious respiratory disease with diverse causes and ethnic or geographic differences. However, few large-scale studies of its etiology have been conducted in Asia. This study aimed to determine the etiology and clinical features of bronchiectasis in Taiwan.
METHODS: This longitudinal cohort study investigated the etiology and clinical features of newly diagnosed non-cystic fibrosis bronchiectasis patients from January 2002 to December 2016. The clinical, functional and microbiological data of patients were retrieved from the Chang Gung Research Database, which includes seven medical facilities throughout Taiwan. The index date was the date of the first bronchiectasis diagnosis. Known diseases that were diagnosed before the index date were regarded as etiologies of bronchiectasis.
RESULTS: The cohort comprised 15,729 adult patients with bronchiectasis. Idiopathic (32%) was the most common cause, followed by post-pneumonia (24%). Other causes included post-tuberculosis (12%), chronic obstructive pulmonary disease (14%), asthma (10%), gastroesophageal reflux disease (2%) and rheumatic diseases (2%). At diagnosis, 8487 patients had sputum culture. Pseudomonas aeruginosa (5.3%) was the most common bacteria, followed by non-tuberculosis mycobacteria (3.6%), Haemophilus influenzae (3.4%) and Klebsiella pneumoniae (3.1%), but 6155 (72.1%) had negative sputum cultures. Patients with post-tuberculosis had a higher sputum isolation rate of non-tuberculosis mycobacteria than P. aeruginosa. Patients with post-tuberculosis and post-pneumonia bronchiectasis had a higher frequency of chronic lung infection than other groups (p < 0.05). Clinical characteristics, such as gender, lung function, comorbidities and microbiology, were significantly different between idiopathic and known etiologies.
CONCLUSIONS: Idiopathic, post-infection and tuberculosis constitute major bronchiectasis etiologies in Taiwan. Clinical characteristics and sputum microbiology were distinct among separate etiology phenotypes.

PMID: 32070324 [PubMed - in process]

Commentary: Direct-acting antiviral regimens usher in the era of hepatitis C virus-positive donors in lung transplant.

J Thorac Cardiovasc Surg. 2019 10;158(4):e159-e160

Authors: Fung JYY, Hsin MKY

PMID: 31256960 [PubMed - indexed for MEDLINE]

Is out-patient based treatment of bronchiectasis exacerbations in children comparable to inpatient based treatment?

Pediatr Pulmonol. 2020 Feb 18;:

Authors: O'Rourke C, Schilling S, Martin R, Joyce P, Bernadette Chang A, Kapur N

Abstract
BACKGROUND AND OBJECTIVE: Children with bronchiectasis have recurrent exacerbations and may require hospitalization. "Hospital in the home (HITH)" is used as an alternative to hospitalization for children with cystic fibrosis (CF) but to date, there is no published data on children without CF. We describe our experience of HITH (intravenous [IV] antibiotics and at least once-daily physiotherapy-treated airway clearance therapy) in a cohort of children with bronchiectasis, comparing outcomes between hospital and HITH-based pathways.
METHODS: Medical records were retrospectively reviewed in children with bronchiectasis who were hospitalized in our center from July 2016 to July 2018. We compared treatment duration, symptom resolution, adverse events, oral antibiotic prescription on discharge and "time-to-next hospitalization" between children managed with the two treatment pathways.
RESULTS: Exacerbations in 63 children (median age = 6 years [range: 1-17]; females = 33, indigenous = 8) with bronchiectasis treated with IV antibiotic therapy were analyzed (HITH n = 45, 71.5%). Duration of treatment and symptom resolution was similar between groups (hospital: median = 14 days [interquartile range {IQR}: 14-14] and 12/18 [66.6%], respectively vs HITH: 14 [14-15.5] and 31/45 [69%]; P = .53 and .85, respectively). There was no significant difference in adverse events (16.6% vs 9%), prescription of oral antibiotics on discharge (44% vs 24%), or "time-to-next hospitalization" (median 42 [IQR: 24-100] vs 67 [IQR: 32-95] weeks) between hospital and HITH groups, respectively.
CONCLUSIONS: In children with bronchiectasis treated for a severe exacerbation, receiving treatment in the home setting with HITH does not compromise short-term clinical outcomes compared to hospital only treatment. Prospective studies are required to provide more robust evidence in this under-researched area.

PMID: 32068973 [PubMed - as supplied by publisher]

Amplifiers co-translationally enhance CFTR biosynthesis via PCBP1-mediated regulation of CFTR mRNA.

J Cyst Fibros. 2020 Feb 14;:

Authors: Dukovski D, Villella A, Bastos C, King R, Finley D, Kelly JW, Morimoto RI, Hartl FU, Munoz B, Lee PS, Zecevic M, Miller JP

Abstract
BACKGROUND: Cystic fibrosis (CF) is a recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. We previously described a first-in-class CFTR modulator that functions as an amplifier to selectively increase CFTR expression and function. The amplifier mechanism is distinct from and complementary to corrector and potentiator classes of CFTR modulators. Here we characterize the mechanism by which amplifiers increase CFTR mRNA, protein, and activity.
METHODS: Biochemical studies elucidated the action of amplifiers on CFTR mRNA abundance and translation and defined the role of an amplifier-binding protein that was identified using chemical proteomics.
RESULTS: Amplifiers stabilize CFTR mRNA through a process that requires only the translated sequence of CFTR and involves translational elongation. Amplifiers enrich ER-associated CFTR mRNA and increase its translational efficiency through increasing the fraction of CFTR mRNA associated with polysomes. Pulldowns identified the poly(rC)-binding protein 1 (PCBP1) as directly binding to amplifier. A PCBP1 consensus element was identified within the CFTR open reading frame that binds PCBP1. This sequence proved necessary for amplifier responsiveness.
CONCLUSIONS: Small molecule amplifiers co-translationally increase CFTR mRNA stability. They enhance translation through addressing the inherently inefficient membrane targeting of CFTR mRNA. Amplifiers bind directly to PCBP1, show enhanced affinity in the presence of bound RNA, and require a PCBP1 consensus element within CFTR mRNA to elicit translational effects. These modulators represent a promising new and mechanistically novel class of CFTR therapeutic. They may be useful as a monotherapy or in combination with other CFTR modulators.

PMID: 32067958 [PubMed - as supplied by publisher]

In vivo demonstration of Pseudomonas aeruginosa biofilms as independent pharmacological microcompartments.

J Cyst Fibros. 2020 Feb 14;:

Authors: Christophersen L, Schwartz FA, Lerche CJ, Svanekjær T, Kragh KN, Laulund AS, Thomsen K, Henneberg KÅ, Sams T, Høiby N, Moser C

Abstract
BACKGROUND: Pseudomonas aeruginosa is difficult to eradicate from the lungs of cystic fibrosis (CF) patients due to biofilm formation. Organs and blood are independent pharmacokinetic (PK) compartments. Previously, we showed in vitro biofilms behave as independent compartments impacting the pharmacodynamics. The present study investigated this phenomenon in vivo.
METHODS: Seaweed alginate beads with P. aeruginosa resembling biofilms, either freshly produced (D0) or incubated for 5 days (D5) were installed s.c in BALB/c mice. Mice (n = 64) received tobramycin 40 mg/kg s.c. and were sacrificed at 0.5, 3, 6, 8, 16 or 24 h after treatment. Untreated controls (n = 14) were sacrificed, correspondingly. Tobramycin concentrations were determined in serum, muscle tissue, lung tissue and beads. Quantitative bacteriology was determined.
RESULTS: The tobramycin peak concentrations in serum was 58.3 (±9.2) mg/L, in lungs 7.1 mg/L (±2.3), muscle tissue 2.8 mg/L (±0.5) all after 0.5 h and in D0 beads 19.8 mg/L (±3.5) and in D5 beads 24.8 mg/L (±4.1) (both 3 h). A 1-log killing of P. aeruginosa in beads was obtained at 8h, after which the bacterial level remained stable at 16 h and even increased in D0 beads at 24 h. Using the established diffusion retardation model the free tobramycin concentration inside the beads showed a delayed buildup of 3 h but remained lower than the MIC throughout the 24 h.
CONCLUSIONS: The present in vivo study based on tobramycin exposure supports that biofilms behave as independent pharmacological microcompartments. The study indicates, reducing the biofilm matrix would increase free tobramycin concentrations and improve therapeutic effects.

PMID: 32067957 [PubMed - as supplied by publisher]

Outracing Lung Signal Decay - Potential of Ultrashort Echo Time MRI.

Rofo. 2019 May;191(5):415-423

Authors: Wielpütz MO, Triphan SMF, Ohno Y, Jobst BJ, Kauczor HU

Abstract
BACKGROUND:  Magnetic resonance imaging (MRI) of the pulmonary parenchyma is generally hampered by multiple challenges related to patient respiratory- and circulation-related motion, low proton density and extremely fast signal decay due to the structure of the lungs evolved for gas exchange.
METHODS:  Systematic literature database research as well as annual participation in conferences dedicated to pulmonary MRI for more than the past 20 years by at least one member of the author team.
RESULTS AND CONCLUSION:  The problem of motion has been addressed in the past by developments such as triggering, gating and parallel imaging. The second problem has, in part, turned out to be an advantage in those diseases that lead to an increase in lung substance and thus an increase in signal relative to the background. To reduce signal decay, ultrashort echo time (UTE) methods were developed to minimize the time between excitation and readout. Having been postulated a while ago, improved hardware and software now open up the possibility of achieving echo times shorter than 200 µs, increasing lung signal significantly by forestalling signal decay and more effectively using the few protons available. Such UTE techniques may not only improve structural imaging of the lung but also enhance functional imaging, including ventilation and perfusion imaging as well as quantitative parameter mapping. Because of accelerating progress in this field of lung MRI, the review at hand seeks to introduce some technical properties as well as to summarize the growing data from applications in humans and disease, which promise that UTE MRI will play an important role in the morphological and functional assessment of the lung in the near future.
KEY POINTS:   · Ultrashort echo time MRI is technically feasible with state-of-the-art scanner hardware.. · UTE MRI allows for CT-like image quality for structural lung imaging.. · Preliminary studies show improvements over conventional morphological imaging in lung cancer and airways diseases.. · UTE may improve sensitivity for functional processes like perfusion and tissue characterization..
CITATION FORMAT: · Wielpütz MO, Triphan SM, Ohno Y et al. Outracing Lung Signal Decay - Potential of Ultrashort Echo Time MRI. Fortschr Röntgenstr 2019; 191: 415 - 423.

PMID: 30257269 [PubMed - indexed for MEDLINE]

The cell division protein FtsZ as a cellular target to hit cystic fibrosis pathogens.

Eur J Med Chem. 2020 Feb 08;190:112132

Authors: Buroni S, Makarov V, Scoffone VC, Trespidi G, Riccardi G, Chiarelli LR

Abstract
Cystic fibrosis is a rare genetic disease characterized by the production of dehydrated mucus in the lung able to trap bacteria and rendering their proliferation particularly dangerous, thus leading to chronic infections. Among these bacteria, Staphylococcus aureus and Pseudomonas aeruginosa play a major role while, within emerging pathogens, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, Burkholderia cepacia complex species, as well as non-tuberculous mycobacteria are listed. Since a common feature of these bacteria is the high level of drug resistance, cell division, and in particular FtsZ, has been explored as a novel therapeutic target for the design of new molecules with antibacterial properties. This review summarizes and provides insight into recent advances in the discovery of compounds targeting FtsZ: the majority of them exhibit anti-staphylococcal activity, while a few were directed against the cystic fibrosis Gram negative pathogens.

PMID: 32066012 [PubMed - as supplied by publisher]

At the forefront of cystic fibrosis Basic Science research: 16th ECFS Basic Science Conference.

J Cyst Fibros. 2020 Feb 13;:

Authors: Taggart CC, Weldon S, Mall MA

PMID: 32063486 [PubMed - as supplied by publisher]

Targeting defective pulmonary innate immunity - A new therapeutic option?

Pharmacol Ther. 2020 Feb 12;:107500

Authors: Belchamber KBR, Donnelly LE

Abstract
Chronic pulmonary conditions now account for 1 in 15 deaths in the US and mortality is increasing. Chronic obstructive pulmonary disease (COPD) is due to become the 3rd largest cause of mortality by 2030 and mortality from other respiratory conditions such as asthma, idiopathic pulmonary fibrosis and cystic fibrosis are not reducing. There is an urgent need for novel therapies to address this problem as many of the current strategies targeting inflammation are not sufficient. The innate immune system of the lung is an important defence against invading pathogens, but in many chronic pulmonary diseases, this system mounts an inappropriate response. In COPD, macrophages are increased in number, but fail to clear pathogens correctly and become highly activated. This leads to increased damage and remodelling of the airways. In idiopathic fibrosis, there is a switch of macrophage phenotype to a cell that promotes abnormal repair. Neutrophils also display dysfunction in COPD where aberrant migratory profiles may lead to increased damage to lung tissue and emphysema; while in cystic fibrosis the proteolytic lung environment damages neutrophil receptors leading to ineffective phagocytosis and migration. Targeting the innate immune system to restore 'normal function' could have enormous benefits. Improving phagocytosis of pathogens could reduce exacerbations and hence the associated decline in lung function, and novel therapeutics such as sulforaphane appear to do this in vitro. Other natural products such as resveratrol and derivatives also have anti-inflammatory properties. Statins have traditionally been used to manage cholesterol levels in hypercholesterolaemia, however these molecules also have beneficial effects on the innate immune cells. Statins have been shown to be anti-inflammatory and restore aberrant neutrophil chemotaxis in aged cells. Other possible agents that may be efficacious are senolytics. These compounds include natural products such as quercetin which have anti-inflammatory properties but can also suppress viral replication. As viruses have been shown to suppress phagocytosis of macrophages, it is possible that these compounds could have benefit during viral exacerbations to protect this innate response. These compounds demonstrate that it is possible to address defective innate responses in the lung but a better understanding of the mechanisms driving defective innate immunity in pulmonary disease may lead to improved therapeutics.

PMID: 32061706 [PubMed - as supplied by publisher]

Predictive effects of low birth weight and small for gestational age status on respiratory and nutritional outcomes in cystic fibrosis.

J Cyst Fibros. 2020 Feb 12;:

Authors: Atteih SE, Raraigh KS, Blackman SM, Cutting GR, Collaco JM

Abstract
INTRODUCTION: Prior literature shows that neonates with cystic fibrosis (CF) are more likely to be born low birth weight (LBW, <2500 grams) and/or small for gestational age (SGA, <10th percentile for weight) than non-CF counterparts. There is limited literature exploring the predictive effects of birth parameters on long-term outcomes.
METHODS: The study population (CF Twin and Sibling Study) was recruited between 2000-2013 (n = 1677). Relationships between FEV1 percent predicted at 6, 12, or 18 years or BMI z-score at 2, 6, 12, or 18 years, and predictor variables (LBW or SGA status) were assessed using adjusted linear regressions.
RESULTS: Mean birth weight was 3.3 ± 0.7 kg (Females: 3.2 ± 0.7kg; males: 3.4 ± 0.7kg) and mean gestational age was 38.4 ± 2.6 weeks, with 10.2% of participants classified as SGA. Predictors of LBW included female sex, pancreatic insufficiency, and prematurity. Predictors of SGA included female sex. After adjustment, LBW was associated with lower BMI at ages 2-12 years and SGA was associated with lower BMI at age 2 years. LBW was associated with lower FEV1 percent predicted only at age 6 years. SGA was not associated with FEV1.
CONCLUSIONS: We did not observe higher rates of LBW or SGA in full term infants compared to the general population. We observed associations particularly between LBW and BMI or FEV1, but these associations decreased with age, suggesting that alternate factors contribute to outcomes over time. In lieu of the ability to target growth during gestation, efforts could be considered to optimize infant nutritional status, which may improve later life outcomes.

PMID: 32061517 [PubMed - as supplied by publisher]

Lymphocyte responses to Mycobacterium tuberculosis and Mycobacterium bovis are similar between BCG-vaccinated patients with cystic fibrosis and healthy controls.

J Cyst Fibros. 2020 Feb 12;:

Authors: Mauch RM, Alves PCM, Levy CE, Ribeiro JD, Ribeiro AF, Høiby N, Nolasco da Silva MT

Abstract
BACKGROUND: The low rate of nontuberculous mycobacteria (NTM) among Brazilian patients with cystic fibrosis (CF) may be due to cross-reactive Bacille Calmette-Guérin (BCG) vaccination. In the present pilot study, we aimed to compare the lymphocyte responses against Mycobacterium tuberculosis(Mtb) and Mycobacterium bovis (BCG) in BCG-vaccinated CF patients and healthy controls.
METHODS: The lymphocyte responses of CF patients (n = 10) and healthy controls (n = 10) were assessed in terms of lymphocyte proliferation index (LPI), using flow cytometry. Median rates of each cell subtype - CD4, CD8, γδ T cells and CD19 (B) cells - were also determined.
RESULTS: Median LPIs (CF vs. controls) were 22.9% vs. 13.0% (p = 0.481) and 23.1% vs. 17.6% (p = 0.481), upon stimulation with Mtb and BCG, respectively. Both groups had a predominant CD4 T cell response to Mtb (median rate = 82.5% vs. 79.7%; p = 0.796) and BCG (LPI = 84.3% vs. 83.0%; p = 0.853), which were significantly higher than the CD8, CD19 and γδ responses within both groups. CF patients tended to have a higher CD8 T cell response upon stimulation with the phytohemagglutinin mitogen than healthy controls (median rate = 42.8% vs. 31.7%, p = 0.075).
CONCLUSION: The responses of BCG-vaccinated CF patients to Mtb and BCG are at least similar to those of healthy individuals. These are probably memory responses elicited by the BCG vaccination, which can cross-react with NTM and may explain the low frequency of NTM lung infection in our CF center.

PMID: 32061516 [PubMed - as supplied by publisher]

Heterogeneous Liver on Research Ultrasound Identifies Children with Cystic Fibrosis at High Risk of Advanced Liver Disease: Interim Results of a Prospective Observational Case-Controlled Study.

J Pediatr. 2020 Feb 11;:

Authors: Siegel MJ, Freeman AJ, Ye W, Palermo JJ, Molleston JP, Paranjape SM, Stoll J, Leung D, Masand P, Karmazyn B, Harned R, Ling SC, Navarro OM, Karnsakul W, Alazraki A, Schwarzenberg SJ, Seidel FG, Towbin A, Alonso EM, Nicholas JL, Murray KF, Otto RK, Sherker AH, Magee JC, Narkewicz MR, CFLD Network

Abstract
OBJECTIVE: To assess if a heterogeneous pattern on research liver ultrasound examination can identify children at risk for advanced cystic fibrosis (CF) liver disease.
STUDY DESIGN: Planned 4-year interim analysis of a 9-year multicenter, case-controlled cohort study (Prospective Study of Ultrasound to Predict Hepatic Cirrhosis in CF). Children with pancreatic insufficient CF aged 3-12 years without known cirrhosis, Burkholderia species infection, or short bowel syndrome underwent a screening research ultrasound examination. Participants with a heterogeneous liver ultrasound pattern were matched (by age, Pseudomonas infection status, and center) 1:2 with participants with a normal pattern. Clinical status and laboratory data were obtained annually and research ultrasound examinations biannually. The primary end point was the development of a nodular research ultrasound pattern, a surrogate for advanced CF liver disease.
RESULTS: There were 722 participants who underwent screening research ultrasound examination, of which 65 were heterogeneous liver ultrasound pattern and 592 normal liver ultrasound pattern. The final cohort included 55 participants with a heterogeneous liver ultrasound pattern and 116 participants with a normal liver ultrasound pattern. All participants with at least 1 follow-up research ultrasound were included. There were no differences in age or sex between groups at entry. Alanine aminotransferase (42 ± 22 U/L vs 32 ± 19 U/L; P = .0033), gamma glutamyl transpeptidase (36 ± 34 U/L vs 15 ± 8 U/L; P < .001), and aspartate aminotransferase to platelet ratio index (0.7 ± 0.5 vs 0.4 ± 0.2; P < .0001) were higher in participants with a heterogeneous liver ultrasound pattern compared with participants with a normal liver ultrasound pattern. Participants with a heterogeneous liver ultrasound pattern had a 9.1-fold increased incidence (95% CI, 2.7-30.8; P = .0004) of nodular pattern vs a normal liver ultrasound pattern (23% in heterogeneous liver ultrasound pattern vs 2.6% in normal liver ultrasound pattern).
CONCLUSIONS: Research liver research ultrasound examinations can identify children with CF at increased risk for developing advanced CF liver disease.

PMID: 32061406 [PubMed - as supplied by publisher]

CFTR regulation of aquaporin-mediated water transport.

Vitam Horm. 2020;112:163-177

Authors: Carrageta DF, Bernardino RL, Alves MG, Oliveira PF

Abstract
The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel responsible for the direct transport of bicarbonate and chloride. CFTR-dependent ionic transport is crucial for pH regulation and fluid homeodynamics among epithelial surfaces. Particularly, CFTR performs an essential role in the male reproductive tract, which requires a tight regulation of water and electrolytes in order to produce healthy spermatozoa. The absence or malfunction of CFTR results in cystic fibrosis, the most common lethal disease among Caucasians, that is characterized by an impaired fluid and ionic homeostasis in the whole organism. Due to the wide expression and importance of CFTR, the male reproductive tract is highly affected by cystic fibrosis, resulting in male infertility. Although CFTR is not permeable to water, this protein acts as a regulator of other protein channels, such as aquaporins. In fact, CFTR acts as a molecular partner of aquaporins in epithelial cells, regulating fluid homeodynamics. Herein, up-to-date data concerning the regulation of aquaporin-mediated water transport by CFTR will be discussed, highlighting the role of both channels in the male reproductive tract.

PMID: 32061340 [PubMed - in process]

Essential oils against bacterial isolates from cystic fibrosis patients by means of antimicrobial and unsupervised machine learning approaches.

Sci Rep. 2020 Feb 14;10(1):2653

Authors: Ragno R, Papa R, Patsilinakos A, Vrenna G, Garzoli S, Tuccio V, Fiscarelli E, Selan L, Artini M

Abstract
Recurrent and chronic respiratory tract infections in cystic fibrosis (CF) patients result in progressive lung damage and represent the primary cause of morbidity and mortality. Staphylococcus aureus (S. aureus) is one of the earliest bacteria in CF infants and children. Starting from early adolescence, patients become chronically infected with Gram-negative non-fermenting bacteria, and Pseudomonas aeruginosa (P. aeruginosa) is the most relevant and recurring. Intensive use of antimicrobial drugs to fight lung infections inevitably leads to the onset of antibiotic resistant bacterial strains. New antimicrobial compounds should be identified to overcome antibiotic resistance in these patients. Recently interesting data were reported in literature on the use of natural derived compounds that inhibited in vitro S. aureus and P. aeruginosa bacterial growth. Essential oils, among these, seemed to be the most promising. In this work is reported an extensive study on 61 essential oils (EOs) against a panel of 40 clinical strains isolated from CF patients. To reduce the in vitro procedure and render the investigation as convergent as possible, machine learning clusterization algorithms were firstly applied to pick-up a fewer number of representative strains among the panel of 40. This approach allowed us to easily identify three EOs able to strongly inhibit bacterial growth of all bacterial strains. Interestingly, the EOs antibacterial activity is completely unrelated to the antibiotic resistance profile of each strain. Taking into account the results obtained, a clinical use of EOs could be suggested.

PMID: 32060344 [PubMed - in process]

Ablation of IL-33 Suppresses Th2 Responses but Is Accompanied by Sustained Mucus Obstruction in the Scnn1b Transgenic Mouse Model.

J Immunol. 2020 Feb 14;:

Authors: Lewis BW, Vo T, Choudhary I, Kidder A, Bathula C, Ehre C, Wakamatsu N, Patial S, Saini Y

Abstract
Cystic fibrosis is characterized by dehydration of the airway surface liquid layer with persistent mucus obstruction. Th2 immune responses are often manifested as increased mucous cell density (mucous cell metaplasia) associated with mucus obstruction. IL-33 is a known inducer of Th2 immune responses, but its roles in mucus obstruction and related phenotypes in a cystic fibrosis-like lung disease model (i.e., Scnn1b-Tg-positive [Tg+]) mouse, remain unclear. Accordingly, IL-33 knockout (IL-33KO) Tg+ mice were examined and compared with IL-33 heterozygous (IL-33HET) Tg+ mice. As compared with IL-33HET/Tg+ mice, IL-33KO/Tg+ mice had complete absence of bronchoalveolar lavage fluid eosinophilia, accompanied with significant reduction in bronchoalveolar lavage fluid concentration of IL-5, a cytokine associated with eosinophil differentiation and recruitment, and IL-4, a major Th2 cytokine. As compared with IL-33HET/Tg+ mice, IL-33KO/Tg+ mice had significantly reduced levels of Th2-associated gene signatures (Slc26a4, Clca1, Retnla, and Chi3l4), along with complete loss of intracellular mucopolysaccharide staining in the airway epithelium. As compared with IL-33HET/Tg+ mice, although the IL-33KO/Tg+ mice had significantly reduced levels of MUC5AC protein expression, they showed no reduction in the degree of mucus obstruction, MUC5B protein expression, bacterial burden, and neonatal mortality. Interestingly, the histological features, including subepithelial airway inflammation and alveolar space enlargement, were somewhat exaggerated in IL-33KO/Tg+ mice compared with IL-33HET/Tg+ mice. Taken together, our data indicate that although IL-33 modulates Th2 inflammatory responses and MUC5AC protein production, mucus obstruction is not dependent on IL-33.

PMID: 32060135 [PubMed - as supplied by publisher]

Precise Targeting of miRNA Sites Restores CFTR Activity in CF Bronchial Epithelial Cells.

Mol Ther. 2020 Feb 06;:

Authors: De Santi C, Fernández Fernández E, Gaul R, Vencken S, Glasgow A, Oglesby IK, Hurley K, Hawkins F, Mitash N, Mu F, Raoof R, Henshall DC, Cutrona MB, Simpson JC, Harvey BJ, Linnane B, McNally P, Cryan SA, MacLoughlin R, Swiatecka-Urban A, Greene CM

Abstract
MicroRNAs that are overexpressed in cystic fibrosis (CF) bronchial epithelial cells (BEC) negatively regulate CFTR and nullify the beneficial effects of CFTR modulators. We hypothesized that it is possible to reverse microRNA-mediated inhibition of CFTR using CFTR-specific target site blockers (TSBs) and to develop a drug-device combination inhalation therapy for CF. Lead microRNA expression was quantified in a series of human CF and non-CF samples and in vitro models. A panel of CFTR 3' untranslated region (UTR)-specific locked nucleic acid antisense oligonucleotide TSBs was assessed for their ability to increase CFTR expression. Their effects on CFTR activity alone or in combination with CFTR modulators were measured in CF BEC models. TSB encapsulation in poly-lactic-co-glycolic acid (PLGA) nanoparticles was assessed as a proof of principle of delivery into CF BECs. TSBs targeting the CFTR 3' UTR 298-305:miR-145-5p or 166-173:miR-223-3p sites increased CFTR expression and anion channel activity and enhanced the effects of ivacaftor/lumacaftor or ivacaftor/tezacaftor in CF BECs. Biocompatible PLGA-TSB nanoparticles promoted CFTR expression in primary BECs and retained desirable biophysical characteristics following nebulization. Alone or in combination with CFTR modulators, aerosolized CFTR-targeting TSBs encapsulated in PLGA nanoparticles could represent a promising drug-device combination therapy for the treatment for CFTR dysfunction in the lung.

PMID: 32059764 [PubMed - as supplied by publisher]

Challenges in the Diagnosis and Management of Bacterial Lung Infections in Solid Organ Recipients: A Narrative Review.

Int J Mol Sci. 2020 Feb 12;21(4):

Authors: Carugati M, Morlacchi LC, Peri AM, Alagna L, Rossetti V, Bandera A, Gori A, Blasi F, Working Group I

Abstract
Respiratory infections pose a significant threat to the success of solid organ transplantation, and the diagnosis and management of these infections are challenging. The current narrative review addressed some of these challenges, based on evidence from the literature published in the last 20 years. Specifically, we focused our attention on (i) the obstacles to an etiologic diagnosis of respiratory infections among solid organ transplant recipients, (ii) the management of bacterial respiratory infections in an era characterized by increased antimicrobial resistance, and (iii) the development of antimicrobial stewardship programs dedicated to solid organ transplant recipients.

PMID: 32059371 [PubMed - in process]