Comparison of Hyperpolarized 3He and 129Xe MR Imaging in Cystic Fibrosis Patients.

Acad Radiol. 2021 Jan 21;:

Authors: Shammi UA, D'Alessandro MF, Altes T, Hersman FW, Ruset IC, Mugler J, Meyer C, Mata J, Qing K, Thomen R

Abstract
PURPOSE: In this study, we compared hyperpolarized 3He and 129Xe images from patients with cystic fibrosis using two commonly applied magnetic resonance sequences, standard gradient echo (GRE) and balanced steady-state free precession (TrueFISP) to quantify regional similarities and differences in signal distribution and defect analysis.
MATERIALS AND METHODS: Ten patients (7M/3F) with cystic fibrosis underwent hyperpolarized gas MR imaging with both 3He and 129Xe. Six had MRI with both GRE, and TrueFISP sequences and four patients had only GRE sequence but not TrueFISP. Ventilation defect percentages (VDPs) were calculated as lung voxels with <60% of the whole-lung hyperpolarized gas signal mean and was measured in all datasets. The voxel signal distributions of both 129Xe and 3He gases were visualized and compared using violin plots. VDPs of hyperpolarized 3 He and 129 Xe were compared in Bland-Altman plots; Pearson correlation coefficients were used to evaluate the relationships between inter-gas and inter-scan to assess the reproducibility.
RESULTS: A significant correlation was demonstrated between 129Xe VDP and 3He VDP for both GRE and TrueFISP sequences (ρ = 0.78, p<0.0004). The correlation between the GRE and TrueFISP VDP for 3He was ρ = 0.98 and was ρ = 0.91 for 129Xe. Overall, 129Xe (27.2±9.4) VDP was higher than 3He (24.3±6.9) VDP on average on cystic fibrosis patients.
CONCLUSION: In patients with cystic fibrosis, the selection of hyperpolarized 129Xe or 3He gas is most likely inconsequential when it comes to measure the overall lung function by VDP although 129Xe may be more sensitive to starker lung defects, particularly when using a TrueFISP sequence.

PMID: 33487537 [PubMed - as supplied by publisher]

Conflicting verdicts on peanut oral immunotherapy from the Institute for Clinical and Economic Review and US Food and Drug Administration Advisory Committee: Where do we go from here?

J Allergy Clin Immunol. 2020 04;145(4):1153-1156

Authors: Eiwegger T, Anagnostou K, Arasi S, Bégin P, Ben-Shoshan M, Beyer K, Blumchen K, Brough H, Caubet JC, Chan ES, Chen M, Chinthrajah S, Davis CM, Des Roches A, Du Toit G, Elizur A, Galli SJ, Håland G, Hoffmann-Sommergruber K, Kim H, Leung DYM, Long A, Muraro A, Nurmatov UB, Pajno GB, Sampath V, Saxena J, Sindher S, Upton J, Worm M, Nadeau KC

PMID: 31678426 [PubMed - indexed for MEDLINE]

Assessing the validity and applicability of the French 3-year prognostic score in the UK cystic fibrosis population - a national cohort study.

Transpl Int. 2021 Jan 24;:

Authors: Frost F, Nazareth D, Shaw M, Al-Aloul M

Abstract
Models that predict outcomes, aid prognostication and inform the assessment of urgency for lung transplantation (LT) in CF are in demand. A prognostic score derived from the French adult CF registry to predict death or LT over 3-year follow-up was described in 2017 and validated using Canadian CF registry data. We assessed its performance in the UK CF population. The French prognostic score was applied to untransplanted adults with CF. The index year (2014) and outcomes (Death or LT) were evaluated to 2017. Receiver operator characteristics plots and area under curve (AUC) was computed. 4407 adults with CF met the inclusion criteria. After 3 years, 7.1% (P < 0.001) were dead or had received LT compared to the French (12.8%) and Canadian (9.4%) cohorts. The French score deemed 592 (26.2%) 'High-risk' - death/LT occurred in 189/592 (30.2%), less than previously reported in France and Canada (P < 0.0001). The discriminatory power of the French score was lower (AUC 0.830) than reported. Recalibration yielded only marginal improvement in model performance (AUC 0.833). The French prognostic score does not perform as well in the UK as reported elsewhere. Bespoke UK scores are needed to aid prognostication and inform LT decision-making.

PMID: 33486768 [PubMed - as supplied by publisher]

Pharmacokinetic and Pharmacodynamic Optimization of Antibiotic Therapy in Cystic Fibrosis Patients: Current Evidences, Gaps in Knowledge and Future Directions.

Clin Pharmacokinet. 2021 Jan 24;:

Authors: Magréault S, Roy C, Launay M, Sermet-Gaudelus I, Jullien V

Abstract
Antibiotic therapy is one of the main treatments for cystic fibrosis (CF). It aims to eradicate bacteria during early infection, calms down the inflammatory process, and leads to symptom resolution of pulmonary exacerbations. CF can modify both the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of antibiotics, therefore specific PK/PD endpoints should be determined in the context of CF. Currently available data suggest that optimal PK/PD targets cannot be attained in sputum with intravenous aminoglycosides. Continuous infusion appears preferable for β-lactam antibiotics, but optimal concentrations in sputum are unlikely to be reached, with some possible exceptions such as meropenem and ceftolozane. Usual doses are likely suboptimal for fluoroquinolones and linezolid, whereas daily doses of 45-60 mg/kg and 200 mg could be convenient for vancomycin and doxycycline, respectively. Weekly azithromycin doses of 22-30 mg/kg could also be appropriate for its anti-inflammatory effect. The difficulty with achieving optimal concentrations supports the use of combined treatments and the inhaled administration route, as very high local concentrations, concomitantly with low systemic exposure, can be obtained with the inhaled route for aminoglycosides, colistin, and fluoroquinolones, thus minimizing the risk of toxicity.

PMID: 33486720 [PubMed - as supplied by publisher]

In vitro evaluation of drug delivery behavior for inhalable amorphous nanoparticle formulations in a human lung epithelial cell model.

Int J Pharm. 2021 Jan 21;:120211

Authors: Chen J, Ahmed MU, Zhu C, Yu S, Pan W, Velkov T, Li J, Tony Zhou Q

Abstract
Respiratory tract infections caused by multidrug-resistant (MDR) Gram-negative bacteria such as Pseudomonas aeruginosa are serious burdens to public health, especially in cystic fibrosis patients. The combination of colistin, a cationic polypeptide antibiotic, and ivacaftor, a cystic fibrosis transmembrane regulator (CFTR) protein modulator, displays a synergistic antibacterial effect against P. aeruginosa. The primary aim of the present study is to investigate the transport, accumulation and toxicity in lung epithelial Calu-3 cells of a novel nanoparticle formulation containing colistin and ivacaftor. The cell viability results demonstrated that ivacaftor alone or in combination with colistin in the physical mixture showed significant toxicity at an ivacaftor concentration of 10 µg/mL or higher. However, the cellular toxicity was significantly reduced in the nanoparticle formulation. Ivacaftor transport into the cells reached a plateau rapidly as compared to colistin. Colistin transport across the Calu-3 cell monolayer was less than ivacaftor. A substantial amount (46-83%) of ivacaftor, independent of dose, was accumulated in the cell monolayer following transport from the apical into the basal chamber, whereas the intracellular accumulation of colistin was relatively low (2-15%). The nanoparticle formulation significantly reduced the toxicity of colistin and ivacaftor to Calu-3 cells by reducing the accumulation of both drugs in the cell and potential protective effects by bovine serum albumin (BSA), which could be a promising safer option for the treatment of respiratory infections caused by MDR P. aeruginosa.

PMID: 33486036 [PubMed - as supplied by publisher]

Changing paradigms in the treatment of gastrointestinal complications of cystic fibrosis in the era of cystic fibrosis transmembrane conductance regulator modulators.

Paediatr Respir Rev. 2020 Dec 24;:

Authors: Konrad J, Eber E, Stadlbauer V

Abstract
Cystic fibrosis (CF) - although primarily a lung disease - also causes a variety of gastrointestinal manifestations which are important for diagnosis, prognosis and quality of life. All parts of the gastrointestinal tract can be affected by CF. Besides the well-known pancreatic insufficiency, gastroesophageal reflux disease, liver disease and diseases of the large intestine are important pathologies that impact on prognosis and also impair quality of life. Diagnosis and management of gastrointestinal manifestations will be discussed in this review. Since optimisation of CF therapy is associated with a significantly longer life-span of CF patients nowadays, also gastrointestinal malignancies, which are more common in CF than in the non-CF population need to be considered. Furthermore, novel evidence on the role of the gut microbiome in CF is emerging. The introduction of cystic fibrosis transmembrane conductance regulator (CFTR) protein modulators gives hope for symptom alleviation and even cure of gastrointestinal manifestations of CF.

PMID: 33485777 [PubMed - as supplied by publisher]

Nanoparticles for Delivery of Agents to Fetal Lungs.

Acta Biomater. 2021 Jan 20;:

Authors: Ullrich SJ, Freedman-Weiss M, Ahle S, Mandl HK, Piotrowski-Daspit AS, Roberts K, Yung N, Maassel N, Bauer-Pisani T, Ricciardi AS, Egan ME, Glazer PM, Saltzman WM, Stitelman DH

Abstract
Fetal treatment of congenital lung disease, such as cystic fibrosis, surfactant protein syndromes, and congenital diaphragmatic hernia, has been made possible by improvements in prenatal diagnostic and interventional technology. Delivery of therapeutic agents to fetal lungs in nanoparticles improves cellular uptake. The efficacy and safety of nanoparticle-based fetal lung therapy depends on targeting of necessary cell populations. This study aimed to determine the relative distribution of nanoparticles of a variety of compositions and sizes in the lungs of fetal mice delivered through intravenous and intra-amniotic routes. Intravenous delivery of particles was more effective than intra-amniotic delivery for epithelial, endothelial and hematopoietic cells in the fetal lung. The most effective targeting of lung tissue was with 250nm Poly-Amine-co-Ester (PACE) particles accumulating in 50% and 44% of epithelial and endothelial cells. This study demonstrated that route of delivery and particle composition impacts relative cellular uptake in fetal lung, which will inform future studies in particle-based fetal therapy.

PMID: 33484911 [PubMed - as supplied by publisher]

Containment of Procedure-Associated Aerosols by an Extractor Tent: effect on nebulised drug particle dispersal.

J Hosp Infect. 2021 Jan 20;:

Authors: Fennelly M, Keane J, Dolan L, Plant BJ, O'Connor D, Sodeau J, Prentice MB

Abstract
BACKGROUND: Several medical procedures involving the respiratory tract are considered 'aerosol generating'. Aerosols from these procedures may be inhaled by bystanders and there are consequent concerns regarding infection transmission, or, specific to nebulised therapy, secondary drug exposure.
AIMS: Assess the efficacy of a proprietary HEPA-filtering extractor tent on reducing the aerosol dispersal of nebulised bronchodilator drugs.
METHODS: The study was conducted in an unoccupied outpatient room at St. James's Hospital, Dublin. A novel real-time, fluorescent particle counter, the Wideband Integrated Bioaerosol Sensor (WIBS), monitored room air continuously for three hours. Baseline airborne particle counts and counts during nebulisation of bronchodilator drug solutions were recorded.
FINDINGS: Nebulising within the tent prevented any increase over background levels, nebulising directly into room air resulted in mean fluorescent particle counts of 4.75 x 105/m3 and 4.21 x 105/m3 for Ventolin and Ipramol, respectively, representing more than 400-fold increases over the mean background count. >99.3% of drug particles were less than 2 μm in diameter, small enough to enter the lower respiratory tract.
CONCLUSION: These results show the extractor tent was completely effective in preventing airborne spread of drug particles of respirable size from nebulised therapy. This suggests extractor tents of this kind would be efficacious in preventing airborne infection from aerosol-generating procedures during the COVID-19 pandemic.

PMID: 33484782 [PubMed - as supplied by publisher]

Myriocin modulates the altered lipid metabolism and storage in cystic fibrosis.

Cell Signal. 2021 Jan 19;:109928

Authors: Signorelli P, Pivari F, Barcella M, Merelli I, Zulueta A, Cas MD, Ghidoni R, Caretti A, Paroni R, Mingione A

Abstract
Cystic fibrosis (CF) is a hereditary disease mostly related to ΔF508 CFTR mutation causing a proteinopathy that is characterized by multiple organ dysfunction, primarily lungs chronic inflammation, and infection. Defective autophagy and accumulation of the inflammatory lipid ceramide have been proposed as therapeutic targets. Accumulation of lipids and cholesterol was reported in the airways of CF patients, together with altered triglycerides and cholesterol levels in plasma, thus suggesting a disease-related dyslipidemia. Myriocin, an inhibitor of sphingolipids synthesis, significantly reduces inflammation and activates TFEB-induced response to stress, enhancing fatty acids oxidation and promoting autophagy. Myriocin ameliorates the response against microbial infection in CF models and patients' monocytes. Here we show that CF broncho-epithelial cells exhibit an altered distribution of intracellular lipids. We demonstrated that lipid accumulation is supported by an enhanced synthesis of fatty acids containing molecules and that Myriocin is able to reduce such accumulation. Moreover, Myriocin modulated the transcriptional profile of CF cells in order to restore autophagy, activate an anti-oxidative response, stimulate lipid metabolism and reduce lipid peroxidation. Moreover, lipid storage may be altered in CF cells, since we observed a reduced expression of lipid droplets related proteins named perilipin 3 and 5 and seipin. To note, Myriocin up-regulates the expression of genes that are involved in lipid droplets biosynthesis and maturation. We suggest that targeting sphingolipids de novo synthesis may counteract lipids accumulation by modulating CF altered transcriptional profile, thus restoring autophagy and lipid metabolism homeostasis.

PMID: 33482299 [PubMed - as supplied by publisher]

Safety of research bronchoscopy with BAL in stable adult patients with cystic fibrosis.

PLoS One. 2021;16(1):e0245696

Authors: Aridgides D, Dessaint J, Atkins G, Carroll J, Ashare A

Abstract
Data on adverse events from research bronchoscopy with bronchoalveolar lavage (BAL) in patients with cystic fibrosis (CF) is lacking. As research bronchoscopy with BAL is useful for isolation of immune cells and investigation of CF lung microbiome, we sought to investigate the safety of bronchoscopy in adult patients with CF. Between November 2016 and September 2019, we performed research bronchoscopies on CF subjects (32) and control subjects (82). Control subjects were nonsmokers without respiratory disease. CF subjects had mild or moderate obstructive lung disease (FEV1 > 50% predicted) and no evidence of recent CF pulmonary exacerbation. There was no significant difference in the age or sex of each cohort. Neither group experienced life threatening adverse events. The number of adverse events was similar between CF and control subjects. The most common adverse events were sore throat and cough, which occurred at similar frequencies in control and CF subjects. Fever and headache occurred more frequently in CF subjects. However, the majority of fevers were seen in CF subjects with FEV1 values below 65% predicted. We found that CF subjects had similar adverse event profiles following research bronchoscopy compared to healthy subjects. While CF subjects had a higher rate of fevers, this adverse event occurred with greater frequency in CF subjects with lower FEV1. Our data demonstrate that research bronchoscopy with BAL is safe in CF subjects and that safety profile is improved if bronchoscopies are limited to subjects with an FEV1 > 65% predicted.

PMID: 33481845 [PubMed - as supplied by publisher]

EGFR activity upregulates lactate dehydrogenase A (LDHA) expression, LDH activity and lactate secretion in cultured IB3-1 cystic fibrosis lung epithelial cells.

Biochem Cell Biol. 2021 Jan 22;:

Authors: Massip-Copiz MM, Valdivieso ÁG, Clauzure M, Mori C, Asensio CJA, Aguilar MÁ, Santa-Coloma T

Abstract
Cystic fibrosis (CF) is caused by mutations in the CFTR gene. It has been postulated that a reduced HCO3- transport in CF through CFTR may lead to a decreased airway surface liquid (ASL) pH. In contrast, others have reported no changes in the extracellular pH (pHe). We have recently reported that in carcinoma Caco-2/pRS26 cells (shRNA for CFTR) or CF lung epithelial IB3-1 cells, the CFTR failure decreased mitochondrial Complex I activity due to an autocrine IL1B loop, and increased lactic acid production. The secreted lactate accounted for the reduced pHe since oxamate fully restored the pHe. These effects were attributed to the IL-1β autocrine loop and the downstream signaling kinases c-Src and JNK. Here we show that the pHe of IB3-1 cells can be restored to normal pHe values (~7.4) by incubation with the epidermal growth factor receptor (EGFR, HER1, ErbB1) inhibitors AG1478 or PD168393. The inhibitor PD168393, fully restored the pHe values of IB3-1 cells, suggesting that the reduced pHe is mainly due to the increased EGFR activity and lactate. Also, in IB3-1 CF cells, the LDHA mRNA, protein expression, and activity are down-regulated under EGFR inhibition. Thus, a constitutive EGFR activation seems to be responsible for the reduced pHe in IB3-1 CF cells.

PMID: 33481676 [PubMed - as supplied by publisher]

Pediatrician intervention impacts parental smoking in cystic fibrosis, diabetes and bronchiolitis.

Pediatr Pulmonol. 2021 Jan 22;:

Authors: Lafont M, Morin C, Arrouy A, Rabeau A, Labouret G, Roditis L, Michelet M, Mittaine M

Abstract
BACKGROUND: Child exposure to cigarette smoke is harmful. It should be reduced through parental smoking cessation interventions. The aim of our study was to determine the impact of simple advice provided by the pediatrician on the smoking habits of parents of children with cystic fibrosis (CF), diabetes mellitus (DM) and infants hospitalized for bronchiolitis.
METHODS: Parents were interviewed on their smoking habits. Smoking cessation advice was provided by the pediatrician. A new smoking habits assessment was done at three months by phone interviews.
RESULTS: Two hundred and sixty parents were interviewed (91 in the CF group, 136 in the DM group and 33 in the bronchiolitis group). Seventy parents were active smokers: 33% of parents of children with CF, 23.5% of parents of children with DM and 24.2 % for those with infants hospitalized for bronchiolitis (p = 0.42). In the CF group, smoking cessation had been significantly more frequently discussed with the medical team previously. Sixty-seven smoking parents (95.7%) answered the 3-month assessment: 29.8% reported having started a smoking cessation process; 10.4% had quit smoking. The quitting rate was significantly higher in the groups of patients followed for a respiratory disorder (37.5% for bronchiolitis, 15% for CF versus 0% for DM, p= 0.005).
CONCLUSION: This study shows the important role that information and simple advice from pediatricians can have in initiating smoking cessation in parents of patients followed in specialized clinics or who are hospitalized, with a greater efficiency in parents of patients suffering from lung disorders. This article is protected by copyright. All rights reserved.

PMID: 33480170 [PubMed - as supplied by publisher]

Incidence and risk factors for respiratory tract bacterial colonization and infection in lung transplant recipients.

Eur J Clin Microbiol Infect Dis. 2021 Jan 21;:

Authors: Paglicci L, Borgo V, Lanzarone N, Fabbiani M, Cassol C, Cusi MG, Valassina M, Scolletta S, Bargagli E, Marchetti L, Paladini P, Luzzi L, Fossi A, Bennett D, Montagnani F

Abstract
To evaluate incidence of and risk factors for respiratory bacterial colonization and infections within 30 days from lung transplantation (LT). We retrospectively analyzed microbiological and clinical data from 94 patients transplanted for indications other than cystic fibrosis, focusing on the occurrence of bacterial respiratory colonization or infection during 1 month of follow-up after LT. Thirty-three percent of patients developed lower respiratory bacterial colonization. Bilateral LT and chronic heart diseases were independently associated to a higher risk of overall bacterial colonization. Peptic diseases conferred a higher risk of multi-drug resistant (MDR) colonization, while longer duration of aerosol prophylaxis was associated with a lower risk. Overall, 35% of lung recipients developed bacterial pneumonia. COPD (when compared to idiopathic pulmonary fibrosis, IPF) and higher BMI were associated to a lower risk of bacterial infection. A higher risk of MDR infection was observed in IPF and in patients with pre-transplant colonization and infections. The risk of post-LT respiratory infections could be stratified by considering several factors (indication for LT, type of LT, presence of certain comorbidities, and microbiologic assessment before LT). A wider use of early nebulized therapies could be useful to prevent MDR colonization, thus potentially lowering infectious risk.

PMID: 33479881 [PubMed - as supplied by publisher]

Virulence attenuating combination therapy: a potential multi-target synergy approach to treat Pseudomonas aeruginosa infections in cystic fibrosis patients.

RSC Med Chem. 2020 Mar 01;11(3):358-369

Authors: Shaw E, Wuest WM

Abstract
The World Health Organization considers the discovery of new treatments for P. aeruginosa a top priority. Virulence attenuating combination therapy (VACT) is a pragmatic strategy to improve bacterial clearance, repurpose outmoded antibiotics, improve drug efficacy at lower doses, and reduce the evolution of resistance. In vitro and in vivo studies have shown that adding a quorum sensing inhibitor or an extracellular polymeric substance repressor to classical antibiotics synergistically improves antipseudomonal activity. This review highlights why VACT could specifically benefit cystic fibrosis patients harboring chronic P. aeruginosa infections, outlines the current landscape of synergistic combinations between virulence-targeting small-molecules and anti-pseudomonal drugs, and suggests future directions for VACT research.

PMID: 33479641 [PubMed]

Abnormal glucose tolerance and lung function in children with cystic fibrosis. Comparing oral glucose tolerance test and continuous glucose monitoring.

J Cyst Fibros. 2021 Jan 18;:

Authors: Elidottir H, Diemer S, Eklund E, Hansen CR

Abstract
BACKGROUND: Cystic fibrosis (CF) related diabetes (CFRD) is a common complication of CF. CFRD is associated with declining lung function even before its onset. Regular screening for CFRD using oral glucose tolerance test (OGTT) is recommended. Additionally, continuous glucose monitoring (CGM) has surfaced as a possible surveillance method, but evidence for its use and concordance with OGTT has not been established.
METHODS: Children were prospectively recruited at CF center Lund to undergo both intermittent scan CGM (isCGM) and OGTT. Lung function was evaluated by spirometry and multiple breath washout. Demographic and clinical data were collected from the Swedish national CF registry.
RESULTS: 32 patients participated in the study, yielding 28 pairs of isCGMs and OGTTs. The OGTTs showed that two patients met the criteria of CFRD, seven had impaired glucose tolerance (IGT) and indeterminate glycemia (INDET) was found in eleven cases. The isCGM percent of measurements >8mmol/L and the number of peaks per day >11 mmol/L have correlations with intermediate OGTT glucose time points, but not the 2hour glucose value. Patients with abnormal glucose tolerance (AGT) had lower lung function than those with normal glucose tolerance demonstrated by both FEV1% predicted and lung clearance index (LCI).
CONCLUSION: Correlations can be found between isCGM and OGTT in regards to the latter's intermediate time points. LCI demonstrates as well as FEV1% of predicted, worse lung function in children and adolescents with abnormal glucose tolerance in CF.

PMID: 33478894 [PubMed - as supplied by publisher]

Neutrophil extracellular traps are present in the airways of ENaC-overexpressing mice with cystic fibrosis-like lung disease.

BMC Immunol. 2021 Jan 21;22(1):7

Authors: Tucker SL, Sarr D, Rada B

Abstract
BACKGROUND: Neutrophils are key components of the exacerbated inflammation and tissue damage in cystic fibrosis (CF) airways. Neutrophil extracellular traps (NETs) trap and kill extracellular pathogens. While NETs are abundant in the airways of CF patients and have been hypothesized to contribute to lung damage in CF, the in vivo role of NETs remains controversial, partially due to lack of appropriate animal models. The goal of this study was to detect NETs and to further characterize neutrophil-mediated inflammation in the airways of mice overexpressing the epithelial sodium channel (βENaC-Tg mice on C57BL/6 background) in their lung with CF-like airway disease, in the absence of any apparent bacterial infections.
METHODS: Histology scoring of lung tissues, flow cytometry, multiplex ELISA, immunohistochemistry and immunofluorescence were used to characterize NETs and the airway environment in uninfected, βENaC-Tg mice at 6 and 8 weeks of age, the most chronic time points so far studied in this model.
RESULTS: Excessive neutrophilic infiltration characterized the lungs of uninfected, βENaC-Tg mice at 6 and 8 weeks of age. The bronchoalveolar lavage fluid (BALF) of βENaC-Tg mice contains increased levels of CF-associated cytokines and chemokines: KC, MIP-1α/β, MCP-1, G-CSF, IL-5, and IL-6. The BALF of βENaC-Tg mice contain MPO-DNA complexes, indicative of the presence of NETs. Immunofluorescence and flow cytometry of BALF neutrophils and lung tissues demonstrated increased histone citrullination, a NET-specific marker, in βENaC-Tg mice.
CONCLUSIONS: NETs are detected in the airways of βENaC-Tg mice, in the absence of bacterial infections. These data demonstrate the usefulness of the βENaC-Tg mouse to serve as a model for studying the role of NETs in chronic CF airway inflammation.

PMID: 33478382 [PubMed - in process]

Cellular Redox State Acts as Switch to Determine the Direction of NNT-Catalyzed Reaction in Cystic Fibrosis Cells.

Int J Mol Sci. 2021 Jan 19;22(2):

Authors: Favia M, Atlante A

Abstract
The redox states of NAD and NADP are linked to each other in the mitochondria thanks to the enzyme nicotinamide nucleotide transhydrogenase (NNT) which, by utilizing the mitochondrial membrane potential (mΔΨ), catalyzes the transfer of redox potential between these two coenzymes, reducing one at the expense of the oxidation of the other. In order to define NNT reaction direction in CF cells, NNT activity under different redox states of cell has been investigated. Using spectrophotometric and western blotting techniques, the presence, abundance and activity level of NNT were determined. In parallel, the levels of NADPH and NADH as well as of mitochondrial and cellular ROS were also quantified. CF cells showed a 70% increase in protein expression compared to the Wt sample; however, regarding NNT activity, it was surprisingly lower in CF cells than healthy cells (about 30%). The cellular redox state, together with the low mΔΨ, pushes to drive NNT reverse reaction, at the expense of its antioxidant potential, thus consuming NADPH to support NADH production. At the same time, the reduced NNT activity prevents the NADH, produced by the reaction, from causing an explosion of ROS by the damaged respiratory chain, in accordance with the reduced level of mitochondrial ROS in NNT-loss cells. This new information on cellular bioenergetics represents an important building block for further understanding the molecular mechanisms responsible for cellular dysfunction in cystic fibrosis.

PMID: 33478087 [PubMed - in process]

Microstructured Lipid Carriers (MLC) Based on N-Acetylcysteine and Chitosan Preventing Pseudomonas aeruginosa Biofilm.

Int J Mol Sci. 2021 Jan 17;22(2):

Authors: Guerini M, Grisoli P, Pane C, Perugini P

Abstract
The aim of this work was the development of microstructured lipid carriers (MLC) based on chitosan (CH) and containing N-acetylcysteine (NAC), a mucolytic and antioxidant agent, to inhibit the formation of Pseudomonas aeruginosa biofilm. MLC were prepared using the high shear homogenization technique. The MLC were characterized for morphology, particle size, Z potential, encapsulation efficiency and drug release. The antioxidant properties of NAC-loaded microstructured carriers were evaluated through an in vitro spectrophotometer assay. Finally, the activity of NAC-CH-MLC on biofilm production by Pseudomonas aeruginosa was also evaluated. Results obtained from this study highlighted that the use of chitosan into the inner aqueous phase permitted to obtain microstructured particles with a narrow size range and with good encapsulation efficiency. NAC-loaded MLC showed higher antioxidant activity than the free molecule, demonstrating how encapsulation increases the antioxidant effect of the molecule. Furthermore, the reduction of biofilm growth resulted extremely high with MLC being 64.74% ± 6.2% and 83.74% ± 9.95%, respectively, at 0.5 mg/mL and 2 mg/mL. In conclusion, this work represents a favorable technological strategy against diseases in which bacterial biofilm is relevant, such as cystic fibrosis.

PMID: 33477393 [PubMed - in process]

The PROSPECT Is Bright for CFTR Modulators.

Ann Am Thorac Soc. 2021 01;18(1):32-33

Authors: Montemayor K, Lechtzin N

PMID: 33385230 [PubMed - indexed for MEDLINE]

From micro to macro; joining the dots of early CF lung disease.

J Cyst Fibros. 2020 11;19(6):850-851

Authors:

PMID: 32917548 [PubMed - indexed for MEDLINE]