Functional effects of the microbiota in chronic respiratory disease.

Lancet Respir Med. 2019 Apr 08;:

Authors: Budden KF, Shukla SD, Rehman SF, Bowerman KL, Keely S, Hugenholtz P, Armstrong-James DPH, Adcock IM, Chotirmall SH, Chung KF, Hansbro PM

Abstract
The composition of the lung microbiome is increasingly well characterised, with changes in microbial diversity or abundance observed in association with several chronic respiratory diseases such as asthma, cystic fibrosis, bronchiectasis, and chronic obstructive pulmonary disease. However, the precise effects of the microbiome on pulmonary health and the functional mechanisms by which it regulates host immunity are only now beginning to be elucidated. Bacteria, viruses, and fungi from both the upper and lower respiratory tract produce structural ligands and metabolites that interact with the host and alter the development and progression of chronic respiratory diseases. Here, we review recent advances in our understanding of the composition of the lung microbiome, including the virome and mycobiome, the mechanisms by which these microbes interact with host immunity, and their functional effects on the pathogenesis, exacerbations, and comorbidities of chronic respiratory diseases. We also describe the present understanding of how respiratory microbiota can influence the efficacy of common therapies for chronic respiratory disease, and the potential of manipulation of the microbiome as a therapeutic strategy. Finally, we highlight some of the limitations in the field and propose how these could be addressed in future research.

PMID: 30975495 [PubMed - as supplied by publisher]

Supporting medication adherence for adults with cystic fibrosis: a randomised feasibility study.

BMC Pulm Med. 2019 Apr 11;19(1):77

Authors: Hind D, Drabble SJ, Arden MA, Mandefield L, Waterhouse S, Maguire C, Cantrill H, Robinson L, Beever D, Scott AJ, Keating S, Hutchings M, Bradley J, Nightingale J, Allenby MI, Dewar J, Whelan P, Ainsworth J, Walters SJ, O'Cathain A, Wildman MJ

Abstract
BACKGROUND: Preventative medication reduces hospitalisations in people with cystic fibrosis (PWCF) but adherence is poor. We assessed the feasibility of a randomised controlled trial of a complex intervention, which combines display of real time adherence data and behaviour change techniques.
METHODS: Design: Pilot, open-label, parallel-group RCT with concurrent semi-structured interviews.
PARTICIPANTS: PWCF at two Cystic Fibrosis (CF) units. Eligible: aged 16 or older; on the CF registry. Ineligible: post-lung transplant or on the active list; unable to consent; using dry powder inhalers.
INTERVENTIONS: Central randomisation on a 1:1 allocation to: (1) intervention, linking nebuliser use with data recording and transfer capability to a software platform, and behavioural strategies to support self-management delivered by trained interventionists (n = 32); or, (2) control, typically face-to-face meetings every 3 months with CF team (n = 32).
OUTCOMES: RCT feasibility defined as: recruitment of ≥ 48 participants (75% of target) in four months (pilot primary outcome); valid exacerbation data available for ≥ 85% of those randomised (future RCT primary outcome); change in % medication adherence; FEV1 percent predicted (key secondaries in future RCT); and perceptions of trial procedures, in semi-structured interviews with intervention (n = 14) and control (n = 5) participants, interventionists (n = 3) and CF team members (n = 5).
RESULTS: The pilot trial recruited to target, randomising 33 to intervention and 31 to control in the four-month period, June-September 2016. At study completion (30th April 2017), 60 (94%; Intervention = 32, Control =28) participants contributed good quality exacerbation data (intervention: 35 exacerbations; control: 25 exacerbation). The mean change in adherence and baseline-adjusted FEV1 percent predicted were higher in the intervention arm by 10% (95% CI: -5.2 to 25.2) and 5% (95% CI -2 to 12%) respectively. Five serious adverse events occurred, none related to the intervention. The mean change in adherence was 10% (95% CI: -5.2 to 25.2), greater in the intervention arm. Interventionists delivered insufficient numbers of review sessions due to concentration on participant recruitment. This left interventionists insufficient time for key intervention procedures. A total of 10 key changes that were made to RCT procedures are summarised.
CONCLUSIONS: With improved research processes and lower monthly participant recruitment targets, a full-scale trial is feasible.
TRIAL REGISTRATION: ISRCTN13076797 . Prospectively registered on 07/06/2016.

PMID: 30975206 [PubMed - in process]

Derivation of adult canine intestinal organoids for translational research in gastroenterology.

BMC Biol. 2019 Apr 11;17(1):33

Authors: Chandra L, Borcherding DC, Kingsbury D, Atherly T, Ambrosini YM, Bourgois-Mochel A, Yuan W, Kimber M, Qi Y, Wang Q, Wannemuehler M, Ellinwood NM, Snella E, Martin M, Skala M, Meyerholz D, Estes M, Fernandez-Zapico ME, Jergens AE, Mochel JP, Allenspach K

Abstract
BACKGROUND: Large animal models, such as the dog, are increasingly being used for studying diseases including gastrointestinal (GI) disorders. Dogs share similar environmental, genomic, anatomical, and intestinal physiologic features with humans. To bridge the gap between commonly used animal models, such as rodents, and humans, and expand the translational potential of the dog model, we developed a three-dimensional (3D) canine GI organoid (enteroid and colonoid) system. Organoids have recently gained interest in translational research as this model system better recapitulates the physiological and molecular features of the tissue environment in comparison with two-dimensional cultures.
RESULTS: Organoids were derived from tissue of more than 40 healthy dogs and dogs with GI conditions, including inflammatory bowel disease (IBD) and intestinal carcinomas. Adult intestinal stem cells (ISC) were isolated from whole jejunal tissue as well as endoscopically obtained duodenal, ileal, and colonic biopsy samples using an optimized culture protocol. Intestinal organoids were comprehensively characterized using histology, immunohistochemistry, RNA in situ hybridization, and transmission electron microscopy, to determine the extent to which they recapitulated the in vivo tissue characteristics. Physiological relevance of the enteroid system was defined using functional assays such as optical metabolic imaging (OMI), the cystic fibrosis transmembrane conductance regulator (CFTR) function assay, and Exosome-Like Vesicles (EV) uptake assay, as a basis for wider applications of this technology in basic, preclinical and translational GI research. We have furthermore created a collection of cryopreserved organoids to facilitate future research.
CONCLUSIONS: We establish the canine GI organoid systems as a model to study naturally occurring intestinal diseases in dogs and humans, and that can be used for toxicology studies, for analysis of host-pathogen interactions, and for other translational applications.

PMID: 30975131 [PubMed - in process]

Use of ivacaftor in late diagnosed cystic fibrosis monozygotic twins heterozygous for F508del and R117H-7T - a case report.

BMC Pulm Med. 2019 Apr 11;19(1):76

Authors: Welsner M, Straßburg S, Taube C, Sutharsan S

Abstract
BACKGROUND: CFTR modulator therapy with ivacaftor is a treatment option for Cystic Fibrosis (CF) patients with at least one copy of a R117H-7T mutation in the CFTR gene. Desirable effects of this therapy are improvement of lung function, decrease in exacerbation rate, normalization or reduction of sweat chloride and weight gain. Monogenetic CF-twins carry identical genetic information, so therapy response and side effects are expected to be nearly identical under this specific therapy.
CASE PRESENTATION: In monozygotic twins, at the age of 55, two pathogenic variants in the CFTR gene (F508del and R117H-7T) were detected. Both patients presented with a borderline sweat test (30-59 mmol/L) and despite the same genetic information and similar life circumstances the disease proceeds completely different. While one patient has severe pulmonary involvement with chronic P. aeruginosa infection, her twin sister is almost unimpaired. Liver or pancreatic involvement was not seen in either patient. Due to the presence of one copy of a R117H-7T mutation, CFTR modulator therapy with ivacaftor was initiated in both. Response and side effects were significantly different. In the less affected patient, we observed an improvement in lung function and a normalization of sweat chloride. In the severely affected patient, no functional response to treatment was seen, but stabilization of the disease state with a decrease in exacerbation and hospitalization rate and weight gain as well as a normalization of sweat chloride. There was an increase in liver enzymes in the less affected patient, which normalized after halving the dose of ivacaftor, while the therapeutic effect was maintained.
CONCLUSIONS: Despite nearly identical genetic information, as in monogenetic twins, therapy response and onset of side effects of CFTR modulating therapy are very different. In patients with late diagnosis and severe pulmonary involvement, ivacaftor does not seem to improve lung function, whereas in patients with late diagnosis and low disease severity a relevant therapy response was obtained. In addition to lung function, additional clinical parameters such as reduction of exacerbation and hospitalization rate and weight gain should be used to assess therapy response, especially in severely affected patients.

PMID: 30975115 [PubMed - in process]

An update on admissions of cystic fibrosis children in the United States based on national databases.

Hosp Pract (1995). 2019 Apr 11;:

Authors: Ramphul K, Mejias SG, Joynauth J

PMID: 30975000 [PubMed - as supplied by publisher]

Nebulised lipid-polymer hybrid nanoparticles for the delivery of a therapeutic anti-inflammatory microRNA to bronchial epithelial cells.

ERJ Open Res. 2019 Apr;5(2):

Authors: Vencken S, Foged C, Ramsey JM, Sweeney L, Cryan SA, MacLoughlin RJ, Greene CM

Abstract
Modulation of microRNAs (miRNAs), endogenous regulators of gene expression, is a promising strategy for tackling inflammatory lung diseases. In this proof-of-concept study, we tested delivery of miR-17 to bronchial epithelial cells (BECs) using nebulised lipid-polymer hybrid nanoparticles (LPNs). The primary aim was to reduce the induced secretion of miR-17's target, i.e. the pro-inflammatory chemokine interleukin (IL)-8. Synthetic miR-17 mimics were loaded into LPNs composed of poly(dl-lactic-co-glycolic acid) (PLGA) and the cationic lipid 1,2-dioleoyloxy-3-(trimethylammonium)propane (DOTAP) using a double emulsion solvent evaporation method and nebulised using the Aerogen Solo nebuliser. The physicochemical, aerosol, inflammatory and cytotoxic properties of LPNs were characterised. The effect of LPNs on lipopolysaccharide (LPS)-induced IL-8 production from human NuLi-1 BECs was tested by ELISA. The z-average, polydispersity index and ζ-potential of the LPNs and the aerodynamic properties of nebulised suspensions were in a range optimal for deposition in the bronchi and bronchioles post-inhalation. Cytotoxic and pro-inflammatory effects were minimal for LPNs loaded with a model cargo. Nebulisation did not affect the physicochemical or functional properties of the LPNs. Nebulised miR-17-loaded LPNs downregulated LPS-induced IL-8 secretion by >40% in BECs. This study suggests that DOTAP-modified PLGA LPNs are efficient and well-tolerated carriers for delivery of miRNA mimics to BECs.

PMID: 30972350 [PubMed]

Targeting Aspergillus fumigatus Crf Transglycosylases With Neutralizing Antibody Is Relevant but Not Sufficient to Erase Fungal Burden in a Neutropenic Rat Model.

Front Microbiol. 2019;10:600

Authors: Chauvin D, Hust M, Schütte M, Chesnay A, Parent C, Moreira GMSG, Arroyo J, Sanz AB, Pugnière M, Martineau P, Chandenier J, Heuzé-Vourc'h N, Desoubeaux G

Abstract
Aspergillus fumigatus is an airborne opportunistic fungal pathogen responsible for severe infections. Among them, invasive pulmonary aspergillosis has become a major concern as mortality rates exceed 50% in immunocompromised hosts. In parallel, allergic bronchopulmonary aspergillosis frequently encountered in cystic fibrosis patients, is also a comorbidity factor. Current treatments suffer from high toxicity which prevents their use in weakened subjects, resulting in impaired prognostic. Because of their low toxicity and high specificity, anti-infectious therapeutic antibodies could be a new alternative to conventional therapeutics. In this study, we investigated the potential of Chitin Ring Formation cell wall transglycosylases of A. fumigatus to be therapeutic targets for therapeutic antibodies. We demonstrated that the Crf target was highly conserved, regardless of the pathophysiological context; whereas the CRF1 gene was found to be 100% conserved in 92% of the isolates studied, Crf proteins were expressed in 98% of the strains. In addition, we highlighted the role of Crf proteins in fungal growth, using a deletion mutant for CRF1 gene, for which a growth decrease of 23.6% was observed after 48 h. It was demonstrated that anti-Crf antibodies neutralized the enzymatic activity of recombinant Crf protein, and delayed fungal growth by 12.3% in vitro when added to spores. In a neutropenic rat model of invasive pulmonary aspergillosis, anti-Crf antibodies elicited a significant recruitment of neutrophils, macrophages and T CD4 lymphocytes but it was not correlated with a decrease of fungal burden in lungs and improvement in survival. Overall, our study highlighted the potential relevance of targeting Crf cell wall protein (CWP) with therapeutic antibodies.

PMID: 30972049 [PubMed]

CADTH Canadian Drug Expert Committee Recommendation: Lumacaftor/Ivacaftor (Orkambi — Vertex Pharmaceuticals (Canada) Incorporated): Indication: Cystic fibrosis, F508del-cystic fibrosis transmembrane conductance regulator gene mutation in patients aged six years and older

Book. 2018 10

Authors:

PMID: 30973690

The Clinical Features of Bronchiectasis Associated with Alpha-1 Antitrypsin Deficiency, Common Variable Immunodeficiency and Primary Ciliary Dyskinesia--Results from the U.S. Bronchiectasis Research Registry.

Chronic Obstr Pulm Dis. 2019 Apr 09;6(2):

Authors: Eden E, Choate R, Barker A, Addrizzo-Harris D, Aksamit TR, Daley CL, Daniels MLA, DiMango A, Fennelly K, Griffith DE, Johnson MM, Knowles MR, Metersky ML, Noone PG, O'Donnell AE, Olivier KN, Salathe MA, Schmid A, Thomashow B, Tino G, Turino GM, Winthrop KL

Abstract
Objective: This study compares and contrasts the clinical features of non-cystic fibrosis bronchiectasis with 3 uncommon disorders known to be associated with bronchiectasis but with distinctly different underlying defined pathophysiologic derangements, namely severe alpha-1 antitrypsin deficiency (AATD), common variable immunodeficiency (CVI) and primary ciliary dyskinesia (PCD).
Methods: The Bronchiectasis Research Registry provides a central database for studying patients with non-cystic fibrosis bronchiectasis. This report consists of information from 13 U.S. sites pertaining to the 3 study diagnoses. Patients with AATD (SZ and ZZ phenotypes only), CVI (patients with IgG≤500), PCD (history of physician diagnosed Kartagener's syndrome or PCD), and patients with confirmed absence of the above 3 diagnoses (idiopathic control group) were included in the study. Descriptive statistics were computed for the main demographic and clinical characteristics of the sample stratified by group. Values between the groups were compared using Kruskal-Wallis test, and Chi-squared/ Fisher's exact tests respectively. The significance level was set at 0.05. Software SAS 9.4 was used to perform the statistical analyses.
Results: Of the 2170 participants in the database enrolled as of January 2017, 615 respondents had sufficient data and were included in the analyses. Patients with PCD (n=79, mean age 41.9 years [standard deviation (SD)=14.5]) were significantly younger than patients with AATD (n=58, mean age 66.9 [SD=10.7]), CVI (n=18, mean age 66.7 years [SD=10.5]) or the idiopathic group (n=460, mean age 64.2 [SD=15.9]), p<.0001. Compared to other groups, those with PCD had lower pulmonary function (forced expiratory volume in 1 second [FEV1] forced vital capacity [FVC] and FEV1/FVC ratio) (p<0.01), and a greater proportion of them reported having exacerbations and/or hospitalizations in the past 2 years (p<0.01). Overall, Pseudomonas aeruginosa and Staphylococcus aureus were the organisms most commonly isolated from sputum. Mycobacterial infection was most commonly reported in those with AATD.
Conclusion: This report from the U.S. Bronchiectasis Research Registry compares and contrasts differences in the clinical features of patients suffering from 3 rare conditions, with different underlying causes, to those without. The group with PCD had more symptoms, greater morbidity, lower lung function and more commonly were infected by Pseudomonas aeruginosa. A greater percentage of those with AATD reported mycobacterial lung involvement.

PMID: 30974050 [PubMed - as supplied by publisher]

XBP1S Regulates MUC5B in a Promoter Variant-Dependent Pathway in IPF Airway Epithelia.

Am J Respir Crit Care Med. 2019 Apr 11;:

Authors: Chen G, Ribeiro CMP, Sun L, Okuda K, Kato T, Gilmore RC, Martino MB, Dang H, Abzhanova A, Lin JM, Hull-Ryde EA, Volmer AS, Randell SH, Livraghi-Butrico A, Deng Y, Scherer PE, Stripp BR, O'Neal WK, Boucher RC

Abstract
RATIONALE: The goal was to connect elements of IPF pathogenesis, including: chronic endoplasmic reticulum stress in respiratory epithelia associated with injury/inflammation and remodeling; distal airway mucus obstruction and honeycomb cyst formation with accumulation of MUC5B; and associations between IPF risk and polymorphisms in the MUC5B promoter.
OBJECTIVES: Test whether the ER stress sensor protein ER-to-nucleus signaling 2 (ERN2) and its downstream effector, the spliced form of x-box binding protein 1 (XBP1S), regulate MUC5B expression and differentially activate the MUC5B promoter variant in respiratory epithelia.
METHODS AND MEASUREMENTS: Primary human airway epithelia (HAE), transgenic mouse models, human IPF lung tissues, and cell lines expressing XBP1S and MUC5B promoters were used to explore relationships between the ERN2/XBP1S pathway and MUC5B. An inhibitor of the pathway, KIRA6, and XBP1 CRISPR-Cas9 were used in HAE to explore therapeutic potential.
RESULTS: ERN2 regulated both MUC5B and MUC5AC mRNAs. Downstream XBP1S selectively promoted MUC5B expression in vitro and in distal murine airway epithelia in vivo. XBP1S bound to the proximal region of the MUC5B promoter and differentially up-regulated MUC5B expression in the context of the MUC5B promoter rs35705950 variant. High levels of ERN2 and XBP1S were associated with excessive MUC5B mRNAs in distal airways of human IPF lungs. Cytokine-induced MUC5B expression in HAE was inhibited by KIRA6 and XBP1 CRISPR-Cas9.
CONCLUSION: A positive feedback bistable ERN2-XBP1S pathway regulates MUC5B-dominated mucus obstruction in IPF, providing a UPR-dependent mechanism linking the MUC5B promoter rs35705950 polymorphism with IPF pathogenesis. Inhibiting ERN2-dependent pathways/elements may provide a therapeutic option for IPF.

PMID: 30973754 [PubMed - as supplied by publisher]

Optimizing Estimated Glomerular Filtration Rate to Support Adult to Pediatric Pharmacokinetic Bridging Studies in Patients with Cystic Fibrosis.

Clin Pharmacokinet. 2019 Apr 10;:

Authors: Crass RL, Pai MP

Abstract
BACKGROUND: The estimated glomerular filtration rate (eGFR) is often used to model drug clearance (CL) and scale doses across age and body size. Over their lifetime, patients with cystic fibrosis (CF) receive repeated courses of tobramycin, an antibiotic with eGFR-dependent CL, for the treatment of pulmonary exacerbations. Tobramycin population pharmacokinetic (PK) modeling can be used to decipher the best approach to define eGFR for pediatric bridging studies.
METHODS: Inpatients with CF who received intravenous tobramycin between 1 January 2006 and 30 May 2018 were eligible for inclusion. Encounters without tobramycin concentration measurement or missing covariate data were excluded. Population PK analysis was performed using NONMEM.Covariate models were built  following identification of the base model, with specific emphasis on the effect of different methods of estimating renal function as a covariate of tobramycin CL.
RESULTS: A total of 296 CF patients contributed 1029 care encounters (420 pediatric, 609 adult) and 4352 tobramycin concentrations to this analysis. The median (minimum, maximum) age at encounter was 19 years (0.2, 60), with serum creatinine of 0.60 mg/dL (0.10, 3.41). A two-compartment model best described the observed data, with height and eGFR as significant covariates of tobramycin CL. eGFR was best modeled using a combination of the modified Schwartz and Chronic Kidney Disease Epidemiology Collaboration (CKDEPI) equations expressed in absolute units.
CONCLUSIONS: The CKDEPI equation bridges PK data generated in adults to adolescents with CF better than the current regulatory standard. The eGFR should be expressed in absolute units (mL/min) for PK analyses.

PMID: 30972695 [PubMed - as supplied by publisher]

Streptococcus gordonii programs epithelial cells to resist ZEB2 induction by Porphyromonas gingivalis.

Proc Natl Acad Sci U S A. 2019 Apr 10;:

Authors: Ohshima J, Wang Q, Fitzsimonds ZR, Miller DP, Sztukowska MN, Jung YJ, Hayashi M, Whiteley M, Lamont RJ

Abstract
The polymicrobial microbiome of the oral cavity is a direct precursor of periodontal diseases, and changes in microhabitat or shifts in microbial composition may also be linked to oral squamous cell carcinoma. Dysbiotic oral epithelial responses provoked by individual organisms, and which underlie these diseases, are widely studied. However, organisms may influence community partner species through manipulation of epithelial cell responses, an aspect of the host microbiome interaction that is poorly understood. We report here that Porphyromonas gingivalis, a keystone periodontal pathogen, can up-regulate expression of ZEB2, a transcription factor which controls epithelial-mesenchymal transition and inflammatory responses. ZEB2 regulation by P. gingivalis was mediated through pathways involving β-catenin and FOXO1. Among the community partners of P. gingivalis, Streptococcus gordonii was capable of antagonizing ZEB2 expression. Mechanistically, S. gordonii suppressed FOXO1 by activating the TAK1-NLK negative regulatory pathway, even in the presence of P. gingivalis Collectively, these results establish S. gordonii as homeostatic commensal, capable of mitigating the activity of a more pathogenic organism through modulation of host signaling.

PMID: 30971493 [PubMed - as supplied by publisher]

Differential thermostability and response to cystic fibrosis transmembrane conductance regulator (CFTR) potentiators of human and mouse F508del-CFTR.

Am J Physiol Lung Cell Mol Physiol. 2019 Apr 10;:

Authors: Bose SJ, Bijvelds MJC, Wang Y, Liu J, Cai Z, Bot AGM, de Jonge HR, Sheppard DN

Abstract
Cross-species comparative studies have highlighted differences between human and mouse cystic fibrosis transmembrane conductance regulator (CFTR), the epithelial Cl- channel defective in cystic fibrosis (CF). Here, we compare the impact of the most common CF mutation F508del on the function of human and mouse CFTR heterologously expressed in mammalian cells and their response to CFTR modulators using the iodide efflux and patch-clamp techniques. Once delivered to the plasma membrane, human F508del-CFTR exhibited a severe gating defect characterized by infrequent channel openings and was thermally unstable, deactivating within minutes at 37 °C. By contrast, the F508del mutation was without effect on the gating pattern of mouse CFTR and channel activity demonstrated thermostability at 37 °C. Strikingly, at all concentrations tested, the clinically-approved CFTR potentiator ivacaftor was without effect on the mouse F508del-CFTR Cl- channel. Moreover, eight CFTR potentiators, including ivacaftor, failed to generate CFTR-mediated iodide efflux from CHO cells expressing mouse F508del-CFTR. However, they all produced CFTR-mediated iodide efflux with human F508del-CFTR-expressing CHO cells, while fifteen CFTR correctors rescued the plasma membrane expression of both human and mouse F508del-CFTR. Interestingly, the CFTR potentiator genistein enhanced CFTR-mediated iodide efflux from CHO cells expressing either human or mouse F508del-CFTR, whereas it only potentiated human F508del-CFTR Cl- channels in cell-free membrane patches, suggesting that its action on mouse F508del-CFTR is indirect. Thus, the F508del mutation has distinct effects on human and mouse CFTR Cl- channels.

PMID: 30969810 [PubMed - as supplied by publisher]

Multiprobe Nuclear Imaging of the Cystic Fibrosis Lung as a Biomarker of Therapeutic Effect.

J Aerosol Med Pulm Drug Deliv. 2019 Apr 10;:

Authors: Corcoran TE, Huber AS, Myerburg MM, Weiner DJ, Locke LW, Lacy RT, Weber L, Czachowski MR, Johnston DJ, Muthukrishnan A, Lennox AT, Pilewski JM

Abstract
BACKGROUND: Nuclear imaging biomarkers illustrate unique aspects of lung physiology and are useful for assessing therapeutic effects in cystic fibrosis (CF) lung disease. We have developed a multiprobe method to simultaneously measure mucociliary clearance (MCC) and paracellular absorption (ABS). MCC is a direct measure of mucus clearance. ABS has been related to airway surface liquid (ASL) absorption through previous in vitro studies.
METHODS: We describe baseline factors affecting MCC and ABS using data from a retrospective baseline group (n = 22) and the response of the measures to inhaled 7% hypertonic saline (HS) and dry powder mannitol using data from a prospective response group (n = 7). A retrospective healthy control group (n = 15) is also described. The baseline and control groups performed single measurements of MCC/ABS. The response group performed baseline measurements of MCC/ABS and measurements after each intervention.
RESULTS: ABS was correlated (Spearman's ρ = 0.51, p = 0.06) to sweat chloride, a systemic measure of cystic fibrosis transmembrane conductance regulator (CFTR) function, whereas MCC was not. Baseline MCC was depressed after Pseudomonas aeruginosa infection as we have previously described. MCC provided a more sensitive indication of therapeutic effect and indicated improved clearance with mannitol compared with HS.
CONCLUSION: MCC provides a useful and well-established means of testing therapies directed at improving mucus clearance in the lung. ABS may provide a means of detecting local changes in ASL absorption and CFTR function in the lung. Both are useful tools for studying the key aspects of CF lung pathophysiology (ASL hyperabsorption and MCC depression) that link the basic genetic defects of CF to disease manifestations in the lung.

PMID: 30969149 [PubMed - as supplied by publisher]

Antibacterial Properties and Efficacy of a Novel SPLUNC1-Derived Antimicrobial Peptide, α4-Short, in a Murine Model of Respiratory Infection.

MBio. 2019 Apr 09;10(2):

Authors: Jiang S, Deslouches B, Chen C, Di ME, Di YP

Abstract
Multidrug resistance (MDR) by bacterial pathogens constitutes a global health crisis, and resistance to treatment displayed by biofilm-associated infections (e.g., cystic fibrosis, surgical sites, and medical implants) only exacerbates a problem that is already difficult to overcome. Antimicrobial peptides (AMPs) are a promising class of therapeutics that may be useful in the battle against antibiotic resistance, although certain limitations have hindered their clinical development. The goal of this study was to examine the therapeutic potential of novel AMPs derived from the multifunctional respiratory host defense protein SPLUNC1. Using standard growth inhibition and antibiofilm assays, we demonstrated that a novel structurally optimized AMP, α4-short, was highly effective against the most common group of MDR bacteria while showing broad-spectrum bactericidal and antibiofilm activities. With negligible hemolysis and toxicity to white blood cells, the new peptide also demonstrated in vivo efficacy when delivered directly into the airway in a murine model of Pseudomonas aeruginosa-induced respiratory infection. The data warrant further exploration of SPLUNC1-derived AMPs with optimized structures to assess the potential application to difficult-to-cure biofilm-associated infections.IMPORTANCE The rise of superbugs underscores the urgent need for novel antimicrobial agents. Antimicrobial peptides (AMPs) have the ability to kill superbugs regardless of resistance to traditional antibiotics. However, AMPs often display a lack of efficacy in vivo. Sequence optimization and engineering are promising but may result in increased host toxicity. We report here the optimization of a novel AMP (α4-short) derived from the multifunctional respiratory protein SPLUNC1. The AMP α4-short demonstrated broad-spectrum activity against superbugs as well as in vivo efficacy in the P. aeruginosa pneumonia model. Further exploration for clinical development is warranted.

PMID: 30967458 [PubMed - in process]

Is it cystic fibrosis? The challenges of diagnosing cystic fibrosis.

Paediatr Respir Rev. 2019 Feb 28;:

Authors: Simmonds NJ

Abstract
The spectrum of conditions caused by abnormal CFTR function is broad - from 'classic' cystic fibrosis (CF) to single organ conditions termed CFTR-related disorders. Defining and securing the diagnosis in an important minority of patients can be a challenge as the sweat test is equivocal or normal; the impact this has on the patient (at different stages of their life) can be very significant as it has the potential to lead to misdiagnosis and over (or under) treatment with associated psychological burden. The nasal potential difference test and intestinal current measurements are physiological measurements of CFTR function and thus can provide important diagnostic information. This article provides an overview of the latest developments in CF diagnostics, outlining the approach to be taken when the diagnosis is unclear and some of the areas of uncertainty.

PMID: 30967347 [PubMed - as supplied by publisher]

Which pathogens should we worry about?

Paediatr Respir Rev. 2019 Mar 01;:

Authors: Jones AM

Abstract
Aside from the traditional CF pathogens, Haemophilus influenzae, Staphylococcus aureus and Pseudomonas aeruginosa, there are an increasing number of organisms found to have chronic carriage in patients with cystic fibrosis, including gram-negative bacteria, non-tuberculous mycobacteria, anaerobic bacteria and fungal species. Some of these lower prevalence organisms, such as Burkholderia cenocepacia and Mycobacterium abscessus complex, are recognised as true pathogens associated with significant adverse clinical consequences, whilst for others the relative pathogenicity and need for treatment are unclear. This article will highlight some of the challenges in assessing what is a pathogen in CF and the potential implications of infection with different organisms for individual patients.

PMID: 30967346 [PubMed - as supplied by publisher]

Surgical Management of Chronic Rhinosinusitis in Cystic Fibrosis.

Med Sci (Basel). 2019 Apr 07;7(4):

Authors: Zheng Z, Safi C, Gudis DA

Abstract
Cystic fibrosis patients frequently develop chronic rhinosinusitis as a result of their propensity to form inspissated mucus and impairment of mucociliary clearance. They exhibit variable symptom burden even in the setting of positive radiographic and endoscopic findings. Current evidence suggests a positive effect of managing sinonasal disease on pulmonary health. Topical antimicrobial and mucolytic therapies are frequently required to manage the disease with surgery reserved for refractory cases. Endoscopic sinus surgery has been demonstrated to be safe and efficacious in controlling symptoms of chronic rhinosinusitis in patients with comorbid cystic fibrosis. However, the impact of surgery on pulmonary health remains an active area of investigation. In addition, a growing body of research has suggested a more extended surgical approach creating large sinonasal cavities with gravity-dependent drainage pathways, followed by adjuvant medical therapies, as an ideal strategy to optimally control disease and prevent pulmonary exacerbations. In this manuscript, we provide an up-to-date review of current evidence in the surgical management of chronic rhinosinusitis in cystic fibrosis patients.

PMID: 30959944 [PubMed]

FGF10 is an essential regulator of tracheal submucosal gland morphogenesis.

Dev Biol. 2019 Apr 06;:

Authors: May AJ, Teshima THN, Noble A, Tucker AS

Abstract
Mucus secretion and mucociliary clearance are crucial processes required to maintain pulmonary homeostasis. In the trachea and nasal passages, mucus is secreted by submucosal glands (SMGs) that line the airway, with an additional contribution from goblet cells of the surface airway epithelium. The SMG mucus is rich in mucins and antimicrobial enzymes. Defective tracheal SMGs contribute to hyper-secretory respiratory diseases, such as cystic fibrosis, asthma, and chronic obstructive pulmonary disease, however little is known about the signals that regulate their morphogenesis and patterning. Here, we show that Fgf10 is essential for the normal development of murine tracheal SMGs, with gland development arresting at the early bud stage in the absence of FGF10 signalling. As Fgf10 knockout mice are lethal at birth, inducible knockdown of Fgf10 at late embryonic stages was used to follow postnatal gland formation, confirming the essential role of FGF10 in SMG development. In heterozygous Fgf10 mice the tracheal glands formed but with altered morphology and restricted distribution. The reduction in SMG branching in Fgf10 heterozygous mice was not rescued with time and resulted in a reduction in overall tracheal mucus secretion. Fgf10 is therefore a key signal in SMG development, influencing both the number of glands and extent of branching morphogenesis, and is likely, therefore, to play a role in aspects of SMG-dependent respiratory health.

PMID: 30965042 [PubMed - as supplied by publisher]

Microbial Metabolites in Cystic Fibrosis: a Target for Future Therapy?

Am J Respir Cell Mol Biol. 2019 Apr 09;:

Authors: Widder S, Knapp S

PMID: 30965015 [PubMed - as supplied by publisher]