An IL-8 Transiently Transgenized Mouse Model for the In Vivo Long-term Monitoring of Inflammatory Responses.

J Vis Exp. 2017 Jul 07;(125):

Authors: Bergamini G, Stellari F, Sandri A, M Lleo M, Donofrio G, Ruscitti F, Boschi F, Sbarbati A, Villetti G, Melotti P, Sorio C

Abstract
Airway inflammation is often associated with bacterial infections and represents a major determinant of lung disease. The in vivo determination of the pro-inflammatory capabilities of various factors is challenging and requires terminal procedures, such as bronchoalveolar lavage and the removal of lungs for in situ analysis, precluding longitudinal visualization in the same mouse. Here, lung inflammation is induced through the intratracheal instillation of Pseudomonas aeruginosa culture supernatant (SN) in transiently transgenized mice expressing the luciferase reporter gene under the control of a heterologous IL-8 bovine promoter. Luciferase expression in the lung is monitored by in vivo bioluminescent image (BLI) analysis over a 2.5- to 48-h timeframe following the instillation. The procedure can be repeated multiple times within 2 - 3 months, thus permitting the evaluation of the inflammatory response in the same mice without the need to terminate the animals. This approach permits the monitoring of pro- and anti-inflammatory factors acting in the lung in real time and appears suitable for functional and pharmacological studies.

PMID: 28715404 [PubMed - in process]

Mapping targetable inflammation and outcomes with cystic fibrosis biomarkers.

Pediatr Pulmonol. 2017 Jul 17;:

Authors: Giddings O, Esther CR

Abstract
Cystic fibrosis is characterized by an overly exuberant neutrophilic inflammatory response to pathogens and other stimuli that starts very early in disease. The overwhelming nature of this response is a primary cause of remodeling and destruction of the airways, suggesting that anti-inflammatory therapies could be beneficial in CF. However, finding therapies that can effectively reduce the inflammatory response without compromising host defenses remains elusive. New approaches towards mapping inflammatory targets promise to aid in developing novel therapeutic strategies and improve outcomes in individuals with CF.

PMID: 28714611 [PubMed - as supplied by publisher]

CF-related diabetes: Containing the metabolic miscreant of cystic fibrosis.

Pediatr Pulmonol. 2017 Jul 17;:

Authors: Moheet A, Moran A

Abstract
Cystic fibrosis-related diabetes (CFRD) is associated with both an increase in morbidity and mortality in people with cystic fibrosis (CF). With increased screening and improved life expectancy of people with CF, the prevalence of CFRD is expected to rise further. The underlying pathophysiological mechanisms causing glucose intolerance and diabetes in patients with CF are not well understood but both functional and structural abnormalities in islet cells are likely to have key roles. Insulin therapy improves health outcomes in patients with CF. Future research is needed to better understand the mechanisms underlying the development of CFRD and to develop new screening and treatment strategies to minimize the detrimental impact of CFRD on health outcomes in people with CF.

PMID: 28714601 [PubMed - as supplied by publisher]

Harnessing Neutrophil Survival Mechanisms during Chronic Infection by Pseudomonas aeruginosa: Novel Therapeutic Targets to Dampen Inflammation in Cystic Fibrosis.

Front Cell Infect Microbiol. 2017;7:243

Authors: Marteyn BS, Burgel PR, Meijer L, Witko-Sarsat V

Abstract
More than two decades after cloning the cystic fibrosis transmembrane regulator (CFTR) gene, the defective gene in cystic fibrosis (CF), we still do not understand how dysfunction of this ion channel causes lung disease and the tremendous neutrophil burden which persists within the airways; nor why chronic colonization by Pseudomonas aeruginosa develops in CF patients who are thought to be immunocompetent. It appears that the microenvironment within the lung of CF patients provides favorable conditions for both P. aeruginosa colonization and neutrophil survival. In this context, the ability of bacteria to induce hypoxia, which in turn affects neutrophil survival is an additional level of complexity that needs to be accounted for when controlling neutrophil fate in CF. Recent studies have underscored the importance of neutrophils in innate immunity and their functions appear to extend far beyond their well-described role in antibacterial defense. Perhaps a disturbance in neutrophil reprogramming during the course of an infection severely modulates the inflammatory response in CF. Furthermore there is an emerging concept that the CFTR itself may be an immune modulator and stimulating CFTR function in CF patients could promote neutrophil and macrophages antimicrobial function. Fostering the resolution of inflammation by favoring neutrophil apoptosis could preserve their microbicidal activities but decrease their proinflammatory potential. In this context, triggering neutrophil apoptosis with roscovitine may be a potential therapeutic option and this is currently being evaluated in CF patients. In the present review we discuss how neutrophils functions are disturbed in CF and how this may relate to chronic infection with P. aeuginosa and we propose novel research directions aimed at modulating neutrophil survival, dampening lung inflammation and ultimately leading to an amelioration of the lung disease.

PMID: 28713772 [PubMed - in process]

Luminally Acting Agents for Constipation Treatment: A Review Based on Literatures and Patents.

Front Pharmacol. 2017;8:418

Authors: Yang H, Ma T

Abstract
Constipation is one of the most frequently reported gastrointestinal (GI) disorders that negatively impacts quality of life and is associated with a significant economic burden to the patients and society. Traditional treatments including lifestyle modification and laxatives are often ineffective in the more severe forms of constipation and over the long term. New medications targeting at intestinal chloride channels and colonic serotonin receptors have been demonstrated effective in recent years. Emerging agents focusing on improving intestinal secretion and/or colonic motility have been shown effective in animal models and even in clinical trials. Recognization of the role of cystic fibrosis transmembrane regulator (CFTR) and calcium-activated chloride channels (CaCCs) in intestine fluid secretion and motility modulation makes CFTR and CaCCs promising molecule targets for anti-constipation therapy. Although there are multiple choices for constipation treatment, there is still a recognized need for new medications in anti-constipation therapy. The present review covers the discovery of luminally acting agents for constipation treatment described in both patents (2011-present) and scientific literatures.

PMID: 28713271 [PubMed]

Detection of CFTR function and modulation in primary human nasal cell spheroids.

J Cyst Fibros. 2017 Jul 13;:

Authors: Brewington JJ, Filbrandt ET, LaRosa FJ, Ostmann AJ, Strecker LM, Szczesniak RD, Clancy JP

Abstract
BACKGROUND: Expansion of CFTR modulators to patients with rare/undescribed mutations will be facilitated by patient-derived models quantifying CFTR function and restoration. We aimed to generate a personalized model system of CFTR function and modulation using non-surgically obtained nasal epithelial cells (NECs).
METHODS: NECs obtained by curettage from healthy volunteers and CF patients were expanded and grown in 3-dimensional culture as spheroids, characterized, and stimulated with cAMP-inducing agents to activate CFTR. Spheroid swelling was quantified as a proxy for CFTR function.
RESULTS: NEC spheroids recapitulated characteristics of pseudostratified respiratory epithelia. When stimulated with forskolin/IBMX, spheroids swelled in the presence of functional CFTR, and shrank in its absence. Spheroid swelling quantified mutant CFTR restoration in F508del homozygous cells using clinically available CFTR modulators.
CONCLUSIONS: NEC spheroids hold promise for understanding rare CFTR mutations and personalized modulator testing to drive evaluation for CF patients with common, rare or undescribed mutations. Portions of this data have previously been presented in abstract form at the 2016 meetings of the American Thoracic Society and the 2016 North American Cystic Fibrosis Conference.

PMID: 28712885 [PubMed - as supplied by publisher]

Epithelial-mesenchymal transition of human lung adenocarcinoma A549 cells up-regulates cytokine production upon LPS stimulation.

Allergol Int. 2017 Jul 13;:

Authors: Kato T, Kobayashi K, Suzukawa M, Saito M, Okuda K, Koyama K, Igarashi S, Arakawa S, Ohshima N, Matsui H, Nagase T, Ohta K

PMID: 28712741 [PubMed - as supplied by publisher]

Comparing effectiveness and outcomes in asthma and cystic fibrosis.

Paediatr Respir Rev. 2017 Jun 12;:

Authors: Schechter MS

Abstract
As technology yields new treatments, pediatric pulmonologists need determine how best to use them and how to decide which ones are best for any specific group or individual patient. Physicians have always customized therapies based upon patient response, but the new concept of "Personalized (or precision) medicine" focuses attention to a greater degree on the individual needs of patients based on their genetic, biomarker, phenotypic, or psychosocial characteristics. The newly developed biologics for treatment of asthma and CFTR modulators for treatment of cystic fibrosis (CF) highlight this newer approach. As we have more treatments available, new approaches to testing efficacy and effectiveness of these new therapies is necessary in order to efficiently bring them to market and compare their benefits in real world practice. While comparative effectiveness can be tested in pragmatic clinic trials, the most common approaches make use of observational data such as administrative databases and patient registries but their use for this is fraught with pitfalls that may or may not be methodologically surmountable. Once new therapies have been shown to be efficacious and effective, it is important to be cognizant of methods for ensuring that all patients actually receive the treatments that will be best for them. Comparisons of the effectiveness of clinical practice in the form of benchmarking is helpful for this, and consideration of costs and cost-effectiveness is essential to judging the best treatment for patients in a real-world setting.

PMID: 28712576 [PubMed - as supplied by publisher]

Formoterol fumarate + glycopyrrolate for the treatment of chronic obstructive pulmonary disease.

Expert Rev Respir Med. 2016 Oct;10(10):1045-55

Authors: Radovanovic D, Mantero M, Sferrazza Papa GF, Valenti V, Aliberti S, Di Marco F, Santus P

Abstract
INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is characterized by a high disability and increasing mortality. Bronchodilators are the cornerstone of pharmacological treatment in COPD, while therapeutic optimization with an improvement in symptoms and compliance represent the actual goals. This has led to the development of devices that combine different classes of inhalatory drugs. Recently, a novel combination of the long acting antimuscarinic agent glycopyrronium bromide and the beta2-agonist formoterol fumarate has been developed in a metered dose inhaler delivery system.
AREAS COVERED: The present article will discuss the current unmet needs in pharmacological therapy of COPD, will then briefly cover the pharmacokinetic and pharmacodynamic characteristics of the formoterol/glycopyrronium fixed dose combination and present the novel delivery system based on engineered microparticles and the co-suspension technology. Finally, efficacy and safety results of phase I, II and III trials will be reviewed. Expert commentary: The novel combination therapy of formoterol/glycopyrronium is the first available as a metered dose inhaler and proved to have a good efficacy and safety profile compared to monocomponents and tiotropium. Although still limited, data from phase III trials provide good evidence to consider it a valid option in the pharmacological management of patients with COPD.

PMID: 27552524 [PubMed - indexed for MEDLINE]

Causes Of Chronic Non-Infectious Diarrhoea In Infants Less Than 6 Months Of Age: Rarely Recognized Entities.

J Ayub Med Coll Abbottabad. 2017 Jan-Mar;29(1):78-82

Authors: Mushtaq I, Cheema HA, Malik HS, Waheed N, Hashmi MA, Malik HS

Abstract
BACKGROUND: Non-infectious causes of chronic diarrhoea are important and easily missed. The study was done with the objectives to identify different causes of chronic non-infectious diarrhoea in infants less than 6 months of age.
METHODS: All patients less than 6 months of age presenting for the first time to a Paediatric Gastroenterology tertiary care centre with a history of chronic diarrhoea and negative stool cultures were enrolled over a period of 8 months. Demographical profile and various factors under observation were recorded in this observational study. Collected data was analysed using SPSS version 20. Chi square test was applied as a test of significance for any qualitative variable, p value (p<0.05) was taken as significant.
RESULTS: Among 72 enrolled patients, female to male ratio was1.05:1. Age at onset of symptoms was between 15 days to 6 months. Aetiology found was Cow's milk protein allergy (CMPA) in 58 (80.6%), Primary intestinal lymphangiectasia (PIL) 6 (8.3%), Cystic fibrosis (CF) 3 (4.2%), Immunodeficiency (SCID) 2 (2.8%), 1 (1.4%) for each Abetalipoproteinemia (ABL), Glucose galactose malabsorption (GGM) and Congenital chloride diarrhoea (CCD).
CONCLUSIONS: Among noninfectious causes of chronic diarrhoea in early infancy, cow's milk protein allergy is most common followed by Primary intestinal lymphangiectasia and Cystic fibrosis.

PMID: 28712180 [PubMed - in process]

Retrospective observational study of French patients with cystic fibrosis and a Gly551Asp-CFTR mutation after 1 and 2years of treatment with ivacaftor in a real-world setting.

J Cyst Fibros. 2017 Jul 12;:

Authors: Hubert D, Dehillotte C, Munck A, David V, Baek J, Mely L, Dominique S, Ramel S, Danner Boucher I, Lefeuvre S, Reynaud Q, Colomb-Jung V, Bakouboula P, Lemonnier L

Abstract
BACKGROUND: Ivacaftor has been shown to improve lung function and body weight in patients with CF and a gating mutation. Real-world evaluation is warranted to examine its safety and effectiveness over the long term.
METHODS: A retrospective observational multicentre study collected clinical data in the year before and the 2years after ivacaftor initiation in patients with CF and a Gly551Asp-CFTR mutation.
RESULTS: Fifty-seven patients were included. Mean absolute change in FEV1% predicted improved from baseline to Year 1 (8.4%; p<0.001) and Year 2 (7.2%; p=0.006). Statistically significant benefits were observed with increased body mass index, fewer Pseudomonas aeruginosa and Staphylococcus aureus positive cultures, and decreased IV antibiotics and maintenance treatment prescriptions (including azithromycin, Dornase alpha and nutritional supplements). No significant adverse events were reported.
CONCLUSION: The clinical benefits of ivacaftor reported in previous clinical trials were confirmed in a real-world setting two years post-initiation, also reducing treatment burden.

PMID: 28711222 [PubMed - as supplied by publisher]

The evolution of lung transplantation for cystic fibrosis: A 2017 update.

J Cyst Fibros. 2017 Jul 12;:

Authors: Snell G, Reed A, Stern M, Hadjiliadis D

Abstract
Lung transplantation (LTx) is an established therapy for patients with end-stage cystic fibrosis (CF). Indeed, CF is the commonest indication for those aged<50years of age needing LTx. CF LTx is associated with a 45% 10year survival - according to the world's largest registry. It is important all otherwise suitable CF patients with severe lung disease have a timely referral for discussion and consideration of the possibility of LTx. LTx discussions must carefully consider colonisation or infection with Burkholderia cenocepacia, Mycobacterium abscessus and Scediosporium - as good LTx outcomes cannot be guaranteed. A bridge to LTx with extra-corporeal lung support is a realistic option, but remains a relative contraindication to LTx. Improvements in LTx matching technology and post-operative management are steadily improving overall long-term outcomes, although chronic allograft rejection remains problematic. Expert multidisciplinary life-long post-LTx care remains the key to success.

PMID: 28711221 [PubMed - as supplied by publisher]

Elfamycins: Inhibitors of Elongation Factor-Tu.

Mol Microbiol. 2017 Jul 15;:

Authors: Prezioso SM, Brown NE, Goldberg JB

Abstract
Elfamycins are a relatively understudied group of antibiotics that target the essential process of translation through impairment of EF-Tu function. For the most part, the utility of these compounds has been as laboratory tools for the study of EF-Tu and the ribosome, as their poor pharmacokinetic profile and solubility has prevented implementation as therapeutic agents. However, due to the slowing of the antibiotic pipeline and the rapid emergence of resistance to approved antibiotics, this group is being reconsidered. Some researchers are using screens for novel naturally produced variants, while others are making directed, systematic chemical improvements on publically disclosed compounds. As an example of the latter approach, a GE2270 A derivative, LFF571, has completed phase 2 clinical trials, thus demonstrating the potential for elfamycins to become more prominent antibiotics in the future. This article is protected by copyright. All rights reserved.

PMID: 28710887 [PubMed - as supplied by publisher]

Effects of inhaled hypertonic (7%) saline on lung function test in preschool children with cystic fibrosis: results of a crossover, randomized clinical trial.

Ital J Pediatr. 2017 Jul 15;43(1):60

Authors: Nenna R, Midulla F, Lambiase C, De Castro G, Zicari AM, Indinnimeo L, Cimino G, Troiani P, Quattrucci S, Tancredi G

Abstract
BACKGROUND: This crossover, randomized, double-blind study (conducted over a 32-week period) was performed to determine, in clinically stable Cystic fibrosis (CF) preschool children: the effects of 7% inhaled hypertonic saline on spirometry and interrupter resistance technique (Rint), and the possible side effects.
METHODS: Twelve CF children (6M, mean age ± SD: 5.7 ± 0.8 yrs) were enrolled and randomly assigned to receive hypertonic saline (HS-4 ml 7% sodium chloride), or normal saline (NS-0.9% sodium chloride) twice a day. After a 16 weeks period, therapy was exchanged to allow all the patients enrolled in the study to carry out both treatments. Monitoring visits, spirometry (COSMED Quark PFT4 ergo) and Rint were scheduled at 0,4,16,20,32 weeks. At T0, spirometric measurements and Rint were performed immediately before and 30 min after the inhalation therapy. Salbutamol (400 mcg) was administered before the drug at each visit.
RESULTS: After a 16-weeks treatment with HS an improvement of FVC (p = 0.02) and a favorable trend of FEV1 were registered. A worsening of FEV1 (p < 0.0001) and of FEF25-75 (p = 0.019) were found in NS group. No differences were found in expiratory and inspiratory Rint in both groups. No serious adverse events occurred.
CONCLUSIONS: Seven percent hypertonic saline therapy proved to be a useful and safe treatment in young CF children with clinically stable conditions.
TRIAL REGISTRATION: ISRCTN12345678 .

PMID: 28709466 [PubMed - in process]

Innovating cystic fibrosis clinical trial designs in an era of successful standard of care therapies.

Curr Opin Pulm Med. 2017 Jul 13;:

Authors: VanDevanter DR, Mayer-Hamblett N

Abstract
PURPOSE OF REVIEW: Evolving cystic fibrosis 'standards of care' have influenced recent cystic fibrosis clinical trial designs for new therapies; care additions/improvements will require innovative trial designs to maximize feasibility and efficacy detection.
RECENT FINDINGS: Three cystic fibrosis therapeutic areas (pulmonary exacerbations, Pseudomonas aeruginosa airway infections, and reduced cystic fibrosis transmembrane conductance regulator [CFTR] protein function) differ with respect to the duration for which recognized 'standards of care' have been available. However, developers of new therapies in all the three areas are affected by similar challenges: standards of care have become so strongly entrenched that traditional placebo-controlled studies in cystic fibrosis populations likely to benefit from newer therapies have become less and less feasible. Today, patients/clinicians are more likely to entertain participation in active-comparator trial designs, that have substantial challenges of their own. Foremost among these are the selection of 'valid' active comparator(s), estimation of a comparator's current clinical efficacy (required for testing noninferiority hypotheses), and effective blinding of commercially available comparators.
SUMMARY: Recent and future cystic fibrosis clinical trial designs will have to creatively address this collateral result of successful past development of effective cystic fibrosis therapies: patients and clinicians are much less likely to accept simple, placebo-controlled studies to evaluate future therapies.

PMID: 28708817 [PubMed - as supplied by publisher]

Chirp-Evoked Otoacoustic Emissions and Middle Ear Absorbance for Monitoring Ototoxicity in Cystic Fibrosis Patients.

Ear Hear. 2017 Jul 13;:

Authors: Garinis AC, Keefe DH, Hunter LL, Fitzpatrick DF, Putterman DB, McMillan GP, Gold JA, Feeney MP

Abstract
OBJECTIVES: The goal of this study was to investigate the use of transient-evoked otoacoustic emissions (TEOAEs) and middle ear absorbance measurements to monitor auditory function in patients with cystic fibrosis (CF) receiving ototoxic medications. TEOAEs were elicited with a chirp stimulus using an extended bandwidth (0.71 to 8 kHz) to measure cochlear function at higher frequencies than traditional TEOAEs. Absorbance over a wide bandwidth (0.25 to 8 kHz) provides information on middle ear function. The combination of these time-efficient measurements has the potential to identify early signs of ototoxic hearing loss.
DESIGN: A longitudinal study design was used to monitor the hearing of 91 patients with CF (median age = 25 years; age range = 15 to 63 years) who received known ototoxic medications (e.g., tobramycin) to prevent or treat bacterial lung infections. Results were compared to 37 normally hearing young adults (median age = 32.5 years; age range = 18 to 65 years) without a history of CF or similar treatments. Clinical testing included 226-Hz tympanometry, pure-tone air-conduction threshold testing from 0.25 to 16 kHz and bone conduction from 0.25 to 4 kHz. Experimental testing included wideband absorbance at ambient and tympanometric peak pressure and TEOAEs in three stimulus conditions: at ambient pressure and at tympanometric peak pressure using a chirp stimulus with constant incident pressure level across frequency and at ambient pressure using a chirp stimulus with constant absorbed sound power across frequency.
RESULTS: At the initial visit, behavioral audiometric results indicated that 76 of the 157 ears (48%) from patients with CF had normal hearing, whereas 81 of these ears (52%) had sensorineural hearing loss for at least one frequency. Seven ears from four patients had a confirmed behavioral change in hearing threshold for ≥3 visits during study participation. Receiver operating characteristic curve analyses demonstrated that all three TEOAE conditions were useful for distinguishing CF ears with normal hearing from ears with sensorineural hearing loss, with an area under the receiver operating characteristic curve values ranging from 0.78 to 0.92 across methods for frequency bands from 2.8 to 8 kHz. Case studies are presented to illustrate the relationship between changes in audiometric thresholds, TEOAEs, and absorbance across study visits. Absorbance measures permitted identification of potential middle ear dysfunction at 5.7 kHz in an ear that exhibited a temporary hearing loss.
CONCLUSIONS: The joint use of TEOAEs and absorbance has the potential to explain fluctuations in audiometric thresholds due to changes in cochlear function, middle ear function, or both. These findings are encouraging for the joint use of TEOAE and wideband absorbance objective tests for monitoring ototoxicity, particularly, in patients who may be too ill for behavioral hearing tests. Additional longitudinal studies are needed in a larger number of CF patients receiving ototoxic drugs to further evaluate the clinical utility of these measures in an ototoxic monitoring program.

PMID: 28708814 [PubMed - as supplied by publisher]

Epithelial Sodium Channel ENaC is a Modifier of the Long Term Non-progressive Phenotype Associated with F508del CFTR Mutations.

Am J Respir Cell Mol Biol. 2017 Jul 14;:

Authors: Agrawal PB, Wang R, Li HL, Schmitz-Abe K, Simone-Roach C, Chen J, Shi J, Louie T, Sheng S, Towne MC, Brainson CF, Matthay MA, Kim CF, Bamshad M, Emond MJ, Gerard NP, Kleyman TR, Gerard C

Abstract
BACKGROUND: Cystic Fibrosis (CF) remains the most lethal genetic disease in the Caucasian population. However, there is great variability of clinical phenotype and survival, even among patients harboring the same genotype. We identified five CF patients with a homozygous F508del mutation in the CFTR gene living in their 5th or 6th decade of life, all with minimal change in lung function over longitudinal period of more than 20 years. Because of the rarity of this long-term non-progressive phenotype, we hypothesized those individuals may carry rare genetic variants in modifier genes that ameliorate disease severity.
METHODS: Individuals at the extremes of survival time and lung function trajectory underwent whole exome sequencing, and the data was filtered for missense, stopgain, indel, and splicing variants present with mean allele frequency <0.2%, and their potential impact on protein function was evaluated. The mutations in δ-ENaC were generated via site-directed mutagenesis, and expressed to carry out Xenopus oocyte assay.
RESULTS: Four of the five individuals carried extremely rare or never reported variants in the SCNN1D and SCNN1B genes of the epithelial sodium channel (ENaC). Separately, an independently enriched rare variant in SCNN1D was identified in the exome variant server database associated with a milder pulmonary disease phenotype. Functional analysis using Xenopus oocytes revealed two of the three variants in δ-ENaC encoded by SCNN1D exhibited hypomorphic channel activity.
CONCLUSION: Our data suggest a potential role of δ-ENaC in control of the sodium reabsorption in the airways, and advance the plausibility of ENaC as a therapeutic target in CF.

PMID: 28708422 [PubMed - as supplied by publisher]

Association of Antibiotics, Airway Microbiome and Inflammation in Infants with Cystic Fibrosis.

Ann Am Thorac Soc. 2017 Jul 14;:

Authors: Pittman JE, Wylie KM, Akers K, Storch GA, Hatch J, Quante J, Frayman KB, Clarke N, Davis M, Stick SM, Hall GL, Montgomery G, Ranganathan S, Davis SD, Ferkol TW, AREST CF

Abstract
RATIONALE: The underlying defect in the cystic fibrosis (CF) airway leads to defective mucociliary clearance and impaired bacterial killing, resulting in endobronchial infection and inflammation that contributes to progressive lung disease. Little is known about the respiratory microbiota in the early CF airway and its relationship to inflammation.
OBJECTIVES: To examine the bacterial microbiota and inflammatory profiles in bronchoalveolar lavage fluid and oropharyngeal secretions in infants with CF.
METHODS: Infants with CF from U.S. and Australian centers were enrolled in a prospective, observational study examining the bacterial microbiota and inflammatory profiles of the respiratory tract. Bacterial diversity and density (load) were measured. Lavage samples were analyzed for inflammatory markers (interleukin-8, unbound neutrophil elastase, and absolute neutrophil count) in the epithelial lining fluid.
RESULTS: Thirty-two infants (mean age 4.7 months) underwent BAL and oropharyngeal sampling. Shannon diversity strongly correlated between upper and lower airway samples from a given subject, though community compositions differed. Microbial diversity was lower in younger subjects and in those receiving daily anti-staphylococcal antibiotic prophylaxis. In lavage samples, reduced diversity correlated strongly with lower interleukin-8 concentration and absolute neutrophil count.
CONCLUSIONS: In infants with CF, reduced bacterial diversity in the upper and lower airways was strongly associated with the use of prophylactic antibiotics and younger age at the time of sampling; less diversity in the lower airway correlated with lower inflammation on bronchoalveolar lavage. Our findings suggest modification of the respiratory microbiome in infants with CF may influence airway inflammation.

PMID: 28708417 [PubMed - as supplied by publisher]

Immunomodulatory Cell Therapy to Target Cystic Fibrosis Inflammation.

Am J Respir Cell Mol Biol. 2017 Jul 14;:

Authors: Khoury O, Barrios C, Ortega V, Atala A, Murphy SV

Abstract
Cystic fibrosis (CF) is associated with exaggerated and prolonged inflammation in the lungs, which contributes to lung injury, airway mucus obstruction, bronchiectasis and loss of lung function. This hyper-inflammatory phenotype appears to be caused by an imbalance between the pro- and anti-inflammatory regulatory pathways, with heightened pro-inflammatory stimuli, a decreased counter-regulatory response, and reduced effectiveness of immune cell function and inflammatory resolution. Thus, therapies that can target this inflammatory environment would have a major impact in preventing the progression of lung disease. Due to the complex phenotype of CF inflammation, current anti-inflammatory regimens have proven to be inadequate for the targeting of these multiple dysregulated pathways and effects. Several approaches utilizing cell therapies have shown potential therapeutic benefit for the treatment of CF inflammation. This review provides an overview of the immune dysfunctions in CF and current therapeutic regimens and explores the field of cell therapy as a treatment for CF inflammation, and focuses on the various cell types utilized, their immunomodulatory functions, and the current approaches to mitigate the inflammatory response and reduce the long-term damage for CF patients.

PMID: 28707978 [PubMed - as supplied by publisher]

Mycobacterium abscessus in patients with cystic fibrosis: low impact of inter-human transmission in Italy.

Eur Respir J. 2017 Jul;50(1):

Authors: Tortoli E, Kohl TA, Trovato A, Baldan R, Campana S, Cariani L, Colombo C, Costa D, Cristadoro S, Di Serio MC, Manca A, Pizzamiglio G, Rancoita PMV, Rossolini GM, Taccetti G, Teri A, Niemann S, Cirillo DM

PMID: 28705942 [PubMed - in process]