Bronchiectasis with secondary pulmonary infection in a child: A case report.

Medicine (Baltimore). 2020 Sep 25;99(39):e22475

Authors: Zhu T, Gu H, Vinturache A, Ding G, Lu M

Abstract
RATIONALE: Although bronchiectasis is conventionally considered a chronic pulmonary disease of adulthood, knowledge of pediatric bronchiectasis not related to cystic fibrosis started to emerge. Limited information in this field is available and the management is based on expert opinion.
PATIENT CONCERNS: An 8-year-old girl admitted for 7 days history of wet cough, purulent fetid sputum, shortness of breath and low-grade fever. The wet cough has presented for the past 4 years, during which she had frequent hospitalization for recurrent lower respiratory tract infections.
DIAGNOSIS: Chest high-resolution computerized tomography revealed diffuse bronchial dilations accompanied by inflammation in the bilateral lung fields. Microbiologic investigation for bronchoalveolar lavage fluid was positive for Pseudomonas aeruginosa.
INTERVENTIONS: With a working diagnosis of bronchiectasis with secondary pulmonary infection, sensitive cefoperazone-sulbactam was administrated for 14 days with gradual improvement of clinical symptoms. Bronchoscopy washing substantially soothed the symptoms, reducing the cough and sputum volumes.
OUTCOMES: The child was discharged after 14 days, and treated on long-term prophylactic antibiotic use (amoxicillin-clavulanic acid, 20 mg/kg/d, ≥ 4 weeks).
LESSONS: Although bronchiectasisis are condition in childhood, the diagnosis is suspected in children with persistent wet or productive cough, and should be confirmed by a chest high-resolution computerized tomography scan. Antibiotics and airway clearance techniques represent the milestones of bronchiectasis management although there are only a few guidelines in children.

PMID: 32991486 [PubMed - as supplied by publisher]

Scedosporium Cell Wall: From Carbohydrate-Containing Structures to Host-Pathogen Interactions.

Mycopathologia. 2020 Sep 29;:

Authors: Rollin-Pinheiro R, Xisto MIDDS, Rochetti VP, Barreto-Bergter E

Abstract
Scedosporium species are filamentous fungi usually found in sewage and soil from human-impacted areas. They cause a wide range of diseases in humans, from superficial infections, such as mycetoma, to invasive and disseminated cases, especially associated in immunocompromised patients. Scedosporium species are also related to lung colonization in individuals presenting cystic fibrosis and are considered one of the most frequent fungal pathogens associated to this pathology. Scedosporium cell wall contains glycosylated molecules involved in important biological events related to virulence and pathogenicity and represents a significant source of antigens. Polysaccharides, peptidopolysaccharides, O-linked oligosaccharides and glycosphingolipids have been identified on the Scedosporium surface. Their primary structures were determined based on a combination of techniques including gas chromatography, ESI-MS, and 1H and 13C nuclear magnetic resonance. Peptidorhamnnomannans are common cell wall components among Scedosporium species. Comparing different species, minor structural differences in the carbohydrate portions were detected which could be useful to understand variations in virulence observed among the species. N- and O-linked peptidorhamnomannans are major pathogen-associated molecular patterns and, along with α-glucans, play important roles in triggering host innate immunity. Glycosphingolipids, such as glucosylceramides, have highly conserved structures in Scedosporium species and are crucial for fungal growth and virulence. The present review presents current knowledge on structural and functional aspects of Scedosporium glycoconjugates that are relevant for understanding pathogenicity mechanisms and could contribute to the design of new agents capable of inhibiting growth and differentiation of Scedosporium species. Other cell components such as melanin and ectophosphatases will be also included.

PMID: 32990888 [PubMed - as supplied by publisher]

A 96-well format microvascularized human lung-on-a-chip platform for microphysiological modeling of fibrotic diseases.

Lab Chip. 2020 Sep 29;20(19):3601-3611

Authors: Mejías JC, Nelson MR, Liseth O, Roy K

Abstract
Development of organoids and microfluidic on-chip models has enabled studies of organ-level disease pathophysiologies in vitro. However, current lung-on-a-chip platforms are primarily monolayer epithelial-endothelial co-cultures, separated by a thin membrane, lacking microvasculature-networks or interstitial-fibroblasts. Here we report the design, microfabrication, and characterization of a unique microphysiological on-chip device that recapitulates the human lung interstitium-airway interface through a 3D vascular network, and normal or diseased fibroblasts encapsulated within a fibrin-collagen hydrogel underneath an airlifted airway epithelium. By incorporating fibroblasts from donors with idiopathic pulmonary fibrosis (IPF), or healthy-donor fibroblasts treated with TGF-β1, we successfully created a fibrotic, alpha smooth muscle actin (αSMA)-positive disease phenotype which led to fibrosis-like transformation in club cells and ciliated cells in the airway. Using this device platform, we further modeled the cystic fibrosis (CF) epithelium and recruitment of neutrophils to the vascular networks. Our results suggest that this microphysiological model of the human lung could enable more pathophysiologically relevant studies of complex pulmonary diseases.

PMID: 32990704 [PubMed - as supplied by publisher]

Skin-Interfaced Microfluidic Systems that Combine Hard and Soft Materials for Demanding Applications in Sweat Capture and Analysis.

Adv Healthc Mater. 2020 Sep 29;:e2000722

Authors: Choi J, Chen S, Deng Y, Xue Y, Reeder JT, Franklin D, Oh YS, Model JB, Aranyosi AJ, Lee SP, Ghaffari R, Huang Y, Rogers JA

Abstract
Eccrine sweat contains a rich blend of electrolytes, metabolites, proteins, metal ions, and other biomarkers. Changes in the concentrations of these chemical species can indicate alterations in hydration status and they can also reflect health conditions such as cystic fibrosis, schizophrenia, and depression. Recent advances in soft, skin-interfaced microfluidic systems enable real-time measurement of local sweat loss and sweat biomarker concentrations, with a wide range of applications in healthcare. Uses in certain contexts involve, however, physical impacts on the body that can dynamically deform these platforms, with adverse effects on measurement reliability. The work presented here overcomes this limitation through the use of microfluidic structures constructed in relatively high modulus polymers, and designed in geometries that offer soft, system level mechanics when embedded low modulus elastomers. Analytical models and finite element analysis quantitatively define the relevant mechanics of these systems, and serve as the basis for layouts optimized to allow robust operation in demanding, rugged scenarios such as those encountered in football, while preserving mechanical stretchability for comfortable, water-tight bonding to the skin. Benchtop testing and on-body field studies of measurements of sweat loss and chloride concentration under imposed mechanical stresses and impacts demonstrate the key features of these platforms.

PMID: 32989913 [PubMed - as supplied by publisher]

Factors Contributing to Vitamin D Status at Hospital Admission for Pulmonary Exacerbation in Adults With Cystic Fibrosis.

Am J Med Sci. 2020 Aug 20;:

Authors: Bhimavarapu A, Deng Q, Bean M, Lee N, Ziegler TR, Alvarez JA, Tangpricha V

Abstract
BACKGROUND: Individuals with cystic fibrosis (CF) have difficulty maintaining optimal vitamin D status due to pancreatic insufficiency-induced malabsorption, inadequate sunlight exposure, and poor intake of vitamin D containing foods. Vitamin D deficiency may increase the risk of pulmonary exacerbations of CF. The objective of this study was to assess factors impacting vitamin D status in patients with CF recently hospitalized for a pulmonary exacerbation of CF.
METHODS: This was a pre-planned analysis of vitamin D intake in patients enrolled in a multi-center, double-blind, randomized controlled study examining vitamin D therapy for pulmonary exacerbation of CF. Demographic information, responses from a habitual sun exposure questionnaire and food frequency questionnaire, and vitamin D supplement usage were queried and compared to serum 25-hydroxyvitamin D (25(OH)D) concentrations.
RESULTS: A total of 48 subjects were included in this analysis. Subjects were taking approximately 1,200 IU of vitamin D daily. Reported vitamin D intake, age, race, employment, and education were not significantly associated with vitamin D status in this population. However, smoking status, sunlight exposure in the last 3 years, and skin type (in the bivariate model) were all significantly associated with vitamin D status (all p<0.05).
CONCLUSIONS: Sunlight exposure was the most predictive determinant of vitamin D status in patients with CF prior to pulmonary exacerbation. Subjects reported vitamin D intake below the recommended amounts. The role and mode of optimizing vitamin D status prior to a pulmonary exacerbation needs further investigation.

PMID: 32988598 [PubMed - as supplied by publisher]

Effect of highly effective modulator therapy on quality of life in adults with cystic fibrosis.

Int Forum Allergy Rhinol. 2020 Sep 28;:

Authors: DiMango E, Spielman DB, Overdevest J, Keating C, Francis SF, Dansky D, Gudis DA

Abstract
BACKGROUND: Elexacaftor/tezacaftor/ivacaftor is a highly effective modulator that improves function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, resulting in improved pulmonary function in patients with cystic fibrosis (CF). We hypothesize that improvements in lung function are associated with improvements in health-related quality of life and sinonasal health. The aim of this study is to measure the effect of elexacaftor/tezacaftor/ivacaftor on patient-reported sinonasal and overall quality of life, and to determine the relationship between changes in these 2 outcome measures.
METHODS: A prospective cohort study was conducted at an accredited adult CF care center. Participants completed the 22-item Sino-Nasal Outcome Test (SNOT-22) and the Cystic Fibrosis Questionnaire-Revised (CFQ-R), a validated patient-reported outcome metric for CF patients, at baseline and at 3 months after initiation of elexacaftor/tezacaftor/ivacaftor.
RESULTS: Forty-three individuals completed the study. There was significant improvement in nearly all domains of the SNOT-22 and CFQ-R after 3 months of therapy. SNOT-22 improved from 34.8 to 24.4 (p = 0.000003). Mean baseline FEV-1 improved from 65% to 76% predicted (p = 0.0000005). The greatest effect was seen in those participants previously taking modulator therapy. Linear regression between the change in SNOT-22 individual domains and the CFQ-R respiratory domain revealed the strongest correlation between the extranasal domain score and the respiratory domain of the CFQ-R (R2 = 0.24).
CONCLUSION: CF patients taking elexacaftor/tezacaftor/ivacaftor experience a significant improvement in both sinonasal and health-related quality of life.

PMID: 32985756 [PubMed - as supplied by publisher]

Epithelial Barrier Properties of the 16HBE14o- Human Bronchial Epithelial Cell Culture Model.

Biosci Rep. 2020 Sep 28;:

Authors: Callaghan P, Ferrick B, Rybakovsky E, Thomas S, Mullin J

Abstract
The human bronchial epithelial cell line, 16HBE14o- (16HBE), is widely used as a model for respiratory epithelial diseases and barrier function. During differentiation, transepithelial electrical resistance (TER) increased to approximately 800 ohms x cm2 while 14C-D-mannitol flux rates (Jm) simultaneously decreased. Tight junctions were shown by diffusion potential studies to be anion selective with PC1/PNa = 1.9. Transepithelial leakiness could be induced by the phorbol ester, protein kinase C activator, 12-O-tetradecanoylphorbol-13-acetate (TPA), and the proinflammatory cytokine, Tumor Necrosis Factor-α (TNF-α). Basal barrier function could not be improved by the micronutrients, zinc or quercetin. Of methodological significance, TER was observed to be more variable and to spontaneously, significantly decrease after initial barrier formation, whereas Jm did not significantly fluctuate or increase. Unlike the strong inverse relationship between TER and Jm during differentiation, differentiated cell layers manifested no relationship between TER and Jm. There was also much greater variability for TER values compared to Jm. Investigating the dependence of 16HBE TER on transcellular ion conductance, inhibition of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) chloride channel with GlyH-101 produced a large decrease in short circuit current (Isc) and a slight increase in TER, but no significant change in Jm. A strong temperature dependence was observed not only for Isc, but also for TER. In summary, research utilizing 16HBE as a model in airway barrier function studies needs to be aware of the complexity of TER as a parameter of barrier function given the influence of CFTR-dependent transcellular conductance on TER.

PMID: 32985670 [PubMed - as supplied by publisher]

Antibacterial and antibiofilm activities of ceragenins against Achromobacter species isolated from cystic fibrosis patients.

J Chemother. 2020 Sep 26;:1-12

Authors: Damar-Çelik D, Mataracı-Kara E, Savage PB, Özbek-Çelik B

Abstract
Achromobacter species, which are recognized as emerging pathogens isolated from patients with cystic fibrosis, are capable of forming biofilm in the respiratory tract in patients and innate multidrug resistance to antimicrobials. CSAs are cationic salt derivatives that mimic the activity of antimicrobial peptides and exhibit antimicrobial activity against bacteria. In this study, the in vitro activities of various ceragenins against Achromobacter-species biofilms were investigated comparatively with a conventional antibiotic (meropenem). Biofilm-formation inhibition and biofilm-adhesion inhibition were investigated on five strong biofilm-producing strains. The lowest MIC50 result was obtained with CSA-13. All of the tested CSAs showed significant biofilm inhibitory activity in the manner of a time- and concentration-dependent effect. To the best of our knowledge, this is the first article to evaluate the antibacterial and antibiofilm activities of tested CSAs against Achromobacter species.

PMID: 32985386 [PubMed - as supplied by publisher]

Inpatient Mortality According to Level of Respiratory Support Received for Severe Acute Respiratory Syndrome Coronavirus 2 (Coronavirus Disease 2019) Infection: A Prospective Multicenter Study.

Crit Care Explor. 2020 Sep;2(9):e0220

Authors: Palazzuoli A, Ruberto F, De Ferrari GM, Forleo G, Secco GG, Ruocco GM, D'Ascenzo F, Mojoli F, Monticone S, Paggi A, Vicenzi M, Corcione S, Palazzo AG, Landolina M, Taravelli E, Tavazzi G, Blasi F, Mancone M, Birtolo LI, Alessandri F, Infusino F, Pugliese F, Fedele F, De Rosa FG, Emmett M, Schussler JM, McCullough PA, Tecson KM

Abstract
Objectives: To describe patients according to the maximum degree of respiratory support received and report their inpatient mortality due to coronavirus disease 2019.
Design: Analysis of patients in the Coracle registry from February 22, 2020, to April 1, 2020.
Setting: Hospitals in the Piedmont, Lombardy, Tuscany, and Lazio regions of Italy.
Patients: Nine-hundred forty-eight patients hospitalized for coronavirus disease 2019.
Interventions: None.
Measurements and Main Results: Among 948 patients, 122 (12.87%) received invasive ventilation, 637 (67.19%) received supplemental oxygen only, and 189 (19.94%) received no respiratory support. The median (quartile 1-quartile 3) age was 65 years (54-76.59 yr), and there was evidence of differential respiratory treatment by decade of life (p = 0.0046); patients greater than 80 years old were generally not intubated. There were 606 men (63.9%) in this study, and they were more likely to receive respiratory support than women (p < 0.0001). The rate of in-hospital death for invasive ventilation recipients was 22.95%, 12.87% for supplemental oxygen recipients, and 7.41% for those who received neither (p = 0.0004). A sensitivity analysis of the 770 patients less than 80 years old revealed a lower, but similar mortality trend (18.02%, 8.10%, 5.23%; p = 0.0008) among the 14.42%, 65.71%, and 19.87% of patients treated with mechanical ventilation, supplemental oxygen only, or neither. Overall, invasive ventilation recipients who died were significantly older than those who survived (median age: 68.5 yr [60-81.36 yr] vs 62.5 yr [55.52-71 yr]; p = 0.0145).
Conclusions: Among patients hospitalized for coronavirus disease 2019, 13% received mechanical ventilation, which was associated with a mortality rate of 23%.

PMID: 32984838 [PubMed]

Physical activity for cystic fibrosis: perceptions of people with cystic fibrosis, parents and healthcare professionals.

ERJ Open Res. 2020 Jul;6(3):

Authors: Denford S, Cox NS, Mackintosh KA, McNarry MA, O'Halloran P, Holland AE, Tomlinson OW, Barker AR, Williams CA

Abstract
Background: The benefits of physical activity (PA) for people with cystic fibrosis (pwCF) are widely accepted, yet how PA is promoted and utilised by pwCF is unclear.
Method: An online questionnaire to explore attitudes, practices and promotion of PA in cystic fibrosis was completed by healthcare providers (HCP), pwCF and parents/caregivers.
Results: 351 respondents (105 HCP, 120 pwCF, and 126 parents/caregivers) from 12 countries completed the survey. Importance of PA was rated highly by the majority of respondents. Physical (e.g. health), psychological (e.g. enjoyment) and social (e.g. social interaction) factors were motives for PA for 82%, 49% and 37% of pwCF, respectively, irrespective of country. Common barriers to PA included time (49% and 36%) and tiredness (61% and 7%) for pwCF and parents/carers, respectively. pwCF also reported psychosocial barriers (e.g. stigma, demoralisation), while parents/caregivers reported structural barriers (e.g. cost). Clinical teams varied substantially in terms of the emphasis placed on PA, facilities available, staff and training, and advice given to pwCF.
Conclusion: Despite the majority of participants rating the importance of PA highly, substantial variability was evident regarding the facilities and clinical support available to them, as well as why and how people were active. There remains a need to identify what constitutes "best practice" for PA promotion within clinics.

PMID: 32984419 [PubMed]

A TLR2-Activating Fraction From Mycobacterium abscessus Rough Variant Demonstrates Vaccine and Diagnostic Potential.

Front Cell Infect Microbiol. 2020;10:432

Authors: Le Moigne V, Roux AL, Jobart-Malfait A, Blanc L, Chaoui K, Burlet-Schiltz O, Gaillard JL, Canaan S, Nigou J, Herrmann JL

Abstract
Mycobacterium abscessus is a prevalent pathogenic mycobacterium in cystic fibrosis (CF) patients and one of the most highly drug resistant mycobacterial species to antimicrobial agents. It possesses the property to transition from a smooth (S) to a rough (R) morphotype, thereby influencing the host innate immune response. This transition from the S to the R morphotype takes place in patients with an exacerbation of the disease and a persistence of M. abscessus. We have previously shown that the exacerbation of the Toll-like receptor 2 (TLR2)-mediated inflammatory response, following this S to R transition, is essentially due to overproduction of bacilli cell envelope surface compounds, which we were able to extract by mechanical treatment and isolation by solvent partition in a fraction called interphase. Here, we set up a purification procedure guided by bioactivity to isolate a fraction from the R variant of M. abscessus cells which exhibits a high TLR2 stimulating activity, referred to as TLR2-enriched fraction (TLR2eF). As expected, TLR2eF was found to contain several lipoproteins and proteins known to be stimuli for TLR2. Vaccination with TLR2eF showed no protection toward an M. abscessus aerosol challenge, but provided mild protection in ΔF508 mice and their FVB littermates when intravenously challenged by M. abscessus. Interestingly however, antibodies against TLR2eF compounds were detected during disease in CF patients. In conclusion, we show the potential for compounds in TLR2eF as vaccine and diagnostic candidates, in order to enhance diagnosis, prevent and/or treat M. abscessus-related infections.

PMID: 32984067 [PubMed - in process]

Mycobacterium abscessus Infection after Breast Lipotransfer: A Report of 2 Cases.

Plast Reconstr Surg Glob Open. 2020 Aug;8(8):e3063

Authors: Miguel Escuredo I, Vicario Elorduy E, Guío Carrión L, Elvira Segura J, Iraurgui Arcarazo P, García Gutiérrez JJ

Abstract
Mycobacterium abscessus is a rare, non-tuberculous, rapidly growing mycobacterium. Although it has been usually associated with chronic pulmonary infections in cystic fibrosis patients, the second most frequent infection sites are the skin and subcutaneous tissue. Most of the cutaneous infections described in the literature occur secondary to cosmetic invasive procedures, many of them in the context of medical tourism. Its atypical presentation and antibiotic-resistant nature make its diagnosis and therapeutics challenging. In this case report, we present 2 cases of M. abscessus infections secondary to breast lipotransfer reported in the same private center. Case 1 patient underwent surgery to treat scar contracture resulting from previous quadrantectomy. Case 2 patient underwent breast augmentation with lipotransfer. Both of them developed lesions in the breast and in the donor site (abdomen). The therapeutic regimen used was amikacin (1 g/24 h) + tigecycline (50 mg/12 h). In case 1, we performed a simple mastectomy, and in case 2, periodical ultrasound-guided drainages were performed as additional procedures. To our knowledge, these are the first 2 cases that describe an infection secondary to breast lipotransfer. The aim of our report was to illustrate the presentation, diagnosis, therapeutic management, and strategies available to prevent this complication.

PMID: 32983807 [PubMed]

Predicting Antibiotic-Associated Virulence of Pseudomonas aeruginosa Using an ex vivo Lung Biofilm Model.

Front Microbiol. 2020;11:568510

Authors: Hassan MM, Harrington NE, Sweeney E, Harrison F

Abstract
Background: Bacterial biofilms are known to have high antibiotic tolerance which directly affects clearance of bacterial infections in people with cystic fibrosis (CF). Current antibiotic susceptibility testing methods are either based on planktonic cells or do not reflect the complexity of biofilms in vivo. Consequently, inaccurate diagnostics affect treatment choice, preventing bacterial clearance and potentially selecting for antibiotic resistance. This leads to prolonged, ineffective treatment.
Methods: In this study, we use an ex vivo lung biofilm model to study antibiotic tolerance and virulence of Pseudomonas aeruginosa. Sections of pig bronchiole were dissected, prepared and infected with clinical isolates of P. aeruginosa and incubated in artificial sputum media to form biofilms, as previously described. Then, lung-associated biofilms were challenged with antibiotics, at therapeutically relevant concentrations, before their bacterial load and virulence were quantified and detected, respectively.
Results: The results demonstrated minimal effect on the bacterial load with therapeutically relevant concentrations of ciprofloxacin and meropenem, with the latter causing an increased production of proteases and pyocyanin. A combination of meropenem and tobramycin did not show any additional decrease in bacterial load but demonstrated a slight decrease in total proteases and pyocyanin production.
Conclusion: In this initial study of six clinical isolates of P. aeruginosa showed high levels of antibiotic tolerance, with minimal effect on bacterial load and increased proteases production, which could negatively affect lung function. Thus, the ex vivo lung model has the potential to be effectively used in larger studies of antibiotic tolerance in in vivo-like biofilms, and show how sub optimal antibiotic treatment of biofilms may potentially contribute to exacerbations and eventual lung failure. We demonstrate a realistic model for understanding antibiotic resistance and tolerance in biofilms clinically and for molecules screening in anti-biofilm drug development.

PMID: 32983077 [PubMed]

Combined Bacteriophage and Antibiotic Treatment Prevents Pseudomonas aeruginosa Infection of Wild Type and cftr- Epithelial Cells.

Front Microbiol. 2020;11:1947

Authors: Luscher A, Simonin J, Falconnet L, Valot B, Hocquet D, Chanson M, Resch G, Köhler T, van Delden C

Abstract
With the increase of infections due to multidrug resistant bacterial pathogens and the shortage of antimicrobial molecules with novel targets, interest in bacteriophages as a therapeutic option has regained much attraction. Before the launch of future clinical trials, in vitro studies are required to better evaluate the efficacies and potential pitfalls of such therapies. Here we studied in an ex vivo human airway epithelial cell line model the efficacy of phage and ciprofloxacin alone and in combination to treat infection by Pseudomonas aeruginosa. The Calu-3 cell line and the isogenic CFTR knock down cell line (cftr-) infected apically with P. aeruginosa strain PAO1 showed a progressive reduction in transepithelial resistance during 24 h. Administration at 6 h p.i. of single phage, phage cocktails or ciprofloxacin alone prevented epithelial layer destruction at 24 h p.i. Bacterial regrowth, due to phage resistant mutants harboring mutations in LPS synthesis genes, occurred thereafter both in vitro and ex vivo. However, co-administration of two phages combined with ciprofloxacin efficiently prevented PAO1 regrowth and maintained epithelial cell integrity at 72 p.i. The phage/ciprofloxacin treatment did not induce an inflammatory response in the tested cell lines as determined by nanoString® gene expression analysis. We conclude that combination of phage and ciprofloxacin efficiently protects wild type and cftr- epithelial cells from infection by P. aeruginosa and emergence of phage resistant mutants without inducing an inflammatory response. Hence, phage-antibiotic combination should be a safe and promising anti-Pseudomonas therapy for future clinical trials potentially including cystic fibrosis patients.

PMID: 32983005 [PubMed]

The Role of Specialized Pro-Resolving Mediators in Cystic Fibrosis Airways Disease.

Front Pharmacol. 2020;11:1290

Authors: Briottet M, Shum M, Urbach V

Abstract
Cystic Fibrosis (CF) is a recessive genetic disease due to mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene encoding the CFTR chloride channel. The ion transport abnormalities related to CFTR mutation generate a dehydrated airway surface liquid (ASL) layer, which is responsible for an altered mucociliary clearance, favors infections and persistent inflammation that lead to progressive lung destruction and respiratory failure. The inflammatory response is normally followed by an active resolution phase to return to tissue homeostasis, which involves specialized pro-resolving mediators (SPMs). SPMs promote resolution of inflammation, clearance of microbes, tissue regeneration and reduce pain, but do not evoke unwanted immunosuppression. The airways of CF patients showed a decreased production of SPMs even in the absence of pathogens. SPMs levels in the airway correlated with CF patients' lung function. The prognosis for CF has greatly improved but there remains a critical need for more effective treatments that prevent excessive inflammation, lung damage, and declining pulmonary function for all CF patients. This review aims to highlight the recent understanding of CF airway inflammation and the possible impact of SPMs on functions that are altered in CF airways.

PMID: 32982730 [PubMed]

Neutrophil elastase promotes macrophage cell adhesion and cytokine production through the integrin-Src kinases pathway.

Sci Rep. 2020 Sep 28;10(1):15874

Authors: Krotova K, Khodayari N, Oshins R, Aslanidi G, Brantly ML

Abstract
There are a number of respiratory diseases characterized by the presence of excess neutrophil elastase (NE) activity in tissues, including cystic fibrosis and chronic obstructive pulmonary disease (COPD). NE is considered a primary contributor to disease development, but the precise mechanism has yet to be fully determined. We hypothesized that NE alters the function of macrophages (Mɸ) which play a critical role in many physiological processes in healthy lungs. We demonstrate that monocyte-derived Mɸ exposed to NE releases active matrix metalloproteinases (MMPs), increase expression of pro-inflammatory cytokines TNFα, IL-1β, and IL-8, and reduce capacity to phagocytose bacteria. Changes in Mɸ function following NE treatment were accompanied by increased adhesion and cytoskeleton re-arrangement, indicating the possibility of integrin involvement. To support this observation, we demonstrate that NE induces phosphorylation of kinases from the Src kinase family, a hallmark of integrin signaling activation. Moreover, pretreatment of Mɸ with a specific Src kinase inhibitor, PP2 completely prevents NE-induced pro-inflammatory cytokine production. Taken together these findings indicate that NE participates in lung destruction not only through direct proteolytic degradation of matrix proteins, but also through activation of Mɸ inflammatory and proteolytic functions.

PMID: 32981934 [PubMed - in process]

Abnormal glucose tolerance in a pediatric cystic fibrosis cohort: Trends in clinical outcomes and associated factors in the preceding years.

Nutr Metab Cardiovasc Dis. 2020 Aug 08;:

Authors: Nguyen CQT, Denis MH, Chagnon M, Rabasa-Lhoret R, Mailhot G

Abstract
BACKGROUND AND AIMS: Deterioration of anthropometric and lung function parameters was shown to precede the onset of cystic fibrosis-related diabetes (CFRD) in adults. In children, studies have been conducted in small cohorts with relatively short observation period. Study objectives were to document the longitudinal trends of anthropometric, pulmonary, nutritional and metabolic parameters from cystic fibrosis (CF) diagnosis to the ascertainment of abnormal glucose tolerance and identify parameters associated with the incidence of such abnormalities in a pediatric CF cohort.
METHODS AND RESULTS: Retrospective cohort study of 281 children with CF. Longitudinal trends of anthropometric, lung function, nutritional and metabolic data were generated from CF diagnosis to the ascertainment of abnormal glucose tolerance defined as the presence of either impaired glucose tolerance (IGT), unconfirmed CFRD or CFRD. Cox models and Kaplan-Meier curves were used to identify factors associated with developing abnormal glucose tolerance. Forty-five percent of cohort had normal glucose tolerance (NGT), 27% IGT, 10% unconfirmed CFRD and 18% CFRD. Children who developed CFRD displayed lower height z-scores from a very early age. Conversely, HbA1c levels began to rise closer to CFRD ascertainment. Height z-scores (HR: 0.45; CI 95% [0.29-0.69]) and HbA1c (HR: 2.43; CI 95% [1.86-3.18]) in years preceding ascertainment were associated with the risk of developing CFRD.
CONCLUSION: Children who developed CFRD display distinctive trends for height z-scores from a very early age, whereas HbA1c appears as a marker of established glucose metabolism derangements.

PMID: 32981797 [PubMed - as supplied by publisher]

More data are needed about vitamin D supplements in pregnancy and infancy including any impact on allergies.

Acta Paediatr. 2020 Sep 26;:

Authors: Douros K, Loukou I, Tsabouri S

Abstract
The rising prevalence in allergies over the last few decades appears to be a global epidemic. Although we still lack a concise, robust model to adequately interpret this phenomenon, the available evidence points to the role of an increasingly urban and westernised lifestyle. This includes vitamin D deficiency, which is due to staying indoors most of the time without adequate exposure to sunlight and has been identified as one of the contributing risk factors in rising allergy rates. Indeed, a growing body of evidence has suggested that vitamin D deficiency is implicated in the pathogenesis of allergic disorders, although its role is not clear and is open to debate. Vitamin D prophylaxis has already produced excellent results in other areas, for example in reducing the prevalence of rickets.

PMID: 32979876 [PubMed - as supplied by publisher]

The Pseudomonas aeruginosa protease LasB directly activates IL-1β.

EBioMedicine. 2020 Sep 23;60:102984

Authors: Sun J, LaRock DL, Skowronski EA, Kimmey JM, Olson J, Jiang Z, O'Donoghue AJ, Nizet V, LaRock CN

Abstract
BACKGROUND: Pulmonary damage by Pseudomonas aeruginosa during cystic fibrosis lung infection and ventilator-associated pneumonia is mediated both by pathogen virulence factors and host inflammation. Impaired immune function due to tissue damage and inflammation, coupled with pathogen multidrug resistance, complicates the management of these deep-seated infections. Pathological inflammation during infection is driven by interleukin-1β (IL-1β), but the molecular processes involved are not fully understood.
METHODS: We examined IL-1β activation in a pulmonary model infection of Pseudomonas aeruginosa and in vitro using genetics, specific inhibitors, recombinant proteins, and targeted reporters of protease activity and IL-1β bioactivity.
FINDINGS: Caspase-family inflammasome proteases canonically regulate maturation of this proinflammatory cytokine, but we report that plasticity in IL-1β proteolytic activation allows for its direct maturation by the pseudomonal protease LasB. LasB promotes IL-1β activation, neutrophilic inflammation, and destruction of lung architecture characteristic of severe P. aeruginosa pulmonary infection.
INTERPRETATION: Preservation of lung function and effective immune clearance may be enhanced by selectively controlling inflammation. Discovery of this IL-1β regulatory mechanism provides a distinct target for anti-inflammatory therapeutics, such as matrix metalloprotease inhibitors that inhibit LasB and limit inflammation and pathology during P. aeruginosa pulmonary infections.
FUNDING: Full details are provided in the Acknowledgements section.

PMID: 32979835 [PubMed - as supplied by publisher]

The different anion transport capability of prodiginine- and tambjamine-like molecules.

Eur J Pharmacol. 2020 Sep 23;:173592

Authors: Fiore M, García-Valverde M, Carreira-Barral I, Moran O

Abstract
Prodiginines and tambjamines are anion-selective ionophores capable of facilitating the transport of anions across the plasma membrane in mammalian cells. One of the potential applications of these anionophores is the possibility of employing them as a substitutive therapy for pathologies involving anion channels, as in cystic fibrosis. We have studied the interaction of a large anion as gluconate with three prodiginine- and two tambjamine-like compounds. Apparent dissociation constants for the chloride, iodide and gluconate complexes were estimated from iodide influx experiments in mammalian cells exposed to different extracellular anion combinations. Our experiments indicate that gluconate is not transported by the prodiginines, leaving the anionophores free to transport chloride and iodide. Conversely, gluconate would be transported to some extent by the tambjamines, competing with halides for the anionophores, and consequently reducing their flux. This might be related to the different structural features of both families of compounds. These data have important implications for the selection of impermeable anions in the analysis of the anionophore mechanism.

PMID: 32979354 [PubMed - as supplied by publisher]