Reduced Intestinal Inflammation with Lumacaftor/Ivacaftor in Adolescents with Cystic Fibrosis.

J Pediatr Gastroenterol Nutr. 2020 Jul 30;:

Authors: Tétard C, Mittaine M, Bui S, Beaufils F, Maumus P, Fayon M, Burgel PR, Lamireau T, Delhaes L, Mas E, Enaud R

Abstract
A chronic intestinal inflammation may occur in patients with cystic fibrosis (CF), while no therapeutic management is proposed. While Lumacaftor/Ivacaftor is well-known to modulate the defective cystic fibrosis transmembrane conductance regulator (CFTR) protein in lungs, no data are available on the impact of this treatment on CF intestinal disorders. We therefore investigated the evolution of intestinal inflammation after initiation of Lumacaftor/Ivacaftor in CF adolescents (median of follow-up: 336 days (IQR: 278;435)). Median fecal calprotectin concentrations decreased significantly after Lumacaftor/Ivacaftor initiation (102 μg/g (IQR: 69;210)) compared to the baseline (713 μg/g (IQR:148;852), p = 0.001). To our knowledge, this study showed for the first time that CF-related intestinal inflammation is improved by Lumacaftor/Ivacaftor treatment.

PMID: 32740537 [PubMed - as supplied by publisher]

Cystic Fibrosis-Related Liver Disease: The Next Challenge.

J Pediatr Gastroenterol Nutr. 2020 Jul 30;:

Authors: Baker RD, Baker SS

Abstract
Up to 40% of individuals with cystic fibrosis have Cystic Fibrosis-Related Liver Disease (CFLD); however, only 5-10% will have clinically evident disease. With the introduction of powerful cystic fibrosis transmembrane conductance regulator (CFTR) enhancers effective treatment for cystic fibrosis is available. The role of CFTR enhancers in liver disease is unknown at this time. The traditionally accepted theory of the pathogenesis of CFLD is being questioned. A different pathogenesis may lead to new ways to treat CFLD. The way that CFLD is diagnosed and monitored is evolving as new imaging technology become available.

PMID: 32740535 [PubMed - as supplied by publisher]

Extended Screening for Cystic Fibrosis Related Liver Disease Including Elastography Inchildren and Adolescents.

J Pediatr Gastroenterol Nutr. 2020 Jul 28;:

Authors: Højte C, Jørgensen MH, Jensen F, Katzenstein TL, Skov M

Abstract
OBJECTIVES: Advances in treatment of cystic fibrosis (CF) have increased survival and thereby prevalence of patients with liver disease, making chronic liver disease one of the major complications of CF. We describe the prevalence of liver fibrosis, portal hypertension, and liver decompensation by extended screening for cystic fibrosis related liver disease (CFLD) including ultrasound, elastography, and an extended panel of biochemical markers.
METHODS: A cross sectional study of CFLD in all pediatric CF patients (1-18 years) from the Copenhagen CF Center. Screening for liver disease included physical examination, biochemical analysis, Vibration-Controlled Transient Elastography (FibroScan), conventional ultrasound, and Real-Time Shear Wave elastography (SWE). Patients were scored according to Williams' ultrasound scoring scale (WUSS) within six months.
RESULTS: A total of 84 consecutive patients (male sex 46.4%, median age 10.4 years) were included. Eight patients (9.5%) had both ≥ two abnormal results of sonographic methods and ≥ two abnormal biochemical results and were in this study categorized as having manifest CFLD. Manifest CFLD patients were significantly older and had a higher mean value of APRI, but no differences in gender, z-height, z-weight, z-BMI, FEV1% or mean value of bilirubin or albumin were found.
CONCLUSIONS: In total eight patients (9.5%) in this pediatric CF population were categorized as having CFLD according to both biochemical and sonographic tests. Consistency was found among the results of FibroScan and SWE. We suggest WUSS and either FibroScan or SWE, combined with GGT as diagnostic markers for CFLD.

PMID: 32740524 [PubMed - as supplied by publisher]

Aminoglycosides in critically ill patients: which dosing regimens for which pathogens?

Int J Antimicrob Agents. 2020 Jul 30;:106124

Authors: Marsot A, Hraiech S, Cassir N, Daviet F, Parzy G, Blin O, Papazian L, Guilhaumou R

Abstract
BACKGROUND: Modifications of antibiotics pharmacokinetics parameters have been reported in critically ill patients, resulting in a risk of treatment failure. We aimed to determine optimized amikacin (AMK), gentamicin (GEN) and tobramycin (TOB) intravenous dosing regimens in this population.
METHODS: Patients admitted to medical ICU and treated with AMK, GEN or TOB were included. Analyses were realized using a parametric population approach. Monte-Carlo simulations were performed and the probability of target attainment (PTA) was calculated using Cmax/MIC≥8 and through concentrations as targets.
RESULTS: 117 critically ill patients hospitalized, were studied. Median values of clearance (interidividual variability, ɷ2) were 3.51 L/h (0.539), 3.53 L/h (0.297), 2.70 L/h (0.339) and 5.07 L/h (0.339) for AMK, GEN, TOB and TOB with cystic fibrosis (CF), respectively. Median values of central volume of distribution were 30.2 L (0.215), 20.0 L (0.109) and 25.6 L (0.177) for AMK, GEN and TOB, respectively. Simulations showed that doses should be adjusted to the actual body weight and creatinine clearance for AMK and GEN, and according to creatinine clearance and presence of CF for TOB.
CONCLUSION: Our recommendations for treating P. aeruginosa infections in this population include using initial doses of 35mg/kg for AMK or 10mg/kg for TOB (CF and non CF patients). GEN demonstrated the best rates of target attainment against S. aureus infections with a dose of 5mg/kg. High aminoglycosides doses are required in this population, efficacy and safety targets are then conflicting andTDM remain an important tool to deal with this issue.

PMID: 32739478 [PubMed - as supplied by publisher]

Cystic fibrosis and amyotrophic lateral sclerosis, an unexpected association.

Pulmonology. 2020 Jul 29;:

Authors: Jacob M, Cardoso CG, Redondo M, Gonçalves M, Pinto M, Amorim A

PMID: 32739328 [PubMed - as supplied by publisher]

COVID-19 in Severe Asthma Network in Italy (SANI) patients: clinical features, impact of comorbidities and treatments.

Allergy. 2020 Aug 01;:

Authors: Heffler E, Detoraki A, Contoli M, Papi A, Paoletti G, Malipiero G, Brussino L, Crimi C, Morrone D, Padovani M, Guida G, Gerli AG, Centanni S, Senna G, Paggiaro P, Blasi F, Canonica GW, SANI Working Group

PMID: 32738147 [PubMed - as supplied by publisher]

PAN-selective inhibition of cAMP-phosphodiesterase 4 (PDE4) induces gastroparesis in mice.

FASEB J. 2020 Aug 01;:

Authors: McDonough W, Aragon IV, Rich J, Murphy JM, Abou Saleh L, Boyd A, Koloteva A, Richter W

Abstract
Inhibitors of cAMP-phosphodiesterase 4 (PDE4) exert a number of promising therapeutic benefits, but adverse effects, in particular emesis and nausea, have curbed their clinical utility. Here, we show that PAN-selective inhibition of PDE4, but not inhibition of PDE3, causes a time- and dose-dependent accumulation of chow in the stomachs of mice fed ad libitum without changing the animals' food intake or the weight of their intestines, suggesting that PDE4 inhibition impairs gastric emptying. Indeed, PDE4 inhibition induced gastric retention in an acute model of gastric motility that traces the passage of a food bolus through the stomach over a 30 minutes time period. In humans, abnormal gastric retention of food is known as gastroparesis, a syndrome predominated by nausea (>90% of cases) and vomiting (>80% of cases). We thus explored the abnormal gastric retention induced by PDE4 inhibition in mice under the premise that it may represent a useful correlate of emesis and nausea. Delayed gastric emptying was produced by structurally distinct PAN-PDE4 inhibitors including Rolipram, Piclamilast, Roflumilast, and RS25344, suggesting that it is a class effect. PDE4 inhibitors induced gastric retention at similar or below doses commonly used to induce therapeutic benefits (e.g., 0.04 mg/kg Rolipram), thus mirroring the narrow therapeutic window of PDE4 inhibitors in humans. YM976, a PAN-PDE4 inhibitor that does not efficiently cross the blood-brain barrier, induced gastroparesis only at significantly higher doses (≥1 mg/kg). This suggests that PDE4 inhibition may act in part through effects on the autonomic nervous system regulation of gastric emptying and that PDE4 inhibitors that are not brain-penetrant may have an improved safety profile. The PDE4 family comprises four subtypes, PDE4A, B, C, and D. Selective ablation of any of these subtypes in mice did not induce gastroparesis per se, nor did it protect from PAN-PDE4 inhibitor-induced gastroparesis, indicating that gastric retention may result from the concurrent inhibition of multiple PDE4s. Thus, potentially, any of the four PDE4 subtypes may be targeted individually for therapeutic benefits without inducing nausea or emesis. Acute gastric retention induced by PDE4 inhibition is alleviated by treatment with the widely used prokinetic Metoclopramide, suggesting a potential of this drug to alleviate the side effects of PDE4 inhibitors. Finally, given that the cause of gastroparesis remains largely idiopathic, our findings open the possibility that a physiologic or pathophysiologic downregulation of PDE4 activity/expression may be causative in a subset of patients.

PMID: 32738081 [PubMed - as supplied by publisher]

A comprehensive review of therapeutic approaches available for the treatment of cholera.

J Pharm Pharmacol. 2020 Jul 31;:

Authors: Sousa FBM, Nolêto IRSG, Chaves LS, Pacheco G, Oliveira AP, Fonseca MMV, Medeiros JVR

Abstract
OBJECTIVES: The oral rehydration solution is the most efficient method to treat cholera; however, it does not interfere in the action mechanism of the main virulence factor produced by Vibrio cholerae, the cholera toxin (CT), and this disease still stands out as a problem for human health worldwide. This review aimed to describe therapeutic alternatives available in the literature, especially those related to the search for molecules acting upon the physiopathology of cholera.
KEY FINDINGS: New molecules have offered a protection effect against diarrhoea induced by CT or even by infection from V. cholerae. The receptor regulator cystic fibrosis channel transmembrane (CFTR), monosialoganglioside (GM1), enkephalinase, AMP-activated protein kinase (AMPK), inhibitors of expression of virulence factors and activators of ADP-ribosylarginine hydrolase are the main therapeutic targets studied. Many of these molecules or extracts still present unclear action mechanisms.
CONCLUSIONS: Knowing therapeutic alternatives and their molecular mechanisms for the treatment of cholera could guide us to develop a new drug that could be used in combination with the rehydration solution.

PMID: 32737883 [PubMed - as supplied by publisher]

Mindfulness moderates the relationship between emotional eating and body mass index in a sample of people with cystic fibrosis.

Eat Weight Disord. 2020 Jul 31;:

Authors: Egan H, Keyte R, Nash EF, Barrett J, Regan A, Mantzios M

Abstract
PURPOSE: Self-regulation in eating is significant for enhancing life expectancy of people with cystic fibrosis (CF), but research with this population is scarce.
METHODS: In a cross-sectional study, adults with CF completed a number of psychometric scales exploring typical eating behaviours that may increase calorific intake including motivations to eat palatable foods and scales that may be associated with decreased calorific intake: mindfulness, mindful eating and self-compassion.
RESULTS: Findings suggested that motivations to eat palatable foods and eating behaviours correlate with higher BMI, while mindfulness, mindful eating and self-compassion did not reach significance. Mindfulness and mindful eating moderated the relationship between emotional eating and BMI, while self-compassion did not moderate this relationship.
CONCLUSIONS: There is a need to develop healthy and effective means of enhancing calorific intake, where this is indicated, adapting mindful eating principles to focus on increasing both self-regulation and pleasure in eating while reducing emotional eating may be one means of doing this.
LEVEL OF EVIDENCE: Level V, cross-sectional descriptive study.

PMID: 32737812 [PubMed - as supplied by publisher]

DIGEST: Developing innovative gastroenterology specialty training.

J Cyst Fibros. 2020 Jul 28;:

Authors: Lusman SS, Borowitz D, Marshall BC, Narkewicz MR, Gonska T, Grand RJ, Simon RH, Mascarenhas MR, Schwarzenberg SJ, Freedman SD

Abstract
Individuals with cystic fibrosis (CF) now have an increased life expectancy, due to advances in care provided by a multidisciplinary team. The care model has expanded over time to include multiple subspecialties. The Cystic Fibrosis Foundation conducted a survey of Care Center Directors and identified a need for pediatric and adult gastroenterologists with expertise in the diagnosis and treatment of intestinal, pancreatic and hepatic complications of CF. To address this need, the Developing Innovative GastroEnterology Specialty Training (DIGEST) program was created. The development, implementation, and early results of this training program are reported herein.

PMID: 32736950 [PubMed - as supplied by publisher]

Biliary disease and cholecystectomy after initiation of elexacaftor/ivacaftor/tezacaftor in adults with cystic fibrosis.

J Cyst Fibros. 2020 Jul 29;:

Authors: Safirstein J, Grant JJ, Clausen E, Savant D, Dezube R, Hong G

Abstract
Individuals with cystic fibrosis (CF) have an increased risk for gallbladder abnormalities and biliary tract disease, but the reported incidence of these manifestations of CF varies widely in the literature. With the approval of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA), increasing numbers of CF patients have been initiated on highly effective cystic fibrosis transmembrane regulator (CFTR) modulator therapy. While elevations in hepatic panel are known potential side effects of CFTR modulators, there have been no published cases of biliary disease or acute cholecystitis attributed to these medications. In this case series, we describe seven patients at two adult CF centers with biliary colic shortly after initiation with ELX/TEZ/IVA, six of whom required cholecystectomy.

PMID: 32736949 [PubMed - as supplied by publisher]

Cefoperazone sodium liposomal formulation to mitigate P.aeruginosa biofilm in Cystic fibrosis infection: A QbD approach.

Int J Pharm. 2020 Jul 28;:119696

Authors: Ghodake V, Viswakarma J, Vavilala SL, Patravale V

Abstract
Cystic fibrosis (CF), an atypical genetic disorder, develops due to mutations in cystic fibrosis transmembrane conductance regulator gene, which consequently leads to infection and inflammation.CF infections are commonly characterized by the presence of an extracellular polymeric substance (EPS) matrix or the 'biofilm', which presents an entry barrier for the antibiotics. The current research work focuses on systematic Quality by Design based development of cefoperazone sodium loaded liposome formulation. DPPC and cholesterol containing liposomes were formulated by using 'thin film hydration' method. The freeze drying and further characterization of optimized formulation was carried out for particle size distribution, % entrapment efficiency, FTIR, DSC and pXRD. The IC50 value of the formulation (0.42 μg/ml) was found to behalf of that of the drug (0.92 μg/ml). The formulation showed 50% biofilm inhibition and eradication at ̴ 1 μg/ml. The cell surface hydrophobicity was reduced to̴ 50% at MIC value of the formulation while it was78% for the control. The EPS component of P. aeruginosa biofilm reduced to 17% after treatment with 0.42 μg/ml formulation. The effect of formulation on biofilm was further confirmed by SEM analysis which revealed that the biofilm was disintegrated on treatment with 0.42 μg/ml of formulation.

PMID: 32736020 [PubMed - as supplied by publisher]

Airway cholinergic history modifies mucus secretion properties to subsequent cholinergic challenge in diminished chloride and bicarbonate conditions.

Exp Physiol. 2020 Jul 31;:

Authors: Liao YSJ, Collins EN, Guevara MV, Schurmann V, Atanasova KR, Bravo L, Sponchiado M, Hoegger MJ, Reznikov LR

Abstract
NEW FINDINGS: What is the central question of this study? What is the impact of airway cholinergic history on airway mucus secretion properties in a cystic fibrosis-like environment? What is the main finding and its importance? Prior cholinergic challenge mildly modifies mucus secretion characteristics to second cholinergic challenge in a diminished bicarbonate and chloride transport environment. Such modifications may lead to retention of mucus on the airway surface, thereby potentiating airway exacerbations.
ABSTRACT: Viral infections precipitate exacerbations in multiple airway diseases, including asthma and cystic fibrosis (CF). Although viral infections increase cholinergic transmission, few studies have examined how cholinergic history modifies subsequent cholinergic responses in the airway. In our previous work, we found that airway resistance to second cholinergic challenge was increased in young pigs with a history of airway cholinergic stimulation. Given that mucus secretion is regulated by the cholinergic nervous system and that abnormal airway mucus contributes to exacerbations, we hypothesized that prior cholinergic challenge would also modify subsequent mucus responses to a secondary cholinergic challenge. Using our established cholinergic challenge/re-challenge model in pigs, we atomized the cholinergic agonist bethanechol or saline control to pig airways. Forty-eight hours later, we removed tracheas and measured mucus secretion properties in response to a second cholinergic stimulation. The second cholinergic stimulation was conducted under diminished chloride and bicarbonate transport conditions to mimic a CF-like environment. In pigs previously challenged with bethanechol, a second cholinergic stimulation produced a mild increase in sheet-like mucus films; these films were scarcely observed in animals originally challenged with saline control. The subtle increase in mucus films was not associated with changes in mucociliary transport. These data suggest that prior cholinergic history may modify mucus secretion characteristics with subsequent stimulation under certain environmental conditions or disease states. Such modifications and/or more repetitive stimulation may lead to retention of mucus on the airway surface, thereby potentiating airway exacerbations. This article is protected by copyright. All rights reserved.

PMID: 32735372 [PubMed - as supplied by publisher]

Physiologically Based Pharmacokinetic Modeling of CFTR Modulation in People with Cystic Fibrosis Transitioning from Mono or Dual Regimens to Triple-Combination Elexacaftor/Tezacaftor/Ivacaftor.

Pulm Ther. 2020 Jul 30;:

Authors: Tsai A, Wu SP, Haseltine E, Kumar S, Moskowitz SM, Panorchan P, Shah K

Abstract
INTRODUCTION: The triple-combination (TC) cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen elexacaftor, tezacaftor, and ivacaftor was shown to be safe and efficacious in phase 3 trials of people with cystic fibrosis (pwCF) ≥ 12 years of age with ≥ 1 F508del-CFTR allele. Here, a simulation study predicted ivacaftor, tezacaftor, and elexacaftor exposures and impacts on CFTR modulation following transition from ivacaftor [a cytochrome P450 3A (CYP3A) substrate], lumacaftor (a CYP3A inducer)/ivacaftor, or tezacaftor/ivacaftor to TC.
METHODS: Physiologically based pharmacokinetic (PBPK) modeling was used to evaluate plasma exposures during transition from mono- or dual-combination CFTR modulator regimens to TC. PBPK models were parameterized using data from human hepatocytes to account for CYP3A induction by lumacaftor and validated to match clinical data from healthy volunteers and pwCF. Using dosing regimens for pwCF ≥ 12 years of age, simulations were performed for ivacaftor, lumacaftor/ivacaftor, and tezacaftor/ivacaftor dosing for 14 days followed by immediate transition to elexacaftor/tezacaftor/ivacaftor dosing for 14 days. Drug exposures during transitions were compared with respective half-maximal effective concentrations (EC50) estimated from efficacy endpoint data from clinical studies.
RESULTS: In simulations of immediate transition from ivacaftor or tezacaftor/ivacaftor to TC, the preceding treatment had no impact on ivacaftor, tezacaftor, or elexacaftor exposures. In simulations of immediate transition from lumacaftor/ivacaftor to TC, ivacaftor exposure decreased to 64% of maximum effective concentration (EC), due to reduction in ivacaftor dose and residual CYP3A4 induction, then returned to 90-95% of maximum EC. Lumacaftor-mediated CYP3A induction resolved within approximately 2 weeks. In all simulations, ivacaftor, tezacaftor, and elexacaftor exposures approached steady state within 2 weeks following transition and, at all times, ivacaftor and ≥ 1 CFTR corrector remained above EC50.
CONCLUSION: PBPK modeling indicates that immediate transition to the elexacaftor/tezacaftor/ivacaftor regimen from an ivacaftor, lumacaftor/ivacaftor, or tezacaftor/ivacaftor regimen results in sustained CFTR modulation in pwCF ≥ 12 years of age.

PMID: 32734574 [PubMed - as supplied by publisher]

Genomic, transcriptomic, and protein landscape profile of CFTR and cystic fibrosis.

Hum Genet. 2020 Jul 30;:

Authors: Sanders M, Lawlor JMJ, Li X, Schuen JN, Millard SL, Zhang X, Buck L, Grysko B, Uhl KL, Hinds D, Stenger CL, Morris M, Lamb N, Levy H, Bupp C, Prokop JW

Abstract
Cystic Fibrosis (CF) is caused most often by removal of amino acid 508 (Phe508del, deltaF508) within CFTR, yet dozens of additional CFTR variants are known to give rise to CF and many variants in the genome are known to contribute to CF pathology. To address CFTR coding variants, we developed a sequence-to-structure-to-dynamic matrix for all amino acids of CFTR using 233 vertebrate species, CFTR structure within a lipid membrane, and 20 ns of molecular dynamic simulation to assess known variants from the CFTR1, CFTR2, ClinVar, TOPmed, gnomAD, and COSMIC databases. Surprisingly, we identify 18 variants of uncertain significance within CFTR from diverse populations that are heritable and a likely cause of CF that have been understudied due to nonexistence in Caucasian populations. In addition, 15 sites within the genome are known to modulate CF pathology, where we have identified one genome region (chr11:34754985-34836401) that contributes to CF through modulation of expression of a noncoding RNA in epithelial cells. These 15 sites are just the beginning of understanding comodifiers of CF, where utilization of eQTLs suggests many additional genomics of CFTR expressing cells that can be influenced by genomic background of CFTR variants. This work highlights that many additional insights of CF genetics are needed, particularly as pharmaceutical interventions increase in the coming years.

PMID: 32734384 [PubMed - as supplied by publisher]

Diabetes in Patients With Ataxia Telangiectasia: A National Cohort Study.

Front Pediatr. 2020;8:317

Authors: Donath H, Hess U, Kieslich M, Theis M, Ohlenschläger U, Schubert R, Woelke S, Zielen S

Abstract
Background: Ataxia telangiectasia (A-T) is a rare autosomal-recessive multisystem disorder characterized by pronounced cerebellar ataxia, telangiectasia, cancer predisposition and altered body composition. In addition, evidence is rising for endocrine dysfunction. Objectives: To determine the evolution of diabetes and its prevalence in a larger A-T cohort. Methods: A retrospective analysis of the patient charts of 39 subjects from the Frankfurt A-T cohort was performed between August 2002 and 2018 concerning HbA1c and oral glucose tolerance (OGTT). The median follow-up period was 4 years (1-16 years). In addition, in 31 A-T patients aged 1 to 38 years HbA1c and fasting glucose were studied prospectively from 2018 to 2019. Results: In the retrospective analysis, we could demonstrate a longitudinal increase of HbA1c. The prospective analysis showed a significant increase of HbA1c and fasting glucose with age (r = 0.79, p ≤ 0.0001). OGTT has a good sensitivity for insulin resistance screening, whereas HbA1c can be used to evaluate individual courses and therapy response. Seven out of 39 (17.9%) patients suffered from diabetes. Metformin did not always lead to sufficient diabetes control; one patient was treated successfully with repaglinide. Conclusion: Diabetes is a common finding in older A-T patients and often starts in puberty. Our data clearly demonstrate the need for an annual diabetes screening in patients > 12 years.

PMID: 32733823 [PubMed]

The Regulator PltZ Regulates a Putative ABC Transporter System PltIJKNOP of Pseudomonas aeruginosa ATCC 27853 in Response to the Antimicrobial 2,4-Diacetylphloroglucinol.

Front Microbiol. 2020;11:1423

Authors: Guo DD, Luo LM, Ma HL, Zhang SP, Xu H, Zhang H, Wang Y, Yuan Y, Wang Z, He YX

Abstract
Pseudomonas aeruginosa is an opportunistic pathogen commonly infecting immunocompromised patients with diseases like cystic fibrosis (CF) and cancers and has high rates of recurrence and mortality. The treatment efficacy can be significantly worsened by the multidrug resistance (MDR) of P. aeruginosa, and there is increasing evidence showing that it is easy for this pathogen to develop MDR. Here, we identified a gene cluster, pltZ-pltIJKNOP, which was originally assumed to be involved in the biosynthesis of an antimicrobial pyoluteorin, significantly contributing to the antibiotic resistance of P. aeruginosa ATCC 27853. Moreover, the TetR family regulator PltZ binds to a semi-palindromic sequence in the promoter region of the pltIJKNOP operon and recognizes the antimicrobial 2,4-diacetylphloroglucinol (2,4-DAPG), which in turn induces the expression of the pltIJKNOP operon. Using quantitative proteomics method, it was indicated that the regulator PltZ also plays an important role in maintaining metabolic hemostasis by regulating the transporting systems of amino acids, glucose, metal ions, and bacteriocins.

PMID: 32733400 [PubMed]

Glycosaminoglycans as Multifunctional Anti-Elastase and Anti-Inflammatory Drugs in Cystic Fibrosis Lung Disease.

Front Pharmacol. 2020;11:1011

Authors: Voynow JA, Zheng S, Kummarapurugu AB

Abstract
Neutrophil elastase (NE) is a major protease in the airways of patients with cystic fibrosis (CF) that activates airway inflammation by several mechanisms. NE stimulates epithelial toll like receptors (TLR) resulting in cytokine upregulation and release, upregulates MUC5AC, a major airway mucin, degrades both phagocytic receptors and opsonins resulting in both neutrophil and macrophage phagocytic failure, generates oxidative stress via extracellular generation and uptake of heme free iron, and activates other proteases. Altogether, these mechanisms create a significant inflammatory challenge that impairs innate immune function and results in airway remodeling. Currently, a major gap in our therapeutic approach to CF lung disease is the lack of an effective therapeutic strategy targeting active NE and its downstream pro-inflammatory sequelae. Polysulfated glycosaminoglycans (GAGs) are potent anti-elastase drugs that have additional anti-inflammatory properties. Heparin is a prototype of a glycosaminoglycan with both anti-elastase and anti-inflammatory properties. Heparin inhibits NE in an allosteric manner with high potency. Heparin also inhibits cathepsin G, blocks P-selectin and L-selectin, hinders ligand binding to the receptor for advanced glycation endproducts, and impedes histone acetyltransferase activity which dampens cytokine transcription and High Mobility Group Box 1 release. Furthermore, nebulized heparin treatment improves outcomes for patients with chronic obstructive pulmonary disease (COPD), asthma, acute lung injury and smoke inhalation. However, the anticoagulant activity of heparin is a potential contraindication for this therapy to be developed for CF lung disease. Therefore, modified heparins and other GAGs are being developed that retain the anti-elastase and anti-inflammatory qualities of heparin with minimal to no anticoagulant activity. The modified heparin, 2-O, 3-O desulfated heparin (ODSH), maintains anti-elastase and anti-inflammatory activities in vitro and in vivo, and has little residual anticoagulant activity. Heparan sulfate with O-sulfate residues but not N-sulfate residues blocks allergic asthmatic inflammation in a murine model. Polysulfated hyaluronic acid abrogates allergen- triggered rhinosinusitis in a murine model. Finally, nonsaccharide glycosaminoglycan mimetics with specific sulfate modifications can be designed to inhibit NE activity. Altogether, these novel GAGs or GAG mimetics hold significant promise to address the unmet need for inhaled anti-elastase and anti-inflammatory therapy for patients with CF.

PMID: 32733248 [PubMed]

Hyperglycaemia in CF adversely affects BK channel function critical for mucus clearance.

Eur Respir J. 2020 Jul 30;:

Authors: Bengtson CD, Kim MD, Anabtawi A, He J, Dennis JS, Miller S, Yoshida M, Baumlin N, Salathe M

Abstract
Large-conductance, Ca2+-activated, voltage-dependent K+ (BK) channel function is critical for adequate airway hydration and mucociliary function. In airway epithelia, BK function is regulated by its γ subunit leucine-rich repeat-containing protein 26 (LRRC26). Since patients with cystic fibrosis (CF)-related diabetes mellitus (CFRD) have worse lung function outcomes, this study determined the effects of hyperglycaemia on BK function in CF bronchial epithelial (CFBE) cells in vitro and evaluated the correlation between glycaemic excursions and mRNA expression of LRRC26 in the upper airways of CF and CFRD patients.CFBE cells were re-differentiated at the air-liquid interface (ALI) in media containing either 5.5 mM or 12.5 mM glucose. BK activities were measured in Ussing chambers. Airway surface liquid (ASL) volumes were estimated by meniscus scanning and inflammatory marker expression was measured by quantitative real-time PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA). CF patients were assessed by 7 days of continuous glucose monitoring. LRRC26 mRNA expression was measured by qPCR from nasal cells obtained at the end of glucose monitoring.BK currents were significantly decreased in CFBE cells cultured under high glucose. These cells revealed significantly lower ASL volumes and increased inflammation, including RAGE, compared to cells cultured in normal glucose. In vivo, nasal cell expression of LRRC26 mRNA was inversely correlated with hyperglycaemic excursions, consistent with the in vitro results.Our findings demonstrate that hyperglycaemia induces inflammation and impairs BK channel function in CFBE cells in vitro These data suggest that declining lung function in CFRD patients may be related to BK channel dysfunction.

PMID: 32732330 [PubMed - as supplied by publisher]

ENaC inhibition in cystic fibrosis: potential role in the new era of CFTR modulator therapies.

Eur Respir J. 2020 Jul 30;:

Authors: Mall MA

Abstract
Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are the first approved drugs targeting underlying epithelial ion/fluid transport defects in patients with cystic fibrosis (CF). Current CFTR modulators restore mutant CFTR activity to up to ∼50% of normal CFTR Cl- channel function, translating into improvements in percentage predicted FEV1 and other clinical outcomes. In addition, reductions in airway bacterial colonisation are observed; however, patients fail to eradicate bacteria over time and still experience pulmonary exacerbations, and long-term safety of CFTR modulator therapy remains unknown. Currently approved CFTR modulators are predicted to be effective for up to 90% of patients. A mutation-agnostic approach could address the remaining 10% with CFTR mutations unresponsive to CFTR modulator therapy and may act together with CFTR modulator therapy to further improve epithelial ion/fluid transport and clinical outcomes. Together with CFTR and other Cl- channels, the epithelial Na+ channel (ENaC) is key to regulating airway surface liquid homeostasis. ENaC activity is limiting for Na+/fluid absorption and remains intact or may even be increased in CF airways, leading to increased Na+/fluid absorption, airway surface dehydration, impaired mucociliary clearance, bacterial infection, inflammation and progressive lung damage - the major cause of CF-related morbidity and mortality. Inhibition of ENaC in the airways is therefore an attractive therapeutic target to counteract airway surface dehydration and downstream consequences in CF lung disease. This review examines ENaC inhibition in CF therapy, and describes a new ENaC inhibitor with potential mutation-agnostic therapeutic benefit, both alone, and in synergy with CFTR modulators.

PMID: 32732328 [PubMed - as supplied by publisher]