Netw Syst Med. 2020 Dec 1;3(1):159-181. doi: 10.1089/nsm.2020.0009. Epub 2020 Dec 31.

ABSTRACT

Background: Small studies have recently suggested that there are specific plasma metabolic signatures in chronic obstructive pulmonary disease (COPD), but there have been no large comprehensive study of metabolomic signatures in COPD that also integrate genetic variants. Materials and Methods: Fresh frozen plasma from 957 non-Hispanic white subjects in COPDGene was used to quantify 995 metabolites with Metabolon's global metabolomics platform. Metabolite associations with five COPD phenotypes (chronic bronchitis, exacerbation frequency, percent emphysema, post-bronchodilator forced expiratory volume at one second [FEV1]/forced vital capacity [FVC], and FEV1 percent predicted) were assessed. A metabolome-wide association study was performed to find genetic associations with metabolite levels. Significantly associated single-nucleotide polymorphisms were tested for replication with independent metabolomic platforms and independent cohorts. COPD phenotype-driven modules were identified in network analysis integrated with genetic associations to assess gene-metabolite-phenotype interactions. Results: Of metabolites tested, 147 (14.8%) were significantly associated with at least 1 COPD phenotype. Associations with airflow obstruction were enriched for diacylglycerols and branched chain amino acids. Genetic associations were observed with 109 (11%) metabolites, 72 (66%) of which replicated in an independent cohort. For 20 metabolites, more than 20% of variance was explained by genetics. A sparse network of COPD phenotype-driven modules was identified, often containing metabolites missed in previous testing. Of the 26 COPD phenotype-driven modules, 6 contained metabolites with significant met-QTLs, although little module variance was explained by genetics. Conclusion: A dysregulation of systemic metabolism was predominantly found in COPD phenotypes characterized by airflow obstruction, where we identified robust heritable effects on individual metabolite abundances. However, network analysis, which increased the statistical power to detect associations missed previously in classic regression analyses, revealed that the genetic influence on COPD phenotype-driven metabolomic modules was modest when compared with clinical and environmental factors.

PMID:33987620 | PMC:PMC8109053 | DOI:10.1089/nsm.2020.0009

Ann Transl Med. 2021 Apr;9(8):738. doi: 10.21037/atm-20-3591.

ABSTRACT

Primary sclerosing cholangitis (PSC) is a rare progressive cholangitis resulting in cirrhosis and cholangiocellular carcinoma. The pathogenesis is unclear and an effective medical therapy is not available. It is highly associated to ulcerative colitis for which recently a disturbance of the tight junction (TJ) barrier has been claimed as etiologic feature. Genetic mouse models with intestinal TJ disruption showed a defective transport of phosphatidylcholine (PC) to intestinal mucus. Consequently, an ulcerative colitis phenotype developed. In the present study we evaluate whether there is also a paracellular transport of PC through TJ to the apical side of cholangiocytes. As in ulcerative colitis, a TJ defect could lead to deficient PC in biliary mucus. It would impair the protective barrier against aggressive bile acids in bile. Indeed with polarized biliary tumor cells a vectorial transport of PC from basal to luminal side was demonstrated using a transwell culture system. PC was not taken up by the cells but moved paracellularly via TJ to the apical side driven by luminal HCO3- generated by the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and the anion exchange protein 2 (AE2). If such a TJ-mediated PC translocation to the apical surface of cholangiocytes could be disrupted in a genetic mouse model, a PSC phenotype would be expected. With such an experimental model functional operative therapies can be evaluated. We propose that disruption of TJ mediated paracellular transport of PC to the apical side of cholangiocytes could lead to biliary mucus PC depletion. This may be a pathogenetic factor for development of PSC.

PMID:33987436 | PMC:PMC8106090 | DOI:10.21037/atm-20-3591

Front Med (Lausanne). 2021 Apr 27;8:616200. doi: 10.3389/fmed.2021.616200. eCollection 2021.

ABSTRACT

Chronic inflammatory pulmonary diseases are characterized by recurrent and persistent inflammation of the airways, commonly associated with poor clinical outcomes. Although their etiologies vary tremendously, airway neutrophilia is a common feature of these diseases. Neutrophils, as vital regulators linking innate and adaptive immune systems, are a double-edged sword in the immune response of the lung involving mechanisms such as phagocytosis, degranulation, neutrophil extracellular trap formation, exosome secretion, release of cytokines and chemokines, and autophagy. Although neutrophils serve as strong defenders against extracellular pathogens, neutrophils and their components can trigger various cascades leading to inflammation and fibrogenesis. Here, we review current studies to elucidate the versatile roles of neutrophils in chronic pulmonary inflammatory diseases and describe the common pathogenesis of these diseases. This may provide new insights into therapeutic strategies for chronic lung diseases.

PMID:33987189 | PMC:PMC8110706 | DOI:10.3389/fmed.2021.616200

Front Pharmacol. 2021 Apr 27;12:662110. doi: 10.3389/fphar.2021.662110. eCollection 2021.

ABSTRACT

Cystic fibrosis (CF) is a severe genetic disease for which curative treatment is still lacking. Next generation biotechnologies and more efficient cell-based and in vivo disease models are accelerating the development of novel therapies for CF. Gene editing tools, like CRISPR-based systems, can be used to make targeted modifications in the genome, allowing to correct mutations directly in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. Alternatively, with these tools more relevant disease models can be generated, which in turn will be invaluable to evaluate novel gene editing-based therapies for CF. This critical review offers a comprehensive description of currently available tools for genome editing, and the cell and animal models which are available to evaluate them. Next, we will give an extensive overview of proof-of-concept applications of gene editing in the field of CF. Finally, we will touch upon the challenges that need to be addressed before these proof-of-concept studies can be translated towards a therapy for people with CF.

PMID:33986686 | PMC:PMC8111007 | DOI:10.3389/fphar.2021.662110

J Pediatr Nurs. 2021 May 10:S0882-5963(21)00141-X. doi: 10.1016/j.pedn.2021.04.028. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a common autosomal recessive disease with an incidence of 1:2560 live births in Jordan. It affects the quality of life for both the child and the parents. In Jordan knowledge about parents' experience with children diagnosed with CF is limited.

PURPOSE: The purpose of this study was to describe and explore the lived experience of parents of children with CF, and the difficulties and challenges they face.

DESIGN AND METHOD: A qualitative phenomenological method was used. Twenty-five parents of children with CF were interviewed. The Scribber thematic analysis was used in data analysis.

RESULTS: Four themes emerged. First, "Falling into the circle of suffering", Second, "The circle of suffering", with two sub-themes: the challenges, and the limitations in daily life. Third, "Coping within the circle of suffering", with four sub-themes: focus on problems, focus on emotions, social and economic factors, and spirituality. Fourth, "Future outlook", with two sub-themes: optimism about the future, and pessimism about the future.

CONCLUSION: Parents of children with CF suffer from difficulties and challenges that limit their daily lives.

PRACTICE IMPLICATIONS: Education is needed for health care providers, society and parents about CF; and parents need support to improve their quality of life.

PMID:33985856 | DOI:10.1016/j.pedn.2021.04.028

PLoS One. 2021 May 13;16(5):e0251527. doi: 10.1371/journal.pone.0251527. eCollection 2021.

ABSTRACT

OBJECTIVE: To describe the symptoms and clinical course of SARS-CoV-2 infection in patients with cystic fibrosis (CF).

METHODS: We carried out a prospective multicentre cohort study based on 32 CF centres and 6597 patients. Centres were contacted to collect baseline and follow-up data of patients who reported symptoms suggestive of COVID-19 or who had contact with a positive/suspected case between the end of February and July 2020. Symptoms and clinical course of the infection were compared between patients who tested positive by molecular testing (cases) and those who tested negative (controls).

RESULTS: Thirty patients were reported from the centres, 16 of them tested positive and 14 tested negative. No differences in symptoms and outcome of the disease were observed between groups. Fever, cough, asthenia and dyspnea were the most frequently reported symptoms. Eight cases (50%) were hospitalized but none required ICU admission. Two adults with a history of lung transplant required non-invasive ventilation, none required ICU admission and all patients fully recovered without short-term sequelae.

CONCLUSIONS: The course of SARS-CoV-2 in our patients was relatively favorable. However, COVID-19 should not be considered a mild disease in CF patients, particularly for those with severely impaired respiratory function and organ transplant.

PMID:33984027 | DOI:10.1371/journal.pone.0251527

Pediatr Pulmonol. 2021 May 13. doi: 10.1002/ppul.25441. Online ahead of print.

ABSTRACT

Aminoglycosides are commonly used for the treatment of Pseudomonas aeruginosa (PsA) in the setting of acute pulmonary exacerbations (PEx) in pediatric patients with cystic fibrosis (CF). There are controversies and practice differences between institutions related to aminoglycoside dosing and monitoring strategies. The purpose of this review article is to summarize the currently available literature and identify gaps in the literature related to pharmacokinetic parameter goals, aminoglycoside dosing strategies, and methods for monitoring serum aminoglycoside concentrations for treatment of PsA in CF PEx, and throughout will discuss anticipated changes with the increasing availability of highly effective CF transmembrane conductance regulator modulators. This review focuses on tobramycin, as it is the most commonly used aminoglycoside in CF PEx, and will briefly discuss special circumstances surrounding use of amikacin and gentamicin.

PMID:33983680 | DOI:10.1002/ppul.25441

Clin Pharmacokinet. 2021 May 13. doi: 10.1007/s40262-021-01010-4. Online ahead of print.

ABSTRACT

Non-tuberculous mycobacteria (NTM) are an emerging group of pulmonary infectious pathogens of increasing importance to the management of patients with cystic fibrosis (CF). NTM include slow-growing mycobacteria such as Mycobacterium avium complex (MAC) and rapidly growing mycobacteria such as Mycobacterium abscessus. The incidence of NTM in the CF population is increasing and infection contributes to significant morbidity to the patient and costs to the health system. Treating M. abscessus requires the combination of multiple costly antibiotics for months, with potentially significant toxicity associated with treatment. Although international guidelines for the treatment of NTM infection in CF are available, there are a lack of robust pharmacokinetic studies in CF patients to inform dosing and drug choice. This paper aims to outline the pharmacokinetic and pharmacodynamic factors informing the optimal treatment of NTM infections in CF.

PMID:33982266 | DOI:10.1007/s40262-021-01010-4

Front Immunol. 2021 Apr 26;12:659523. doi: 10.3389/fimmu.2021.659523. eCollection 2021.

ABSTRACT

Chronic Pseudomonas aeruginosa infection mysteriously occurs in the airways of patients with cystic fibrosis (CF), bronchiectasis (BE), and chronic obstructive pulmonary disease (COPD) in the absence of neutrophil dysfunction or neutropenia and is strongly associated with autoimmunity to bactericidal permeability-increasing protein (BPI). Here, we define a critical role for BPI in in vivo immunity against P. aeruginosa. Wild type and BPI-deficient (Bpi-/-) mice were infected with P. aeruginosa, and bacterial clearance, cell infiltrates, cytokine production, and in vivo phagocytosis were quantified. Bpi-/- mice exhibited a decreased ability to clear P. aeruginosa in vivo in concert with increased neutrophil counts and cytokine release. Bpi-/- neutrophils displayed decreased phagocytosis that was corrected by exogenous BPI in vitro. Exogenous BPI also enhanced clearance of P. aeruginosa in Bpi-/- mice in vivo by increasing P. aeruginosa uptake by neutrophils in a CD18-dependent manner. These data indicate that BPI plays an essential role in innate immunity against P. aeruginosa through its opsonic activity and suggest that perturbations in BPI levels or function may contribute to chronic lung infection with P. aeruginosa.

PMID:33981306 | PMC:PMC8107240 | DOI:10.3389/fimmu.2021.659523

Int J Integr Care. 2021 Apr 30;21(2):15. doi: 10.5334/ijic.5568.

ABSTRACT

INTRODUCTION: Co-production is more and more considered as a promising tool for dealing with the main challenges in the health sector (e.g., growing rates of chronic diseases, budget constraints, higher patients' expectations of the quality and the value of services, equity to access of care, etc.). However, there is still little evidence on co-production determinants and impacts.

DESCRIPTION: This research protocol aims to present a framework to assess the determinants and impacts of the co-productive approach in healthcare delivery on patients, professionals, and providers from economic, organisational, and clinical perspectives. To this end, the paper examines the co-produced outpatient parenteral antimicrobial therapy (OPAT), applied to cystic fibrosis patients in an Italian hospital. A mixed methods approach will be adopted and data will be collected through semi-structured interviews and surveys of patients, caregivers, and professionals; biological samples of patients; archival sources. Then, the analyses to be performed are the following: (i) cost evaluation, (ii) content, (iii) descriptive and inferential statistical, (iv) microbiome analysis, and (v) desk analysis.

CONCLUSION: The research protocol contributes to both theoretical and practical knowledge. It represents the first attempt to develop a systematic analytical framework for the evaluation of co-production in healthcare. Moreover, the findings gathered within the study will provide evidence to support policy makers and managers in decision-making and managerial processes within the health service.

PMID:33981192 | PMC:PMC8086733 | DOI:10.5334/ijic.5568

Eur Respir Rev. 2021 May 11;30(160):200354. doi: 10.1183/16000617.0354-2020. Print 2021 Jun 30.

ABSTRACT

There is no consensus on how best to measure responses to interventions among children and adults with cystic fibrosis (CF). We have systematically reviewed and summarised the characteristics and measurement properties of tests and tools that have been used to capture outcomes in studies among people with CF, including their reliability, validity and responsiveness. This review is intended to guide researchers when selecting tests or tools for measuring treatment effects in CF trials. A consensus set of these tests and tools could improve consistency in how outcomes are captured and thereby facilitate comparisons and synthesis of evidence across studies.

PMID:33980667 | DOI:10.1183/16000617.0354-2020

BMC Pulm Med. 2021 May 12;21(1):158. doi: 10.1186/s12890-021-01525-3.

ABSTRACT

BACKGROUND: Oscillating Positive Expiratory Pressure (OPEP) devices are important adjuncts to airway clearance therapy in patients with cystic fibrosis (CF). Current devices are typically reusable and require daily, or often more frequent, cleaning to prevent risk of infection by acting as reservoirs of potentially pathogenic organisms. In response, a daily disposable OPEP device, the UL-OPEP, was developed to mitigate the risk of contamination and eliminate the burdensome need for cleaning devices.

METHODS: A convenience sample of 36 participants, all current OPEP device users, was recruited from a paediatric CF service. For one month, participants replaced their current OPEP device with a novel daily disposable device. Assessment included pre- and post-intervention lung function by spirometry, as well as Lung Clearance Index. Quality of life was assessed using the Cystic Fibrosis Questionnaire - Revised, while user experience was evaluated with a post-study survey.

RESULTS: 31 participants completed the study: 18 males; median age 10 years, range 4-16 years. Lung function (mean difference ± SD, %FEV1 = 1.69 ± 11.93; %FVC = 0.58 ± 10.04; FEV1: FVC = 0.01 ± 0.09), LCI (mean difference ± SD, 0.08 ± 1.13), six-minute walk test, and CFQ-R were unchanged post-intervention. Participant-reported experiences of the device were predominantly positive.

CONCLUSIONS: The disposable OPEP device maintained patients' lung function during short term use (≤ 1 month), and was the subject of positive feedback regarding functionality while reducing the risk of airway contamination associated with ineffective cleaning.

REGISTRATION: The study was approved as a Clinical Investigation by the Irish Health Products Regulatory Authority (CRN-2209025-CI0085).

PMID:33980186 | DOI:10.1186/s12890-021-01525-3

Small. 2021 May 12:e2100531. doi: 10.1002/smll.202100531. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa biofilms cause persistent and chronic infections, most known clinically in cystic fibrosis (CF). Tobramycin (TOB) is a standard anti-pseudomonal antibiotic; however, in biofilm infections, its efficacy severely decreases due to limited permeability across the biofilm matrix. Herewith, a biomimetic, nanostructured, lipid liquid crystal nanoparticle-(LCNP)-formulation is discovered to significantly enhance the efficacy of TOB and eradicate P. aeruginosa biofilm infections. Using an advanced, biologically-relevant co-culture model of human CF bronchial epithelial cells infected with P. aeruginosa biofilms at an air-liquid interface, nebulized TOB-LCNPs completely eradicated 1 × 109 CFU mL-1 of P. aeruginosa after two doses, a 100-fold improvement over the unformulated antibiotic. The enhanced activity of TOB is not observed with a liposomal formulation of TOB or with ciprofloxacin, an antibiotic that readily penetrates biofilms. It is demonstrated that the unique nanostructure of the LCNPs drives the enhanced penetration of TOB across the biofilm barrier, but not through the healthy lung epithelium barrier, significantly increasing the available antibiotic concentration at the site of infection. The LCNPs are an innovative strategy to improve the performance of TOB as a directed pulmonary therapy, enabling the administration of lower doses, reducing the toxicity, and amplifying the anti-biofilm activity of the anti-pseudomonal antibiotic.

PMID:33978317 | DOI:10.1002/smll.202100531

Respirol Case Rep. 2021 May 7;9(6):e00755. doi: 10.1002/rcr2.755. eCollection 2021 Jun.

ABSTRACT

Catamenial haemoptysis, the expectoration of blood during menses, has not been extensively reported in the cystic fibrosis (CF) literature. We describe four cases (age range: 25-34 years) of catamenial haemoptysis across four CF centres in the United States. These cases may represent thoracic endometriosis versus hormonal fluctuations in airway inflammation or infection resulting in bronchial artery bleeding. We identify common and nuanced management strategies including use of pro-coagulants, hormone contraceptives, anti-inflammatories, bronchial artery embolization, and use of the newer cystic fibrosis transmembrane conductance regulator (CFTR) modulators.

PMID:33976884 | PMC:PMC8103099 | DOI:10.1002/rcr2.755

Thorax. 2021 May 11:thoraxjnl-2021-216849. doi: 10.1136/thoraxjnl-2021-216849. Online ahead of print.

ABSTRACT

RATIONALE: A previous analysis found significantly higher lung function in the US paediatric cystic fibrosis (CF) population compared with the UK with this difference apparently decreasing in adolescence and adulthood. However, the cross-sectional nature of the study makes it hard to interpret these results.

OBJECTIVES: To compare longitudinal trajectories of lung function in children with CF between the USA and UK and to explore reasons for any differences.

METHODS: We used mixed effects regression analysis to model lung function trajectories in the study populations. Using descriptive statistics, we compared early growth and nutrition (height, weight, body mass index), infections (Pseudomonas aeruginosa, Staphylococcus aureus) and treatments (rhDnase, hypertonic saline, inhaled antibiotics).

RESULTS: We included 9463 children from the USA and 3055 children from the UK with homozygous F508del genotype. Lung function was higher in the USA than in the UK when first measured at age six and remained higher throughout childhood. We did not find important differences in early growth and nutrition, or P.aeruginosa infection. Prescription of rhDNase and hypertonic saline was more common in the USA. Inhaled antibiotics were prescribed at similar levels in both countries, but Tobramycin was prescribed more in the USA and colistin in the UK. S. aureus infection was more common in the USA than the UK.

CONCLUSIONS: Children with CF and homozygous F508del genotype in the USA had better lung function than UK children. These differences do not appear to be explained by early growth or nutrition, but differences in the use of early treatments need further investigation.

PMID:33975926 | DOI:10.1136/thoraxjnl-2021-216849

Eur J Pharmacol. 2021 May 8:174123. doi: 10.1016/j.ejphar.2021.174123. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is a recessive inherited disease caused by mutations affecting anion transport by the epithelial ion channel cystic fibrosis transmembrane conductance regulator (CFTR). The disease is characterized by mucus accumulation in the airways and intestine, but the major cause of mortality in CF is airway mucus accumulation, leading to bacterial colonization, inflammation and respiratory failure. Several drug targets are under evaluation to alleviate airway mucus obstruction in CF and one of these targets is the epithelial sodium channel ENaC. To explore effects of ENaC inhibitors on mucus properties, we used two model systems to investigate mucus characteristics, mucus attachment in mouse ileum and mucus bundle transport in piglet airways. We quantified mucus attachment in explants from CFTR null (CF) mice and tracheobronchial explants from newborn CFTR null (CF) piglets to evaluate effects of ENaC or sodium/hydrogen exchanger (NHE) inhibitors on mucus attachment. ENaC inhibitors detached mucus in the CF mouse ileum, although the ileum lacks ENaC expression. This effect was mimicked by two NHE inhibitors. Airway mucus bundles were immobile in untreated newborn CF piglets but were detached by the therapeutic drug candidate AZD5634 (patent WO 2015140527). These results suggest that the ENaC inhibitor AZD5634 causes detachment of CF mucus in the ileum and airway via NHE inhibition and that drug design should focus on NHE instead of ENaC inhibition.

PMID:33974881 | DOI:10.1016/j.ejphar.2021.174123

Pediatr Pulmonol. 2021 May 11. doi: 10.1002/ppul.25462. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is a chronic multisystem disease with manifestations from birth. It involves the entire respiratory system, with increased cough, and recurrent pulmonary infections, and it also leads to intestinal malabsorption, all of which can have an impact on sleep. In this review, we summarize the available literature on the various sleep disturbances in children with CF. Sleep quality and sleep efficiency are often impaired in children with CF. They may be accompanied by symptoms associated with sleep-disordered breathing (SDB), and objective findings such as nocturnal hypoxemia. Importantly, a strong association has been shown between SDB and the severity of lung disease, and some studies have reported a similar association for sleep quality. Further research is needed to better characterize the association of sleep disturbances with respiratory outcomes and the impact of treatment of sleep disorders on pulmonary status in children with CF. This article is protected by copyright. All rights reserved.

PMID:33974362 | DOI:10.1002/ppul.25462

Adv Exp Med Biol. 2021;1318:109-118. doi: 10.1007/978-3-030-63761-3_7.

ABSTRACT

The outbreak of the COVID-19 pandemic shows a marked geographical variation in its prevalence and mortality. The question arises if the host genetic variation may (partly) affect the prevalence and mortality of COVID-19. We postulated that the geographical variation of human polymorphisms might partly explain the variable prevalence of the infection. We investigated some candidate genes that have the potential to play a role in the immune defense against COVID-19: complement component 3 (C3), galactoside 2-alpha-L-fucosyltransferase 2 (FUT2), haptoglobin (Hp), vitamin D binding protein (DBP), human homeostatic iron regulator protein (HFE), cystic fibrosis transmembrane conductance regulator (CFTR), and angiotensin-converting enzyme 1 (ACE1). In a univariate approach, ACE1 D/I, C3, CFTR, and HFE polymorphisms correlated significantly with COVID-19 prevalence/mortality, whereas Hp and FUT2 polymorphism did not show any significant correlations. In a multivariate analysis, only ACE1 D/I and C3 polymorphisms were determinants for COVID-19 prevalence/mortality. The other polymorphisms (CFTR, DBP, FUT2, HFE, and Hp) did not correlate with COVID-19 prevalence/mortality. Whereas ACE1 D/I polymorphism shows functional links with ACE2 (which is the receptor for the virus) in COVID-19, C3 can act as a critical step in the virus-induced inflammation. Our findings plead against a bystander role of the polymorphisms as a marker for historical migrations, which comigrate with causal genes involved in COVID-19 infection. Further studies are required to assess the clinical outcome of COVID-19 in C3S and ACE1 D allele carriers and to study the role of C3 and ACE1 D/I polymorphisms in COVID-19 and their potential effects on treatment response.

PMID:33973175 | DOI:10.1007/978-3-030-63761-3_7

Thorax. 2021 May 10:thoraxjnl-2021-217095. doi: 10.1136/thoraxjnl-2021-217095. Online ahead of print.

NO ABSTRACT

PMID:33972453 | DOI:10.1136/thoraxjnl-2021-217095

Redox Biol. 2021 Apr 30;43:101998. doi: 10.1016/j.redox.2021.101998. Online ahead of print.

ABSTRACT

Lipopolysaccharide (LPS) serves as the interface between gram-negative bacteria (GNB) and the innate immune response in respiratory epithelial cells (REC). Herein, we describe a novel biological role of LPS that permits GNB to persist in the respiratory tract through inducing CFTR and mucociliary dysfunction. LPS reduced cystic fibrosis transmembrane conductance regulater (CFTR)-mediated short-circuit current in mammalian REC in Ussing chambers and nearly abrogated CFTR single channel activity (defined as forskolin-activated Cl- currents) in patch clamp studies, effects of which were blocked with toll-like receptor (TLR)-4 inhibitor. Unitary conductance and single-channel amplitude of CFTR were unaffected, but open probability and number of active channels were markedly decreased. LPS increased cytoplasmic and mitochondrial reactive oxygen species resulting in CFTR carbonylation. All effects of exposure were eliminated when reduced glutathione was added in the medium along with LPS. Functional microanatomy parameters, including mucociliary transport, in human sinonasal epithelial cells in vitro were also decreased, but restored with co-incubation with glutathione or TLR-4 inhibitor. In vivo measurements, following application of LPS in the nasal cavities showed significant decreases in transepithelial Cl- secretion as measured by nasal potential difference (NPD) - an effect that was nullified with glutathione and TLR-4 inhibitor. These data provide definitive evidence that LPS-generated reactive intermediates downregulate CFTR function in vitro and in vivo which results in cystic fibrosis-type disease. Findings have implications for therapeutic approaches intent on stimulating Cl- secretion and/or reducing oxidative stress to decrease the sequelae of GNB airway colonization and infection.

PMID:33971543 | DOI:10.1016/j.redox.2021.101998