Cystic Fibrosis Research Articles

Effects of GM1 ganglioside and its derivatives on ETI-rescued F508del-CFTR maturation and host-pathogen interactions in cystic fibrosis bronchial cells.

Cystic Fibrosis (CF), a life-threatening hereditary disease, arises from mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, which encodes a chloride-conducting channel widely expressed in epithelial cells. The most common mutation, F508del, causes CFTR misfolding, premature degradation, and impaired mucociliary clearance, leading to recurrent respiratory infections and inflammation. The triple combination therapy with Elexacaftor, Tezacaftor, and Ivacaftor (ETI) has revolutionized CF management by partially restoring mutated CFTR function. However, enhancing CFTR rescue and stabilizing host immune responses remain critical challenges. In airway epithelial cells, CFTR interacts with proteins and lipids in macromolecular complexes that influence its stability. Among these, the ganglioside GM1 plays a key role in modulating plasma membrane protein dynamics, including CFTR. This study investigates the effects of exogenous GM1 supplementation as an adjuvant to ETI treatment. Our results demonstrate that GM1 enhances F508del-CFTR maturation and stability, even under Pseudomonas aeruginosa infection, which typically suppresses CFTR expression and function. Furthermore, GM1 restores xenophagic activity in bronchial epithelial cells, improving host defence mechanisms against the bacteria. These findings underscore the therapeutic potential of GM1 and its analogues in optimizing the plasma membrane environment for CFTR correction, suggesting that by enhancing the efficacy of CFTR modulators, GM1 could pave the way for innovative approaches to improve CF management.

Revealing the impact of Pseudomonas aeruginosa quorum sensing molecule 2’-aminoacetophenone on the human bronchial-airway epithelium and pulmonary endothelium using a human airway-on-a-chip

BackgroundPseudomonas aeruginosa (PA) causes severe respiratory infections utilizing multiple virulence functions. Previous findings on the PA secreted quorum sensing (QS)-regulated small molecule, 2’-aminoacetophenone (2-AA), revealed its impact on immune and metabolic functions, favouring a long-term presence of PA in the host. However, the 2-AA’s specific effects on bronchial-airway epithelium and pulmonary endothelium remain elusive. To evaluate the spatiotemporal changes in 2AA within the human airway, considering endothelial cells as the primary point of contact when the route of lung infection is hematogenic, we utilized the airway-on-achip platform. This dynamic culture system recapitulates critical elements of the human airway microphysiological environment.MethodsWe utilized the microfluidic airway-on-chip platform, lined by polarized primary human pulmonary microvascular endothelial cells (HPMEC) and adjacent primary normal human bronchial epithelial cells (NHBE) obtained from healthy female donors. Cells exposed to 2-AA (20 μm) through continuous flow for 12 hours were used for whole-genome RNA sequencing and analyzed for their responses and potential cross-talk. Transcriptome findings were validated through in vivo studies in mice and additional cell culture experiments.ResultsAnalyses revealed that 2-AA differentially regulates specific signaling and biosynthesis pathways in epithelial cells, including HIF-1 and pyrimidine signaling, glycosaminoglycan and glycosphingolipid biosynthesis. In endothelial cells, fatty acid metabolism, phosphatidylinositol, and estrogen receptor signaling, as well as proinflammatory signaling pathways, were identified. Significant overlap was found in both cell types in response to 2-AA in genes implicated in immune response and cellular functions. In contrast, we found that genes related to barrier permeability, cholesterol metabolism, and oxidative phosphorylation were differentially regulated in response to 2-AA exposure in the studied cell types. Murine in vivo and additional in vitro cell culture studies confirmed the accumulation of cholesterol in epithelial cells. Results also revealed that specific biomarkers associated with cystic fibrosis and idiopathic pulmonary fibrosis were modulated by 2-AA in both cell types, with the expression of cystic fibrosis transmembrane regulator being affected only in endothelial cells.

D-Amino acids affect Pseudomonas aeruginosa biofilm and quorum sensing molecules in lung infection models developed under a cystic fibrosis environment

Pseudomonas aeruginosa commonly infects immunocompromised patients, including those with cystic fibrosis (CF). These infections are difficult to treat due to a variety of factors including the ability of Pseudomonas aeruginosa to resist to antibiotic treatment in part due to formation of biofilms. D-amino acids have known biofilm-disruption and antibacterial properties in some bacteria including P. aeruginosa. However, this treatment remains underexplored especially for inhibiting biofilm biomass production under CF environments. We explore the effects of six individual D-amino acids (alanine, aspartic acid, tyrosine, glutamic acid, serine, and proline) on the quorum sensing signaling and biofilm biomass production of two strains: PAO1 and the CF isolate FRD1. The D-amino acid causing the most significant decrease in biofilm mass and a decrease in quorum sensing molecules was D-aspartic acid. Meanwhile D-glutamic acid and D-serine had the opposite effects with an increase in biofilm mass and increase in quorum sensing molecule abundance. D-proline also showed a decrease in quorum sensing signaling with a decrease in biofilm biomass. P. aeruginosa had a lower or delayed quorum sensing response in the presence of D-aspartic acid and the absence of its L- counterpart at 48 h, a potential therapeutic route to explore.

IDENTIFICATION OF EXON 12 MUTATIONS IN THE CFTR GENE USING A COST-EFFECTIVE CAPILLARY ELECTROPHORESIS (CE) ASSAY

Cystic Fibrosis (CF) is an autosomal recessive genetic disorder caused by mutations in the CFTR gene. The F508del mutation in exon 11 of the CFTR gene is prevalent worldwide, affecting approximately 70% of CF patients, but it is less common in the local Pakistani population. Exon 12 mutations, such as S549N and S549R, have been observed in CF patients with Pakistani ancestry. This research provides accessible and affordable mutation detection using reproducible and cost-effective capillary-electrophoresis (CE) methods. Therefore, this study investigated whether local Pakistani CF patients lacking exon 11 mutations, such as F508del, harbor any common or rare CF-causing mutations in exon 12 of the CFTR gene using a cost-effective Sanger sequencing assay. To achieve this, a new set of primers was meticulously designed and optimized for the amplification of exon 12 through PCR. Additionally, Sanger sequencing-based CE assay was fine-tuned for the sequencing of exon 12 amplicons. The Sanger sequencing results revealed no mutations in exon 12 among the 17 local CF patients who participated in the study. This absence of mutations in both exons 11 and 12 suggests that CF-causing mutations may be located in these patients' other regions of the CFTR gene. Furthermore, it indicates that exon 12 mutations are less prevalent among local Pakistani CF patients. The optimized Sanger sequencing-based CE assay is at least five times more cost-effective and can be employed for the identification of mutations in any sequence with a length of up to 500 bases.

Opportunistic assessment of bone mineral density in cystic fibrosis patients using ultra-low dose thoracic CT

SummaryIn this study, we used routine ultra-low dose computed tomography scans of patients with cystic fibrosis to predict bone mineral density (BMD). A strong correlation was found between the attenuation of trabecular bone in thoracic vertebrae and the BMD in the proximal femur and lumbar spine as measured on DEXA.PurposeOsteoporosis is a serious global health concern with millions of people affected worldwide. A particularly vulnerable cohort in developing osteoporosis are patients with cystic fibrosis (CF). Bone mineral density (BMD) is typically measured with dual energy X-ray absorptiometry (DEXA) scanning; however, this comes at a cost to the healthcare system and an exposure to ionising radiation. In our institution, patients with cystic fibrosis undergo routine ultra-low dose computed tomography (ULDCT) for monitoring of disease progression. The aim of this study was to assess the validity of estimating BMD using data derived from ULDCT scans.MethodsAdult CF patients were included if they had undergone a routine ULDCT scan within 12 months of a DEXA scan. Additionally, 100 non-CF patients with non-contrast standard dose CT scans were selected to act as the control group. Trabecular bone density (T-BD) at T4, T7 and T10 was measured on PACS in Hounsfield units (HU) and compared to DEXA scan results and a formula developed to the predict BMD.ResultsFifty-two female and 62 male patients were included with mean ages of 34.4 and 35.1 respectively. Moderately strong correlation was found between the T-BD and BMD of both the lumbar spine (r = 0.629, p < 0.001) and proximal femur (r = 0.649, p < 0.001). Receiver operator characteristic (ROC) curve analysis found a sensitivity and specificity of 0.700 and 0.714 respectively at predicting osteoporosis at T-BD of 193.33 HU or below.ConclusionT-BD measured on ULDCT may be a valuable tool in the early identification of CF patients at risk of osteoporosis.

Impact of CFTR Modulators on Longitudinal Cystic Fibrosis Survival and Mortality: Review and Secondary Analysis.

Cystic fibrosis (CF) transmembrane conductance regulator modulators (CFTRm) have transformed CF care, shifting treatment from only managing symptoms to also addressing the underlying defects that cause CF. CFTRm first entered clinical practice in 2012 and was followed by additional CFTRm combinations-including the approval of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) in 2019-which treats most CF genotypes. We identified peer-reviewed literature for a narrative review (January 1990 to January 2025) describing longitudinal trends in CF survival and age of death and assessing the influence of CFTRm, particularly ELX/TEZ/IVA. To supplement the existing literature, a secondary analysis of historical, longitudinal trends in the United States CF Foundation Patient Registry (U.S. CFFPR, 1990-2023) was conducted using recent available data. Quantitative data from published studies show that the median age of survival and death increased over time but with varying magnitudes across regions. Most cohort and registry-based studies were conducted in settings where CFTRm were not yet widely available, limiting the evaluation of CFTRm effects on survival trends over time. In the secondary U.S. CFFPR analysis, the median survival age increased from 29.0years in 1990 to 38.6years in 2012 prior to the introduction of CFTRm and to 68.0years in 2023, demonstrating substantial improvement following the introduction of CFTRm. Linear regression analyses showed gains in median survival age increased from 0.48years per year prior to CFTRm to 4.79years per year after approval of ELX/TEZ/IVA in 2019. Study results provide initial evidence of the impact of CFTRm to meaningfully improve survival. Longer-term follow-up data across geographies will provide a deeper understanding of the full impact of CFTRm on predicted CF survival and mortality.

Dietary intakes and quality of Irish adults with cystic fibrosis: Comparisons to nutrition guidelines and HEI-2020.

Dietary intakes and quality of Irish adults with cystic fibrosis: Comparisons to nutrition guidelines and HEI-2020.

Postpartum Tubal Sterilization in Sickle Cell Disease in the 2012-2019 National Inpatient Sample.

Background: Sickle cell disease (SCD) is associated with high-risk pregnancy and low rates of hormonal contraception use. Intersectional vulnerabilities among individuals with SCD in the United States raise historically and socially contingent questions about tubal sterilization (TS), yet immediate postpartum TS rates among individuals with SCD remain unknown. Methods: Using the 2012-2019 National Inpatient Sample, we conducted a repeated cross-sectional study to estimate the rate of TS among delivery hospitalizations for people with SCD, without SCD (non-SCD), Black people with and without SCD, and people with cystic fibrosis (CF). Logistic regression models estimated the adjusted odds of TS between SCD and comparison groups. Interaction analyses examined whether severe maternal morbidity (SMM) modified the association between TS and SCD. Results: After adjusting for patient and hospital characteristics, SCD had higher odds of TS compared with non-SCD deliveries (adjusted odds ratio [aOR] = 1.38 [1.06, 1.79]). Among deliveries coded with Black race, SCD deliveries had higher odds of TS than non-SCD deliveries (aOR = 1.42 [1.06, 1.90]). There was no difference in the odds of TS between SCD and CF deliveries (aOR = 1.0 [0.51, 2.24]). SMM more than doubled the odds of TS in SCD deliveries (interaction: aOR = 2.34 [1.57, 3.47]; aOR = 2.14 [1.40, 3.24] in Black race deliveries). Conclusion: Even after accounting for patient and hospital characteristics, people with SCD have higher odds of immediate postpartum TS compared with comparison groups. Possibly, SMM severity, patient preference, or clinician recommendations inform this finding. SMM is three to seven times more common in SCD than non-SCD pregnancies and may be a modifiable risk factor for TS in SCD deliveries.

Systematic review of culturally targeted behavioral and psychosocial interventions among children from racially and ethnically minoritized backgrounds with chronic health conditions in the United States.

Few reviews have evaluated culturally targeted interventions for youth who have chronic health conditions. This systematic review aimed to describe health, psychosocial, behavioral, and sociocultural outcomes of culturally targeted interventions among children from racially and ethnically minoritized backgrounds who have a chronic condition in the United States. A systematic literature review was conducted (January 1, 2013 through July 1, 2023). We reviewed randomized and non-randomized controlled clinical trials investigating culturally targeted, psychologist-involved interventions among children (ages 0-18years) from racially/ethnically minoritized backgrounds in the United States with obesity, asthma, diabetes, sickle cell disease, cancer, cystic fibrosis, epilepsy, lupus, arthritis, and human immunodeficiency virus. Studies were included that compared culturally targeted interventions to non-targeted interventions or no intervention. Searches were conducted in PubMed, Embase, Central, and PsycINFO. Covidence was used for data screening, assessment, and extraction. Risk of bias was assessed with the Cochrane risk of bias version 2 tool. Extracted outcome variables included child health and healthcare utilization, and child and parent psychosocial, behavioral, and sociocultural outcomes. The review included one study evaluating the effectiveness of the Physician Asthma Care Education (PACE) intervention compared to PACE Plus, a culturally enhanced version, among African American and Latino youth with asthma. Participants included 112 primary care providers and 867 pediatric patients. Health, psychosocial/behavioral, and sociocultural outcomes of culturally targeted interventions for racially and ethnically minoritized youth with chronic health conditions in the United States are unknown. Future research should prioritize the development and evaluation of culturally targeted interventions for these populations.

Genotype and transcript processing of the tumour necrosis factor receptor TNFRSF1A in epithelial cells: implications for survival in cystic fibrosis.

Genotype and transcript processing of the tumour necrosis factor receptor TNFRSF1A in epithelial cells: implications for survival in cystic fibrosis.

Longitudinal Monitoring of Lumacaftor/Ivacaftor Response in Young Children with Cystic Fibrosis Lung Disease Using 129Xe MRI.

Longitudinal Monitoring of Lumacaftor/Ivacaftor Response in Young Children with Cystic Fibrosis Lung Disease Using 129Xe MRI.

N1303K (p.Asn1303Lys) Variant: Expanding Frontiers in the Treatment of Cystic Fibrosis.

N1303K (p.Asn1303Lys) Variant: Expanding Frontiers in the Treatment of Cystic Fibrosis.

NorA and Tet38 efflux pumps enable Staphylococcus aureus survival in the cystic fibrosis airway environment, resistance to antibiotics, and coinfection with Pseudomonas aeruginosa.

Efflux pumps play multiple roles in bacterial physiology, environmental adaptation, and antibiotic resistance. Early cystic fibrosis (CF) airway infections start with Staphylococcus aureus (SA), often later followed by Pseudomonas aeruginosa (PA) infections. In this study, we have evaluated the role of SA pumps NorA and Tet38 in survival and interaction with PA in CF patients. Data showed a ≥4-log10CFU/mL growth deficit of SA mutants ΔnorA and Δtet38 in an artificial sputum medium (ASM), suggesting NorA and Tet38 contributed to SA growth in CF sputum. In ASM, mucin activated norA but inhibited tet38, while extracellular DNA activated tet38 but inhibited norA, demonstrating complementary roles of mucin and DNA in affecting NorA and Tet38 expression. Furthermore, exposure of SA wild type to PA-excreted molecules affected pump expression; 3,4-dihydroxy-2-heptylquinoline PQS caused an increase in tet38 but a decrease in norA, 4-hydroxy-2-heptylquinoline HHQ caused a decrease in norA and tet38, and pyocyanin PYO caused a modest increase in norA, demonstrating differing additional roles of PA-secreted molecules influencing NorA and Tet38 expression. Evaluation of 48 randomly selected unique CF-associated SA showed that 18.8% were NorA-overexpressors and 10.4% were Tet38-overexpressors. NorA-overexpressors showed a fourfold increase in pyocyanin MIC and ≥16-fold in ciprofloxacin MIC. Furthermore, 89% of NorA-overexpressors carried an insertion of CAAT/ACAA/CTAT at the (-10) motif of the norA promoter, and 62.5% of these were co-isolated with PA.These data showed that SA survives PA killing in CF sputum conditions using sputum key components and PA-specific signal molecules to regulate NorA and Tet38 expression.

Effectiveness Of High-Frequency Chest Wall Oscillation In Pulmonary Rehabilitation: An Evidence-Based Analysis

Chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD), bronchiectasis, and cystic fibrosis are frequently associated with impaired mucociliary clearance and mucus retention, leading to airflow obstruction, recurrent infections, and compromised pulmonary function (Hardy, 1994; Tomkiewicz et al., 1994). High-Frequency Chest Wall Oscillation (HFCWO) is a non-invasive airway clearance technique that delivers rapid chest compressions via an inflatable vest to facilitate secretion mobilization (AbdelAzeem et al., 2024; Nicolini et al., 2013). This evidence-based review aimed to assess the clinical effectiveness of HFCWO as part of pulmonary rehabilitation. A comprehensive literature search across PubMed, Scopus, Cochrane Library, and CINAHL included studies published between 2013 and 2025, with randomized controlled trials, systematic reviews, and clinical trials involving adult patients assessed using CASP and JBI appraisal tools. Eight studies, including four RCTs and four experimental trials, were included. Results demonstrated statistically significant improvements in airway clearance, FEV₁, and health-related quality of life in patients receiving HFCWO compared to conventional chest physiotherapy (Huang et al., 2022; Seifer et al., 2020; Ibrahim &amp; Abdellatif, 2020). Additional benefits included improved patient adherence, comfort, and reduced healthcare utilization (Camacho Urribarri et al., 2024; Alahmari et al., 2017). The findings support the integration of HFCWO as an effective adjunct in pulmonary rehabilitation protocols, especially for patients with chronic mucus retention.

Structure-guided combination of novel CFTR correctors to improve the function of F508del-CFTR in airway epithelial cells.

Structure-guided combination of novel CFTR correctors to improve the function of F508del-CFTR in airway epithelial cells.

Symptom factors and their clinical correlates among adults with cystic fibrosis.

Symptom factors and their clinical correlates among adults with cystic fibrosis.

The cGAS-STING signaling pathway in the regulation of pulmonary infections: a systematic review

The lungs are constantly exposed to airborne pathogens and depend on robust innate immune surveillance for protection. The cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling pathway, a core component of the innate immune system, plays a pivotal role in defending against respiratory infections caused by viruses, bacteria, and mycobacteria, including Mycobacterium tuberculosis. Dysregulation of this pathway has been linked to several chronic lung diseases, such as cystic fibrosis, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, and asthma. Upon sensing cytoplasmic DNA, cGAS activates the STING pathway, producing type I interferons and pro-inflammatory cytokines that drive host immune response. However, many pathogens have developed strategies to evade detection or surpass cGAS-STING signaling. This systematic review highlights the molecular mechanisms governing cGAS-STING activation, its interaction with lung pathogens, and its potential as a therapeutic agent in respiratory diseases.

Assessment of Bronchodilator Response in Patients with CF and Non-CF Bronchiectasis-A Randomized Controlled Study.

Objectives: Although patients with bronchiectasis tend to have obstructive nonreversible lung functions, some have bronchodilator response (BDR), and a relatively large number are treated with bronchodilators. We assessed BDR in patients with cystic fibrosis (CF) and other bronchiectatic diseases and healthy controls (HCs) in a randomized controlled setup. Methods: Patients with cystic fibrosis (CF), primary ciliary dyskinesia (PCD) and non-CF non-PCD bronchiectasis (non-CF/PCD), as well as HCs, were recruited. Participants were randomly assigned to receive salbutamol (four puffs) and then a placebo or a placebo and then salbutamol. BDR was calculated using the American Thoracic Society (ATS)/European Respiratory Society (ERS) standard, defined as the change related to the individual's predicted value (new method) or to the initial value (old method). Results: Sixty-nine patients (CF = 30, PCD = 20, non-CF/PCD = 19) and 20 HCs were included. Patients with CF and PCD (but not non-CF/PCD) had a statistically greater mean response to salbutamol compared with the placebo, (CF-salbutamol first: 2.82 vs. 0.85%, p = 0.01; placebo first: 2.39 vs. -0.27%, p = 0.02; PCD-salbutamol first: 5.32 vs. 1.88%, p = 0.01; placebo first: 2.24 vs. 0.77%, p = 0.05). Few patients had significant BDR (new method, >10%)-CF (0), PCD (2), non-CF/PCD (0) and HCs (2)): using the old method, an additional PCD patient and three non-CF/PCD had significant BDR (>12%). Conclusions: Significant BDR seems to be rare in patients with bronchiectasis. In CF and PCD, the response was greater than the placebo; the clinical significance of this difference and its therapeutic implications, as well as the best method to determine BDR, have yet to be determined.

Antimicrobial activity of aqueous-alcoholic extracts from myrtle leaves in relation to strains isolated from patients with cystic fibrosis

The search for new antimicrobial medicines based on medicinal plant raw materials (MPRM) and its effective and safe use in modern pharmaceutical practice remains one of the most pressing issues in pharmacy. Today, the search for new biologically active compounds (BACs) with antimicrobial and antifungal activity is ongoing. Due to the content of the BACs complex, preparations based on MPRMs have a milder effect on the human body compared to synthetic analogues. According to the results of studying some foreign studies and publications on the topic of antimicrobial and antifungal activity, a promising source of BACs, namely the leaves of common myrtle (Myrtus communis L.), is of scientific interest.The aim. Analysis and comparative study of the antibacterial activity of samples of extracts obtained using ethanol of various concentrations, and an infusion of common myrtle leaves (Myrtus communis L.) against clinical strains isolated from patients with cystic fibrosis.Materials and methods. The objects of the study were water-alcohol extracts from common myrtle leaves, comparison preparations — ethanol with a concentration of 40, 70, 96% and eucalyptus tincture. 5 strains of pathogenic microorganisms isolated from the sputum of patients with cystic fibrosis were used as test cultures. The minimum inhibitory concentration was assessed using the method of double serial dilutions in broth.Results. All water-alcohol extracts from common myrtle leaves showed antimicrobial activity exceeding the control samples against 3 mucoid strains — Burkholderia cenocepacia, Stenotrophomonas maltophilia and Pseudomonas aeruginosa. No antimicrobial activity was detected for the remaining 2 strains. A pronounced antimicrobial effect was possessed by 70% tincture and aqueous infusion of leaves.Conclusion. The data obtained during the study allow us to draw conclusions about the further prospects of studying 70% myrtle tincture and aqueous infusion for use in the therapy of patients with cystic fibrosis.

Effects of CFTR Modulators on Pseudomonas aeruginosa Infections in Cystic Fibrosis

Background: Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Modulator therapies have the ability to improve CFTR function in CF patients, but despite the clear evidence of benefits regarding CFTR modulator therapy, including improved lung function, the reduced rate of exacerbations, and an overall improved quality of life, studies focusing on the reduction rates of P. aeruginosa infections during modulator therapy expressed the need for future research on this topic. Objective: This study aimed to evaluate the impact of CFTR modulator therapies on the prevalence, density, and persistence of P. aeruginosa infection in CF patients and to explore the mechanisms involved. Methods: A systematic literature review was performed by searching five major databases (PubMed, Cochrane Library, Scopus, Google Scholar, and Web of Science), and 21 relevant articles investigating the link between CFTR therapy and P. aeruginosa infections were selected following the PRISMA guidelines. Results: The data indicated that Ivacaftor and the combination Elexacaftor/Tezacaftor/Ivacaftor (ETI) can reduce total bacterial load and markers of systemic inflammation. However, clonal lines of P. aeruginosa persist in most cases, and complete eradication is rare, mainly due to biofilm formation and antimicrobial resistance. Conclusions: Although CFTR-modulating therapies help to improve clinical condition and reduce inflammation, they do not consistently lead to the elimination of P. aeruginosa.