J Heart Lung Transplant. 2025 Apr 20:S1053-2498(25)01917-5. doi: 10.1016/j.healun.2025.04.010. Online ahead of print.

ABSTRACT

BACKGROUND: CD26/DPP-IV inhibitors (gliptins) target pro-inflammatory pathways that contribute to the development of chronic lung allograft dysfunction (CLAD). We analyzed longitudinal clinical data from 6 North American lung transplant centers to elucidate the effect of gliptin exposure on CLAD development after lung transplantation.

METHODS: This cohort included 6 North American lung transplant centers, four sites from the Clinical Trials in Organ Transplantation-20 study and 2 additional sites. First lung transplant recipients between December 2015 and August 2018 were eligible with follow up through June 2021. Gliptin exposures prior to CLAD onset in addition to CLAD risk factors were included in the models. The primary endpoint was a composite of probable CLAD, CLAD related deaths, and CLAD related re-transplant. Cox regression models were used to assess the association between gliptin use and the CLAD composite endpoint.

RESULTS: 779 patients met inclusion criteria, with 126 (16.2%) having any gliptin exposure. 233 (29.9%) patients experienced probable CLAD composite outcome. Across all centers, gliptin exposure at any point was not associated with probable CLAD or definite CLAD across the study period. In a post-hoc analysis of centers with median gliptin exposures > 6 months, exposure within the first 90 days post-transplant was associated with a decreased risk of definite CLAD composite across the study period (HR 0.25; 95% CI, 0.07, 0.83; p<0.05).

CONCLUSIONS: The association of gliptins and CLAD is complex, but early gliptin use may help protect against CLAD if started within 90 days post-transplant and used for a prolonged period.

PMID:40300676 | DOI:10.1016/j.healun.2025.04.010

Am J Nephrol. 2025 Apr 29:1-17. doi: 10.1159/000545614. Online ahead of print.

ABSTRACT

INTRODUCTION: Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder that is characterized by the development of fluid-filled kidney cysts, which often lead to kidney failure. The vasopressin receptor 2 antagonist, tolvaptan, is the only approved treatment that slows the progression of ADPKD. There is an unmet need for treatment options for patients with ADPKD because tolvaptan has limited efficacy and non-negligible side effects. In vitro and in vivo data suggest that inhibition of the cystic fibrosis transmembrane conductance regulator (CFTR) may be a suitable approach to treating ADPKD. Here, we assessed the capacity of GLPG2737, a CFTR inhibitor, to inhibit cyst growth in preclinical models of ADPKD.

METHODS: We investigated the ability of GLPG2737 to modulate CFTR activity in mouse kidney inner medullary collecting duct (mIMCD-3) epithelial cells by measuring chloride flux, and to prevent cyst growth in mIMCD-3 cells, cells from human ADPKD kidney donors, and metanephric organ cultures (MOCs). We assessed cyst volume, kidney weight or volume, and blood urea nitrogen (BUN) in two mouse ADPKD models (Pkd1 kidney-specific knockout mouse model; Pkd1RC/RC mouse model) that received GLPG2737, tolvaptan, or their combination. Statistical tests used for data analysis were based on the normality and variance of the data.

RESULTS: GLPG2737 inhibited chloride flux in mIMCD-3 cells with an IC50 of 2.41 µM. In a 3D assay, GLPG2737 inhibited cyst growth in both wild-type (IC50 = 2.36 µM) and Pkd1 knockout (IC50 = 2.5 µM) mIMCD-3 cells. Preincubation of human ADPKD kidney cells with 10 µM of GLPG2737, 10 µM of tolvaptan, or their combination prevented forskolin-induced cyst growth by 40%, 29%, and 70%, respectively. Furthermore, 10 µM of GLPG2737 inhibited cyst growth in MOCs, decreasing the cyst area by 67% and the number of cysts per area by 46% after 6 days of culture. In both in vivo models, GLPG2737, tolvaptan, or their combination improved the projected cyst volume. In the Pkd1RC/RC model, GLPG2737 also improved the total kidney volume normalized to tibia length (LnTKV) and BUN, while tolvaptan improved the LnTKV and fibrosis but did not lower BUN at sacrifice. The combination reduced all parameters measured in the Pkd1RC/RC model, including cyclic adenosine monophosphate (cAMP) content in the kidneys.

CONCLUSIONS: Our findings in preclinical models provide evidence of the therapeutic potential of CFTR inhibition, and its possible combination with tolvaptan. The present work shows that targeting CFTR is a valid strategy to slow ADPKD progression.

PMID:40300563 | DOI:10.1159/000545614

Int J Adolesc Med Health. 2025 May 1. doi: 10.1515/ijamh-2024-0192. Online ahead of print.

ABSTRACT

OBJECTIVES: With over 54,000 people affected, cystic fibrosis is one of the most common rare diseases in Europe. As life expectancy of this disease has steadily increased in recent years, the transition from pediatric to adult care has become a principal issue. This study aimed to identify facilitating and hindering factors in the transitional care of cystic fibrosis patients in order to derive indications for improving care.

METHODS: A qualitative systematized review was conducted in May 2024 with a systematic search carried out in MEDLINE, CINAHL and Livivo, including European studies from 2009 to 2024. The studies' quality was assessed using the Critical Appraisal Skills Programme checklist for qualitative studies. Thematic analysis was applied for analyzing the data to identify categories.

RESULTS: Nine studies met the inclusion criteria. Their quality can be rated as medium to high. Parental support, commitment and social support were identified as beneficial factors. Preparation for the transition, appropriate communication and continuous follow-ups at the adult center also contributed to a continuous transition. However, the parents' changing roles, fears and the usual treatment in pediatrics were obstacles. The adjustment to the adult center and structural problems presented further barriers to transition.

CONCLUSIONS: Various factors were identified to influence the transition process in cystic fibrosis, with consistency across the studies. In practice, comprehensive care is required, focused on the patients' needs, with more information provided and enhanced collaboration among stakeholders. Further research regarding the long-term effects of transition and the utilization of structured transition programs is needed.

PMID:40300192 | DOI:10.1515/ijamh-2024-0192

PLoS One. 2025 Apr 29;20(4):e0321094. doi: 10.1371/journal.pone.0321094. eCollection 2025.

ABSTRACT

The prolonged persistence of extracellular chromatin and DNA is a salient feature of diseases like cystic fibrosis, systemic lupus erythematosus and COVID-19 associated microangiopathy. Since deoxyribonuclease I (DNase1) is a major endonuclease involved in DNA-related waste disposal, recombinant DNase1 is an important therapeutic biologic. Recently we described the production of recombinant murine DNase1 (rmDNase1) in Pichia pastoris by employing the α-mating factor prepro signal peptide (αMF-SP) a method, which we now applied to express recombinant human DNASE1 (rhDNASE1). In addition to an impaired cleavage of the αMF pro-peptide, which we also detected previously for mDNase1, expression of hDNASE1 resulted in a 70-80 times lower yield although both orthologues share a high structural and functional homology. Using mDNase1 expression as a guideline, we were able to increase the yield of hDNASE1 fourfold by optimizing parameters like nutrients, cultivation temperature, methanol supply, and codon usage. In addition, post-translational import into the rough endoplasmic reticulum (rER) was changed to co-translational import by employing the signal peptide (SP) of the α-subunit of the Oligosaccharyltransferase complex (Ost1) from Saccharomyces cerevisiae. These improvements resulted in the purification of ~ 8 mg pure mature rmDNase1 and ~ 0.4 mg rhDNASE1 per Liter expression medium of a culture with a cell density of OD600 = 40 in 24 hours. As a main cause for the expression difference, we assume varying folding abilities to reach a native conformation, which induce an elevated unproductive unfolded protein response within the rER during hDNASE1 expression. Concerning functionality, rhDNASE1 expressed in P. pastoris is comparable to Pulmozyme®, i.e. rhDNASE1 produced in Chinese hamster ovary (CHO) cells by Roche - Genentech. With respect to the biochemical effectivity, rmDNase1 is superior to rhDNASE1 due to its higher specific activity in the presence of Ca2 + /Mg2 + and the lower inhibition by monomeric actin.

PMID:40299953 | DOI:10.1371/journal.pone.0321094

Biomedicines. 2025 Apr 4;13(4):879. doi: 10.3390/biomedicines13040879.

ABSTRACT

Background: Organoids are a valuable model for studying hereditary diseases such as cystic fibrosis (CF). Recombinant adenoviral (rAdV) and adeno-associated viral (rAAV) vectors are promising tools for CF gene therapy and genome editing. Objective: This study aims to determine the most efficient viral vector (rAdV5, rAAV serotypes 5, 6 and 9) and transduction protocol for delivering transgenes to lung organoids (LOs), providing a foundation for future CF gene therapy development. Methods: Three transduction protocols were used taking into account the specificities of LOs' cultivation in specific matrices, both with and without organoid extraction from the matrix. This work was carried out on organoids from a healthy donor (LOs-WT) and on a patient with cystic fibrosis (LOs-CF). Results: High transduction efficiency was observed with rAdV5 (30% cells), rAAV6 (>80% cells), and rAAV9 (>40% cells). rAdV5 and rAAV9 transduced basal and secretory cells with >90% efficiency. For rAAV9, Protocol 1 (without extraction of organoids from the matrix) showed lower transduction efficiency (33% for LOs-WT, 9% for LOs-CF), significantly lower than that of Protocols 2 (60% for LOs-WT, 59% for LOs-CF) and 3 (46% for LOs-WT, 35% for LOs-CF) with organoid extraction from the matrix (p < 0.005). Conclusions: rAdV5 and rAAV9 are the most promising vectors for the delivery of transgenes to basal and secretory cells in a lung organoid model, providing a solid foundation for CF gene therapy development.

PMID:40299508 | DOI:10.3390/biomedicines13040879

Antibiotics (Basel). 2025 Apr 14;14(4):402. doi: 10.3390/antibiotics14040402.

ABSTRACT

Background/Objectives: Antibiotic therapy faces challenges from rising acquired and biofilm-related antibiotic resistance rates. High resistance levels to commonly used antibiotics have been observed in methicillin-resistant Staphylococcus aureus (MRSA) strains among cystic fibrosis (CF) patients, indicating an urgent need for new antibacterial agents. This study aimed to identify potential novel therapeutics with antibacterial and antibiofilm activities against an MRSA CF strain by screening, for the first time, the Drug Repurposing Compound Library (MedChem Express). Methods/Results: Among the 3386 compounds, a high-throughput screening-based spectrophotometric approach identified 2439 (72%), 654 (19.3%), and 426 (12.6%) drugs active against planktonic cells, biofilm formation, and preformed biofilm, respectively, although to different extents. The most active hits were 193 (5.7%), against planktonic cells, causing a 100% growth inhibition; 5 (0.14%), with excellent activity against biofilm formation (i.e., reduction ≥ 90%); and 4, showing high activity (i.e., 60% ≤ biofilm reduction < 90%) against preformed biofilms. The potential hits belonged to several primary research areas, with "cancer" being the most prevalent. After performing a literature review to identify other, already published biological properties that could be relevant to the CF lung environment (i.e., activity against other CF pathogens, and anti-inflammatory and anti-virulence potential), the most interesting hits were the following: 5-(N,N-Hexamethylene)-amiloride (diuretic), Toremifene (anticancer), Zafirlukast (antiasthmatic), Fenretide (anticancer), and Montelukast (antiasthmatic) against planktonic S. aureus cells; Hemin against biofilm formation; and Heparin, Clemastine (antihistaminic), and Bromfenac (nonsteroidal anti-inflammatory) against established biofilms. Conclusions: These findings warrant further in vitro and in vivo studies to confirm the potential of repurposing these compounds for managing lung infections caused by S. aureus in CF patients.

PMID:40298549 | DOI:10.3390/antibiotics14040402

Microbiol Resour Announc. 2025 Apr 29:e0027525. doi: 10.1128/mra.00275-25. Online ahead of print.

ABSTRACT

We describe the genomes of two Pseudomonas aeruginosa phages of the genus Bruynoghevirus, WRAIR_EPa83 and WRAIR_EPa87. They consist of 45,622 and 45,077 bp, with 52.52% and 52.11% guanine-cytosine content, contain 81 and 80 coding sequences, two and three tRNA genes, and direct terminal repeats of 183 and 184 bp, respectively.

PMID:40298417 | DOI:10.1128/mra.00275-25

mSphere. 2025 Apr 29:e0023325. doi: 10.1128/msphere.00233-25. Online ahead of print.

ABSTRACT

Persistent bacterial airway infection is a hallmark feature of cystic fibrosis (CF). Achromobacter spp. are gram-negative rods that can cause persistent airway infection in people with CF (pwCF), but the knowledge of host immune responses to these bacteria is limited. The aim of this study was to investigate if patients develop antibodies against Achromobacter xylosoxidans, the most common Achromobacter species, and to identify the bacterial antigens that induce specific IgG responses. Seven serum samples from pwCF with Achromobacter infection were screened for antibodies against bacteria in an ELISA coated with A. xylosoxidans, A. insuavis, or Pseudomonas aeruginosa. Sera from pwCF with or without P. aeruginosa infection (n = 22 and 20, respectively) and healthy donors (n = 4) were included for comparison. Serum with high titers to A. xylosoxidans was selected for affinity purification of bacterial antigens using serum IgGs bound to protein G beads. The resulting IgG-antigen complexes were then analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Selected antigens of interest were produced in recombinant form and used in an ELISA to confirm the results. Four of the seven patients with Achromobacter infection had serum antibodies against Achromobacter. Using patient serum-IgG for affinity purification of A. xylosoxidans proteins, we identified eight antigens. Three of these, which were not targeted by anti-P. aeruginosa antibodies, were expressed recombinantly for further validation: dihydrolipoyl dehydrogenase (DLD), type I secretion C-terminal target domain-containing protein, and domain of uncharacterized function 336 (DUF336). While specific IgG against all three recombinant antigens was confirmed in the patient serum with high titers against Achromobacter, DLD and DUF336 showed the least binding to serum IgG from pwCF without Achromobacter spp. infection. Using serum IgG affinity purification in combination with LC-MS/MS and confirming the results using ELISA against recombinant proteins, we have identified bacterial antigens from A. xylosoxidans.IMPORTANCEAchromobacter species are opportunistic pathogens that can cause airway infections in people with cystic fibrosis. In this patient population, persistent Achromobacter infection is associated with low lung function, but the knowledge about bacterial interactions with the host is currently limited. In this study, we identify protein antigens that induce specific antibody responses in the host. The identified antigens may potentially be useful in serological assays, serving as a complement to culturing methods for the diagnosis and surveillance of Achromobacter infection.

PMID:40298413 | DOI:10.1128/msphere.00233-25

Vavilovskii Zhurnal Genet Selektsii. 2025 Apr;29(2):279-289. doi: 10.18699/vjgb-25-31.

ABSTRACT

Cystic fibrosis (CF) is a disease with a broad clinical and genetic spectrum of manifestations, significantly impacting the quality and duration of life of patients. At present, a diagnosis of CF enables the disease to be identified at the earliest stages of its development. The accelerated advancement of scientific knowledge and contemporary research techniques has transformed the methodology employed in the treatment of CF, encompassing a spectrum of approaches from symptomatic management to pathogenetic therapies. Pathogenetic therapy represents an approach to treatment that aims to identify methods of restoring the function of the CFTR gene. The objective of this review was to analyse and summarize the available scientific data on the pathogenetic therapy of CF. This paper considers various approaches to the pathogenetic therapy of CF that are based on the use of targeted drugs known as CFTR modulators. The article presents studies employing gene therapy techniques for CF, which are based on the targeted delivery of a normal copy of the CFTR gene cDNA to the respiratory tract via viral or non-viral vectors. Some studies have demonstrated the efficacy of RNA therapeutic interventions in restoring splicing, promoting the production of mature RNA, and increasing the functional expression of the CFTR protein. The review also analyzes literature data that consider methods of etiotropic therapy for CF, which consists of targeted correction of the CFTR gene using artificial restriction enzymes, the CRISPR/Cas9 system and a complex of peptide-nucleic acids. In a prospective plan, the use of cell therapy methods in the treatment of lung damage in CF is considered.

PMID:40297296 | PMC:PMC12036567 | DOI:10.18699/vjgb-25-31

J Pathol Inform. 2025 Mar 27;17:100438. doi: 10.1016/j.jpi.2025.100438. eCollection 2025 Apr.

ABSTRACT

Immune cell differentials are most commonly performed manually or with the use of automated cell sorting devices. However, manual review by research personnel can be both subjective and time consuming, and cell sorting approaches consume samples and demand additional reagents to perform the differential. We have created an artificial intelligence (AI) image processing pipeline using the Biodock.ai platform to classify immune cell types from Giemsa-stained cytospins of mouse bronchoalveolar lavage fluid. Through multiple rounds of training and refinement, we have created a tool that is as accurate as manual review of slide images while removing the subjectivity and making the process mostly hands off, saving researcher time for other tasks and improving core turnaround for experiments. This AI-based image processing is directly compatible with current workflows utilizing stained slides, in contrast to a change to a flow cytometry-based approach, which requires both specialized equipment, reagents, and expertise.

PMID:40297061 | PMC:PMC12036075 | DOI:10.1016/j.jpi.2025.100438

Hum Gene Ther. 2025 Apr 28. doi: 10.1089/hum.2024.258. Online ahead of print.

ABSTRACT

The advent of genome editing has kindled the hope to cure previously uncurable, life-threatening genetic diseases. However, whether this promise can be ultimately fulfilled depends on how efficiently gene editing agents can be delivered to therapeutically relevant cells. Over time, viruses have evolved into sophisticated, versatile, and biocompatible nanomachines that can be engineered to shuttle payloads to specific cell types. Despite the advances in safety and selectivity, the long-term expression of gene editing agents sustained by viral vectors remains a cause for concern. Cell-derived vesicles (CDVs) are gaining traction as elegant alternatives. CDVs encompass extracellular vesicles (EVs), a diverse set of intrinsically biocompatible and low-immunogenic membranous nanoparticles, and virus-like particles (VLPs), bioparticles with virus-like scaffold and envelope structures, but devoid of genetic material. Both EVs and VLPs can efficiently deliver ribonucleoprotein cargo to the target cell cytoplasm, ensuring that the editing machinery is only transiently active in the cell and thereby increasing its safety. In this review, we explore the natural diversity of CDVs and their potential as delivery vectors for the clustered regularly interspaced short palindromic repeats (CRISPR) machinery. We illustrate different strategies for the optimization of CDV cargo loading and retargeting, highlighting the versatility and tunability of these vehicles. Nonetheless, the lack of robust and standardized protocols for CDV production, purification, and quality assessment still hinders their widespread adoption to further CRISPR-based therapies as advanced "living drugs." We believe that a collective, multifaceted effort is urgently needed to address these critical issues and unlock the full potential of genome-editing technologies to yield safe, easy-to-manufacture, and pharmacologically well-defined therapies. Finally, we discuss the current clinical landscape of lung-directed gene therapies for cystic fibrosis and explore how CDVs could drive significant breakthroughs in in vivo gene editing for this disease.

PMID:40295092 | DOI:10.1089/hum.2024.258

JAMA. 2025 Apr 28. doi: 10.1001/jama.2025.2680. Online ahead of print.

ABSTRACT

IMPORTANCE: Non-cystic fibrosis (CF) bronchiectasis is a chronic lung condition caused by permanent bronchial dilatation and inflammation and is characterized by daily cough, sputum, and recurrent exacerbations. Approximately 500 000 people in the US have non-CF bronchiectasis.

OBSERVATIONS: Non-CF bronchiectasis may be associated with prior pneumonia, infection with nontuberculous mycobacteria or tuberculosis, genetic conditions (eg, α1-antitrypsin deficiency, primary ciliary dyskinesia), autoimmune diseases (eg, rheumatoid arthritis, inflammatory bowel disease), allergic bronchopulmonary aspergillosis, and immunodeficiency syndromes (eg, common variable immunodeficiency). Up to 38% of cases are idiopathic. According to US data, conditions associated with non-CF bronchiectasis include gastroesophageal reflux disease (47%), asthma (29%), and chronic obstructive pulmonary disease (20%). The prevalence of non-CF bronchiectasis increases substantially with age (7 per 100 000 in individuals 18-34 years vs 812 per 100 000 in those ≥75 years) and is more common in women than men (180 vs 95 per 100 000). Diagnosis is confirmed with noncontrast chest computed tomography showing dilated airways and often airway thickening and mucus plugging. Initial diagnostic evaluation involves blood testing (complete blood cell count with differential); immunoglobulin quantification testing (IgG, IgA, IgE, and IgM); sputum cultures for bacteria, mycobacteria, and fungi; and prebronchodilator and postbronchodilator spirometry. Treatment includes airway clearance techniques; nebulization of saline to loosen tenacious secretions; and regular exercise, participation in pulmonary rehabilitation, or both. Inhaled bronchodilators (β-agonists and antimuscarinic agents) and inhaled corticosteroids are indicated for patients with bronchiectasis who have asthma or chronic obstructive pulmonary disease. Exacerbations of bronchiectasis, which typically present with increased cough and sputum and worsened fatigue, are associated with progressive decline in lung function and decreased quality of life. Exacerbations should be treated with oral or intravenous antibiotics. Individuals with 3 or more exacerbations of bronchiectasis annually may benefit from long-term inhaled antibiotics (eg, colistin, gentamicin) or daily oral macrolides (eg, azithromycin). Lung transplant may be considered for patients with severely impaired pulmonary function, frequent exacerbations, or both. Among patients with non-CF bronchiectasis, mortality is higher for those with frequent and severe exacerbations, infection with Pseudomonas aeruginosa, and comorbidities, such as chronic obstructive pulmonary disease.

CONCLUSIONS AND RELEVANCE: Non-CF bronchiectasis is a chronic lung condition that typically causes chronic cough and daily sputum production. Exacerbations are associated with progressive decline in lung function and decreased quality of life. Management involves treatment of conditions associated with bronchiectasis, airway clearance techniques, oral or intravenous antibiotics for acute exacerbations, and consideration of long-term inhaled antibiotics or oral macrolides for patients with 3 or more exacerbations annually.

PMID:40293759 | DOI:10.1001/jama.2025.2680

Lancet Reg Health Eur. 2025 Apr 19;53:101303. doi: 10.1016/j.lanepe.2025.101303. eCollection 2025 Jun.

ABSTRACT

BACKGROUND: According to estimates, globally more than 200,000 pregnant women develop tuberculosis (TB) annually. Despite this, data on perinatal TB remain scarce. This study aimed to describe perinatal TB, comprising congenital (cTB) and postnatal (pTB) TB, in a European setting.

METHODS: Retrospective cohort study via the Paediatric Tuberculosis Network European Trials Group (ptbnet) capturing and comparing cases of cTB and pTB diagnosed at 104 participating European healthcare institutions between 1995 and 2019.

FINDINGS: Forty-six cases reported by 20 centres were included in the final analysis (cTB, n = 27; pTB, n = 19). Median age at symptom onset was one week in cTB (IQR: 0-1 weeks), and 12 weeks in pTB patients (IQR: 5-18 weeks). Prematurity was more common in cTB than pTB patients [57.9% (11/19); 95% CI: 36.3-76.9% vs. 21.1% (4/19); 95% CI: 8.5-43.3%; p = 0.049], and the average birth weight was significantly lower [1680 g; IQR: 932-2805 g vs. 2890 g; IQR: 2461-3400 g; p = 0.0043]. Microbiological confirmation was achieved in most patients [85.2% (23/27); 95% CI: 67.5-94.1% vs. 78.9% (15/19); 95% CI: 56.7-91.5%; p = 0.70]. The sensitivity of interferon-gamma release assays was poor in both groups [25.0% (3/12) 95% CI: 8.9-53.2% vs. 35.7% (5/14) 95% CI: 16.3-61.2%; p = 0.68]; in contrast, the sensitivity of the tuberculin skin tests (at 5 mm cut-off) was significantly higher in pTB patients [16.7% (2/12) 95% CI: 4.7-44.8% vs. 66.7% (10/15); 95% CI: 41.7-84.8%; p = 0.0185]. Approximately half of the patients required intensive care support [51.9% (14/27) 95% CI: 34.0-69.3% vs. 47.4% (9/19); 95% CI: 27.3-68.3%; p > 0.99]. Four (4/46; 8.7%) patients died, and four (4/46; 8.7%) had severe long-term sequelae.

INTERPRETATION: There was substantial mortality and morbidity in this patient cohort, despite the high-resource setting. cTB was associated with premature birth and low birth weight. In contrast to microbiological tests, immunological tests perform poorly in perinatal TB, and should therefore not be used as rule-out tests.

FUNDING: No study-specific funding.

PMID:40291400 | PMC:PMC12032942 | DOI:10.1016/j.lanepe.2025.101303

APL Bioeng. 2025 Apr 25;9(2):026110. doi: 10.1063/5.0220367. eCollection 2025 Jun.

ABSTRACT

Dysregulated neutrophil recruitment drives many pulmonary diseases, but most preclinical screening methods are unsuited to evaluate pulmonary neutrophilia, limiting progress toward therapeutics. Namely, high-throughput therapeutic assays typically exclude critical neutrophilic pathophysiology, including blood-to-lung recruitment, dysfunctional activation, and resulting impacts on the air-blood barrier. To meet the conflicting demands of physiological complexity and high throughput, we developed an assay of 96-well leukocyte recruitment in an air-blood barrier array (L-ABBA-96) that enables in vivo-like neutrophil recruitment compatible with downstream phenotyping by automated flow cytometry. We modeled acute respiratory distress syndrome (ARDS) with neutrophil recruitment to 20 ng/mL epithelial-side interleukin 8 and found a dose-dependent reduction in recruitment with physiologic doses of baricitinib, a JAK1/2 inhibitor recently Food and Drug Administration-approved for severe Coronavirus Disease 2019 ARDS. Additionally, neutrophil recruitment to patient-derived cystic fibrosis sputum supernatant induced disease-mimetic recruitment and activation of healthy donor neutrophils and upregulated endothelial e-selectin. Compared to 24-well assays, the L-ABBA-96 reduces required patient sample volumes by 25 times per well and quadruples throughput per plate. Compared to microfluidic assays, the L-ABBA-96 recruits two orders of magnitude more neutrophils per well, enabling downstream flow cytometry and other standard biochemical assays. This novel pairing of high-throughput in vitro modeling of organ-level lung function with parallel high-throughput leukocyte phenotyping substantially advances opportunities for pathophysiological studies, personalized medicine, and drug testing applications.

PMID:40290728 | PMC:PMC12033047 | DOI:10.1063/5.0220367

Biofilm. 2025 Apr 11;9:100279. doi: 10.1016/j.bioflm.2025.100279. eCollection 2025 Jun.

ABSTRACT

Co-infections by Staphylococcus aureus and Pseudomonas aeruginosa are frequent in the airways of patients with cystic fibrosis. These co-infections show higher antibiotic tolerance in vitro compared to mono-infections. In vitro models have been developed to study the interspecies interactions between P. aeruginosa and S. aureus. However, these model systems fail to incorporate clinical isolates with diverse phenotypes, do not reflect the nutritional environment of the CF airway mucus, and/or do not model the biofilm mode of growth observed in the CF airways. Here, we established a dual-species biofilm model grown in artificial sputum medium, where S. aureus was inoculated before P. aeruginosa to facilitate the maintenance of both species over time. It was successfully applied to ten pairs of clinical isolates exhibiting different phenotypes. Co-isolates from individual patients led to robust, stable co-cultures, supporting the theory of cross-adaptation in vivo. Investigation into the cross-adaptation of the VBB496 co-isolate pair revealed that both the P. aeruginosa and S. aureus isolates had reduced antagonism, in part due to reduced production of P. aeruginosa secondary metabolites as well as higher tolerance to those metabolites by S. aureus. Together, these results indicate that the two-species biofilm model system provides a useful tool for exploring interspecies interactions of P. aeruginosa and S. aureus in the context of CF airway infections.

PMID:40290724 | PMC:PMC12033965 | DOI:10.1016/j.bioflm.2025.100279

Pak J Med Sci. 2025 Apr;41(4):1052-1057. doi: 10.12669/pjms.41.4.10877.

ABSTRACT

BACKGROUND & OBJECTIVES: Bronchiectasis is the permanent enlargement of the bronchi following damage to the respiratory tract (bronchi) in the lungs. Bronchiectasis not associated with cystic fibrosis is gaining an increasing place among chronic respiratory diseases worldwide. The purpose of this study was to identify the levels of MMP-9, known to cause bronchial damage in chronic pulmonary illness, and SIRT-1, an anti-aging and anti-infective regulatory protein, in patients with bronchiectasis and to evaluate the importance of these biomarkers in diagnosis.

METHODS: This cross-sectional study was conducted in the Chest Diseases Clinic of Sivas Cumhuriyet University Medical Faculty Hospital between November 2020 and September 2022. We recruited 30 patients with bronchiectasis whose diagnosis was verified by high-resolution chest CT scan and 30 healthy controls. SIRT-1 and MMP-9 levels in the serum of the study group were determined by the ELISA method.

RESULTS: SIRT-1 and MMP-9 concentrations were found to be statistically significant. In comparison to the control group, it was observed that the bronchiectasis group had a lower serum SIRT-1 levels (p<0.001). The bronchiectasis group had higher serum MMP-9 values than the control group (p<0.001). Age-related differences in SIRT-1 and MMP-9 concentrations were not observed. No correlation was found between MMP-9 and SIRT-1. The results of Receiver Operating Characteristic (ROC) analysis indicated that MMP-9 has relatively high sensitivities.

CONCLUSIONS: We concluded that, higher inflammation elevates MMP-9 levels while decreasing SIRT-1 levels. MMP-9 and SIRT-1 may be potential biomarkers in the diagnosis of bronchiectasis.

PMID:40290232 | PMC:PMC12022576 | DOI:10.12669/pjms.41.4.10877

Farm Hosp. 2025 Apr 26:S1130-6343(25)00009-1. doi: 10.1016/j.farma.2025.02.002. Online ahead of print.

ABSTRACT

OBJECTIVE: Inhaled therapy is essential in cystic fibrosis; however, inhalers have a significant environmental impact due to the greenhouse gases (GHGs) emitted. The environmental impact of a product is estimated by its carbon footprint (CF). Pressurized metered-dose inhalers (pMDIs) have a higher CF than dry powder inhalers (DPIs) and soft mist inhalers (SMIs) due to the incorporation of GHGs. The objectives are to analyze the consumption of inhalers (β2-adrenergic agonist bronchodilators, anticholinergics, and/or corticosteroids) in a cystic fibrosis unit and estimate the generated CF.

METHOD: Retrospective determination (January 2018-December 2023) of consumption and CF (tCO2eq) by type of inhaler was conducted. Consumption and CF trends were evaluated using linear regression.

RESULTS: Annually, 1.529 (1.279-1.613) pMDIs, 1.055 (855-1.333) DPIs, and 28 (20-42) SMIs were dispensed, representing 55.97%, 42.33%, and 1.70%, respectively. A statistically significant positive trend in the consumption of SMIs was observed. The median annual CF was: pMDIs 38.3 (31.2-40.3) tCO2eq, DPIs 0.8 (0.6-0.9) tCO2eq, and SMIs 0.02 (0.02-0.03) tCO2eq, representing 97.86%, 2.04%, and 0.10%, respectively.

CONCLUSIONS: pMDIs were the inhalers with the highest consumption and CF, although their consumption appears to be decreasing, with an increase in the consumption of SMIs.

PMID:40288920 | DOI:10.1016/j.farma.2025.02.002

Microb Pathog. 2025 Apr 25:107628. doi: 10.1016/j.micpath.2025.107628. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) lung disease begins early, and prophylactic antibiotics have been used to prevent Staphylococcus aureus infection. This study examined the lung microbiome in two countries with differing antibiotic practices and its relationship to lung function in young children with CF.

METHODS: A binational, longitudinal, observational study was performed to define the lower airway microbiome in infants with CF. 16S rRNA sequencing was performed using lavage fluid to characterize the lung microbiota in 45 infants with and without prophylactic antibiotic therapy at an average age of approximately 3 months and 14 months. The association between pulmonary function, bacterial community diversities, and taxa was assessed.

RESULTS: Expected CF bacterial genera and non-traditional bacteria, such as Streptococcus, were identified as core taxa. Microbial community shifts were observed in infants who received antibiotic prophylaxis, with lower alpha diversity (ANOVA, P<0.05) and a higher proportion of Streptococcus at the first visit. Beta diversity (FEV0.5z; MiRKAT, P<0.05) and Streptococcus were associated with FEV0.5z (LASSO and linear regression, β<0). Functional annotation suggested that alteration of lung microbiota may be linked to antimicrobial resistance.

CONCLUSIONS: Lung microbial diversity in infants with CF varied between the two countries, particularly during early infancy. A shift in the lung microbiome toward a higher relative abundance of Streptococcus was associated with reduced pulmonary function.

PMID:40288428 | DOI:10.1016/j.micpath.2025.107628

Sleep Med. 2025 Apr 23;131:106534. doi: 10.1016/j.sleep.2025.106534. Online ahead of print.

ABSTRACT

Noninvasive ventilation (NIV) is widely used in children. Only a few devices are life support ventilators. The pressure support (PSV) mode is the most common used mode for home NIV, while assist-control pressure ventilation (PAC) is usually used in patients with abnormal central drive. Patient-ventilator asynchrony (PVA) is common during NIV and may have different causes, such as unintentional leaks, inadequate settings or misunderstanding of the settings. However, PVA may also be due to issues related to the NIV device, which is less common and is challenging. We report here the cases of 5 children with PVA due to trigger issues with a recent life support device.

PMID:40288254 | DOI:10.1016/j.sleep.2025.106534

J Cyst Fibros. 2025 Apr 26:S1569-1993(25)00770-2. doi: 10.1016/j.jcf.2025.04.004. Online ahead of print.

ABSTRACT

BACKGROUND: People with cystic fibrosis (pwCF) are living longer and with an increased risk of malignancies, preventative cancer screening is crucial. The objectives of this study were to determine cancer screening rates for pwCF compared to the general population, and assess the impact of primary care provider (PCP) involvement on screening rates among those with CF.

METHODS: This population-based cohort study linked Canadian CF Registry data with health administrative databases. Four screening cohorts were identified: breast, cervical, colorectal pre-transplant, colorectal post-transplant. PCP involvement was defined using billing codes. Screening rates were calculated as the number screened divided by the number of person-years individuals were eligible for screening. Poisson regression was used to describe rates.

RESULTS: In the CF cohort, 74/110 (67.3 %) were screened for breast cancer, and 321/541 (59.3 %) for cervical cancer. 186/402 (46.3 %) in the pre-transplant cohort were screened with colonoscopy and 75/148 (50.7 %) in the post-transplant cohort. Those with CF were significantly more likely to be screened for breast cancer (RR 3.39, 95 % CI 2.70-4.26) and colorectal cancer pre-transplant (RR 1.58, 95 % CI 1.37-1.82) compared to the non-CF cohort. Having a PCP increased the likelihood that pwCF received screening for breast cancer (RR 3.6, 95 % CI 1.13-11.44), cervical cancer (RR 1.71, 95 % CI 1.13-2.57), and colorectal cancer (pre-transplant population only) (RR 1.57, 95 % CI 1.06-2.32).

CONCLUSIONS: Screening rates for cancers in CF remain suboptimal. These results highlight opportunities to improve screening uptake through better integration of PCP in CF care models and to increase awareness of cancer risk.

PMID:40287331 | DOI:10.1016/j.jcf.2025.04.004