Journal of Cystic Fibrosis最新文献

{"title":"Lung transplant for CF: Low lung bacterial burden and immune mediators in year one associate with CLAD development","authors":"Samantha A. Whiteside ,&nbsp;John E. McGinniss ,&nbsp;Rebecca A. Deek ,&nbsp;Carter Merenstein ,&nbsp;Noel Britton ,&nbsp;Aurea Simon-Soro ,&nbsp;Michelle Oyster ,&nbsp;Laurel Kalman ,&nbsp;Melanie C. Brown ,&nbsp;Jevon Graham-Wooten ,&nbsp;John F. McDyer ,&nbsp;Pali Shah ,&nbsp;Franco D’Alessio ,&nbsp;Edward Cantu ,&nbsp;Emily S. Clausen ,&nbsp;Hongzhe Li ,&nbsp;Joshua M. Diamond ,&nbsp;Frederic D. Bushman ,&nbsp;Jason D. Christie ,&nbsp;Ronald G. Collman","doi":"10.1016/j.jcf.2025.10.002","DOIUrl":"10.1016/j.jcf.2025.10.002","url":null,"abstract":"<div><h3>Background</h3><div>Lung transplantation is commonly required for advanced lung disease in cystic fibrosis (CF). Long-term lung allograft survival is limited primarily by chronic lung allograft dysfunction (CLAD), and microbial factors have been implicated in CLAD development. However studies have not specifically investigated CF patients despite the unique microbe-rich nature of the CF respiratory tract. We investigated whether early post-transplantation lung microbiome features associate with CLAD development.</div></div><div><h3>Methods</h3><div>We investigated a longitudinal cohort of 23 CF patients undergoing lung transplantation. Lung lavage was collected from donor lungs, and from recipient allografts serially during the first year post-transplantation. Patients were followed for a median of 4.9 years. This was complemented by a case-control study of 8 CF patients sampled at incident CLAD along with non-CLAD CF transplant controls. Lung bacteria were enumerated by 16S rRNA gene sequencing and quantified by qPCR, and immune mediators investigated by multiplex assay.</div></div><div><h3>Results</h3><div>Cohort patients who developed CLAD had lower lung bacterial burden, lower relative abundances of classic CF lung microbiota, and lower mediator levels during the first-year post-transplantation than those remaining CLAD-free. In contrast, incident CLAD showed elevated lung immune mediators but no microbiome differences.</div></div><div><h3>Conclusions</h3><div>Low lung bacterial content and immune mediators during the first year post-transplantation for CF associate CLAD, whereas CLAD onset is characterized by elevated immune mediators but no lung microbiome differences. Whether airway bacteria early after transplantation for CF may protect against CLAD or serve as a biomarker merits further study.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"25 1","pages":"Pages 52-62"},"PeriodicalIF":6.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145274817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hyperglycemia differentially affects neutrophil transmigration across cystic fibrosis and wildtype bronchial epithelia","authors":"Guiying Cui ,&nbsp;Analía Vazquez Cegla ,&nbsp;Jonica Brown ,&nbsp;Kymry Jones ,&nbsp;Ryan C. Reed ,&nbsp;Rabindra Tirouvanziam ,&nbsp;Michael Koval ,&nbsp;Nael A. McCarty","doi":"10.1016/j.jcf.2025.11.005","DOIUrl":"10.1016/j.jcf.2025.11.005","url":null,"abstract":"<div><h3>Background</h3><div>Hallmarks of Cystic Fibrosis (CF) lung disease are chronic obstruction, infection, and inflammation dominated by lifelong, excessive influx of neutrophils (PMNs) into airways which is further exacerbated by CF-related diabetes (CFRD).</div></div><div><h3>Methods</h3><div>We examined the effect of glycemic state (normal glucose, NG and high glucose, HG) on PMN mucosal-to-luminal transmigration across bronchial epithelia using 16HBE (16HBE-WT, 16HBE-CF) or primary airway epithelial cells expressing either WT- or F508del-CFTR (NhBE and CFhBE) cultured on Transwell filters, and whether rates of transmigration are sensitive to highly effective modulator therapies (HEMTs) used for CF.</div></div><div><h3>Results</h3><div>We observed a time-dependent decrease in transepithelial resistance (TER), during transmigration of healthy PMNs across 16HBE monolayers. TER after transmigration was significantly lower for cells cultured in HG compared to NG. Transmigration rate across 16HBE-WT monolayers was higher when cultured in HG while the rate was higher across 16HBE-CF monolayers cultured in NG. Transmigration rate across NhBE monolayers was higher for cells cultured in HG compared to NG. No differences in rates of transmigration across CF primary monolayers were detected in NG versus HG. Differences in transmigration rates were partly normalized by exposure to HEMTs. Unlike naïve PMNs and PMNs that transmigrated across empty wells, PMNs that crossed 16HBE and primary cell monolayers were enlarged, had a rough plasma membrane morphology, and an abundance of large vacuoles.</div></div><div><h3>Conclusions</h3><div>These data show that HG conditioning impacts PMN transmigration, and that transmigrated PMNs are differentially impacted by the CFTR genotype of the cell monolayer through which they have transmigrated.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"25 1","pages":"Pages 127-134"},"PeriodicalIF":6.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145504664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathogenic CFTR variants as cancer risk modifiers: Findings from the all of us cohort","authors":"Tyler Shugg ,&nbsp;Abi Colwell ,&nbsp;Nick Powell ,&nbsp;Cynthia D. Brown ,&nbsp;James E. Slaven ,&nbsp;Emma M. Tillman","doi":"10.1016/j.jcf.2025.12.009","DOIUrl":"10.1016/j.jcf.2025.12.009","url":null,"abstract":"","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"25 1","pages":"Pages 104-105"},"PeriodicalIF":6.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145768197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Strategies for the identification of people with cystic fibrosis responsive to CFTR modulator triple combinations","authors":"Pierre-Régis Burgel","doi":"10.1016/j.jcf.2025.12.019","DOIUrl":"10.1016/j.jcf.2025.12.019","url":null,"abstract":"<div><div>The triple combinations of CFTR modulators, elexacaftor-tezacaftor-ivacaftor and more recently vanzacaftor-tezacaftor-deutivacaftor, have transformed the clinical course of cystic fibrosis (CF). These drug combinations were identified for their ability to restore CFTR function in F508del epithelial cells, and their efficacy has been shown in large randomized clinical trials involving people with CF with at least one F508del variant. Approximately 20 % of pwCF worldwide have no F508del variant however. Recent data show that CFTR modulator triple combinations may be effective in a large subset of pwCF with non-F508del, often rare, <em>CFTR</em> variants. The purpose of this review is to explore the various strategies that may contribute to the identification of all patients with modulator-responsive <em>CFTR</em> variants in order to expand access to these transformative therapies.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"25 1","pages":"Pages 3-8"},"PeriodicalIF":6.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145863157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysmotility in the ileum of CFTR null swine","authors":"Nicolas Henao-Romero ,&nbsp;Lingxiu Susan Liu ,&nbsp;Amirala O.M. Nazari ,&nbsp;Dain Kim ,&nbsp;Xiaojie Luan ,&nbsp;Kash Desai ,&nbsp;Julian S. Tam ,&nbsp;Juan P. Ianowski ,&nbsp;Verónica A. Campanucci","doi":"10.1016/j.jcf.2025.07.007","DOIUrl":"10.1016/j.jcf.2025.07.007","url":null,"abstract":"<div><h3>Background</h3><div>Gastrointestinal (GI) complications are a common source of morbidity for people with cystic fibrosis (pwCF). The pathobiology of these clinical presentations is not fully understood, but there is evidence that gut dysmotility may be a primary contributor.</div></div><div><h3>Methods</h3><div>We studied gut motility in ileum samples from CF (CFTR-/-) and wild-type (WT) swine at birth (P0) and one week of post-natal life (P7) using organ bath assays.</div></div><div><h3>Results</h3><div>Ileal samples from both WT and CF swine displayed spontaneous peristalsis. CF swine presented with reduced basal amplitude of the peristaltic waves compared to WT swine. Stimulating the ileal samples with increasing concentrations of acetylcholine (ACh) resulted in four main findings: 1) ACh increased the amplitude of smooth muscle contraction in all ileal samples in a dose-dependent manner. 2) At P7, ACh stimulation caused a significant increase in the maximum smooth muscle contraction in the WT but not in the CF samples. 3) Increasing doses of ACh caused fatigue-like contracting decline in smooth muscle from WT samples at both ages, but not in samples from CF swine. 4) ACh stimulation had no effect on the frequency of smooth muscle contraction in either genotype.</div></div><div><h3>Conclusions</h3><div>Our results show ileal dysmotility in the CF swine characterized by a decrease in basal peristalsis and weaker smooth muscle contraction. Our data suggest that GI dysmotility would impact chyme transit through the GI tract, which may predispose pwCF to intestinal manifestations associated with the disease.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"25 1","pages":"Pages 146-150"},"PeriodicalIF":6.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144682670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pulmonary vascular morphology in cystic fibrosis","authors":"Qiwei Xiao ,&nbsp;Goutham Mylavarapu ,&nbsp;James F. Chmiel ,&nbsp;Robert Fleck ,&nbsp;Jean-Pierre Amoakon ,&nbsp;Md Monir Hossain ,&nbsp;Aisaku Nakamura ,&nbsp;Mark DiFrancesco ,&nbsp;Andrew Paisley ,&nbsp;Christine L. Schuler ,&nbsp;Alister Bates ,&nbsp;Matthew Willmering ,&nbsp;Anjaparavanda P Naren ,&nbsp;Raúl San José Estépar ,&nbsp;Raouf Amin","doi":"10.1016/j.jcf.2025.08.007","DOIUrl":"10.1016/j.jcf.2025.08.007","url":null,"abstract":"<div><h3>Background</h3><div>Morphological changes of the pulmonary vasculature in cystic fibrosis (CF) with advancing age, disease progression and modulator therapy are not fully understood.</div></div><div><h3>Methods</h3><div>Sixty-five subjects with CF and baseline pulmonary function underwent a high-resolution CT scan, exercise testing, diffusion capacity and lung clearance index. The ratio of small blood vessel volume (vessels&lt; 5mm² or ^“BV5”) to total blood vessel volume (TBV) was estimated from CT scans (BV5/TBV%). The findings were validated in a second CF cohort with concurrent CT and pulmonary function at baseline. Modulator effects were determined by comparing the changes in BV5/TBV% with age and FEV1 % across groups (subjects who were naïve to modulators, those that received 1^st generation modulators and those that received Trikafta). The relationship between BV5/TBV% and age in healthy controls was examined.</div></div><div><h3>Results</h3><div>BV5/TBV% began to decline in the first decade of life and below FEV1 % of 113; this decline was associated with a decrease in diffusion and exercise parameters. The decline of BV5/TBV% with age was independent from the decline in FEV1 %. There was no significant decline in BV5/TBV% with advancing age in healthy controls or in those who received Trikafta. Early in CF, there was a relative hypervascularity of the small fraction of the pulmonary circulation which reversed to relative hypovascularity with the steady decline of BV5/TBV%.</div></div><div><h3>Conclusions</h3><div>The attrition of small blood vessels measured by BV5/TBV% in CF starts during the first decade of life, when lung function is normal, even with 1^st generation modulator use, but not with Trikafta.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"25 1","pages":"Pages 158-165"},"PeriodicalIF":6.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elexacaftor/tezacaftor/ivacaftor corrects salt-wasting in cystic fibrosis","authors":"Peder Berg ,&nbsp;Amalie Quist Rousing ,&nbsp;Søren Jensen-Fangel ,&nbsp;Sascha Bandulik ,&nbsp;Richard Warth ,&nbsp;Mads Vaarby Sørensen ,&nbsp;Majbritt Jeppesen ,&nbsp;Jens Leipziger","doi":"10.1016/j.jcf.2025.12.006","DOIUrl":"10.1016/j.jcf.2025.12.006","url":null,"abstract":"<div><h3>Background</h3><div>People with cystic fibrosis (pwCF) are at increased risk for fluid and electrolyte imbalances due to continuous salt loss. Congruently, guidelines advocate increased salt intake. However, pwCF are also at increased risk for developing cardiovascular disease. Understanding how CFTR modulators affect fluid and electrolyte homeostasis is important to provide evidence-based guidance for pwCF treated with CFTR modulators.</div></div><div><h3>Methods</h3><div>We quantified the effect of Elexacaftor/tezacaftor/ivacaftor (ETI) treatment on blood pressure, electrolyte- and acid-base balance, aldosterone levels, and the diuretic and natriuretic response to an oral NaHCO₃ and volume loading test in 50 pwCF initiating ETI treatment.</div></div><div><h3>Results</h3><div>In pwCF, ETI treatment increased blood pressure, plasma Na⁺, and the diuretic response to oral NaHCO₃ and volume loading. Congruently, ETI markedly decreased heart rate, aldosterone levels, venous total CO₂ and the proportion of pwCF with low plasma Na⁺.</div></div><div><h3>Conclusions</h3><div>In pwCF, ETI treatment improves NaCl and fluid conservation. Future guidelines should consider an increased risk for cardiovascular disease in pwCF after initiation of CFTR modulator treatment. Salt repletion appears unnecessary in ETI-treated pwCF.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"25 1","pages":"Pages 32-37"},"PeriodicalIF":6.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145714694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pregnancies in women with cystic fibrosis in the era of CFTR modulators: Current challenges and future perspectives. Insights from the Italian cystic fibrosis registry","authors":"Marco Salvatore ,&nbsp;Giuseppe Campagna ,&nbsp;Annalisa Amato ,&nbsp;Daniela Pierannunzio ,&nbsp;Pietro Ripani ,&nbsp;Giovanni Taccetti ,&nbsp;Benedetta Fabrizzi ,&nbsp;Fabio Majo ,&nbsp;Rita Padoan","doi":"10.1016/j.jcf.2025.12.002","DOIUrl":"10.1016/j.jcf.2025.12.002","url":null,"abstract":"<div><h3>Background</h3><div>The prognosis for people with Cystic Fibrosis (CF) has significantly improved due to the introduction of CF Transmembrane Regulator (CFTR) modulators<em>.</em> This study aims to analyze pregnancies and related outcomes in Italian women with CF while also identifying current and potential future challenges<em>.</em></div></div><div><h3>Methods</h3><div>This retrospective study utilized data from the Italian cystic fibrosis Registry (ICFR), focusing on pregnancies occurring between 2016 and 2023. Key clinical variables assessed included genotype, age at conception, body mass index, percent predicted forced respiratory volume (ppFEV₁), presence of CF-related diabetes (CFRD), and CFTR modulator therapy. The outcomes analyzed were pulmonary function and BMI as a surrogate of nutritional status before and after pregnancy, as well as preterm birth rate, birthweight, and mode of delivery.</div></div><div><h3>Results</h3><div>Between 2016 and 2023, the ICFR reported 172 pregnancies, of which 148 (86.0 %) were carried to term. The median age at conception was 31.8 years (range: 17.0–43.9), median BMI 21.6 kg/m² (range: 16.5–38.9), and median ppFEV₁ 79.7 (range: 29.0–120.4). CFRD was present in 32 women (21.6 %), and 55 (37.2 %) were receiving CFTR modulator therapy. Better clinical status at the beginning of pregnancy was observed in 2016-23 period, with a higher mean ppFEV₁, in the mean age at conception and in the mean BMI value. In the present study, only a limited number of women were in severe clinical condition (&lt;5 % had a severe ppFEV₁ value or a BMI showing a malnutrition status).</div><div>The overall preterm birth (&lt;37 weeks gestation) was 24.1 % (34 cases), higher in women with CFRD (40.6 %) and lowest in those receiving CFTRm (22.7 %). Median birthweight was 2,990 g (range: 800–4,155 g). The overall cesarean section rate was 54.9 %, peaking at 81.2 % in women with CFRD.</div></div><div><h3>Conclusion</h3><div>Understanding national pregnancy trends and outcomes is essential for informing effective public health strategies and improving maternal–infant wellbeing. An increasing number of women with CF are achieving successful pregnancies and delivering healthy babies. It is essential to provide women treated with CFTR modulators with up-to-date information regarding the safety of these therapies during pregnancy and breastfeeding<em>.</em></div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"25 1","pages":"Pages 86-91"},"PeriodicalIF":6.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145768176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Imaging brain vascular function in Cystic Fibrosis: an MRI study of cerebral blood flow and brain oxygenation","authors":"HL Chandler ,&nbsp;M Germuska ,&nbsp;TM Lancaster ,&nbsp;C Xanthe ,&nbsp;C O’leary ,&nbsp;S Stirk ,&nbsp;H Lu ,&nbsp;K Murphy ,&nbsp;C Metzler-Baddeley ,&nbsp;RG Wise ,&nbsp;J Duckers","doi":"10.1016/j.jcf.2025.08.010","DOIUrl":"10.1016/j.jcf.2025.08.010","url":null,"abstract":"<div><h3>Background</h3><div>Cystic fibrosis (CF) is a progressive inherited disorder that primarily affects the lungs. With recent breakthroughs in effective treatments for CF that increase life-expectancy, a higher prevalence of age-related comorbidities has been reported including cardiovascular disease, stroke and cognitive decline. Despite the known relationship between cardiovascular health and cerebrovascular function, very little is known about brain blood flow and oxygen metabolism in people with CF (PwCF).</div></div><div><h3>Methods</h3><div>In 14 PwCF and 56 healthy age / sex matched controls, we used pseudo-continuous arterial spin labelling (pCASL) to quantify cerebral perfusion in grey-matter and T₂-Relaxation-Under-Spin-Tagging (TRUST) to estimate global oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen consumption (CMRO₂).</div></div><div><h3>Results</h3><div>Compared to healthy controls, PwCF showed elevated CMRO₂ (<em>p =<!--> </em>0.015). There were no significant between-group differences in grey-matter CBF (<em>p =<!--> </em>0.342), or whole brain OEF (<em>p =<!--> </em>0.091). However, regional analysis showed certain areas with higher CBF in PwCF (<em>p</em> &lt; .05, FDR).</div></div><div><h3>Conclusions</h3><div>Our results show increased CMRO₂ and regional CBF in PwCF, which could be explained by potential differences in PaO₂/PaCO₂ and/or endothelial cell function. Our findings highlight the need for further investment in brain research in PwCF to reduce the risk of early cerebrovascular breakdown that leads to premature cognitive decline.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"25 1","pages":"Pages 166-171"},"PeriodicalIF":6.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GY971 mitigates inflammation by reducing neutrophil recruitment in cystic fibrosis Ex Vivo and In Vivo models","authors":"Chiara Tupini ,&nbsp;Valeria Capurro ,&nbsp;Nicoletta Pedemonte ,&nbsp;Caterina Allegretta ,&nbsp;Onofrio Laselva ,&nbsp;Anna Tamanini ,&nbsp;Giovanni Marzaro ,&nbsp;Adriana Chilin ,&nbsp;Paola Patrignani ,&nbsp;Stefania Tacconelli ,&nbsp;Alessandra De Michele ,&nbsp;Marco Cafora ,&nbsp;Anna Pistocchi ,&nbsp;Giulio Cabrini ,&nbsp;Ilaria Lampronti","doi":"10.1016/j.jcf.2025.12.010","DOIUrl":"10.1016/j.jcf.2025.12.010","url":null,"abstract":"<div><h3>Background</h3><div>There is a prominent need for anti-inflammatory agents for people with Cystic Fibrosis (pwCF), even in the era of CFTR modulators. ETI (Elexacaftor/Tezacaftor/Ivacaftor) reduces but does not eliminate pulmonary inflammation, that chronically damages CF pulmonary tissues and favors recurrent pulmonary exacerbations. Furthermore, although known anti-inflammatory drugs are beneficial to pwCF, their side effects are limiting the clinical use. To address this issue, we developed a new synthetic furocoumarin molecule named GY971, able to reduce the excessive accumulation of neutrophils in the bronchial lumen, by targeting the NF-κB transcription factor (TF).</div></div><div><h3>Methods</h3><div>To assess its efficacy, GY971 was tested in human primary bronchial and nasal epithelial cells obtained <em>ex vivo</em> from different pwCF carrying the <em>F508del</em> mutation and infected with <em>Pseudomonas aeruginosa</em>. Moreover, GY971 was also administered in a zebrafish model infected with <em>P. aeruginosa in vivo</em>.</div></div><div><h3>Results</h3><div>GY971 reduced neutrophil chemotaxis mediators both in CF bronchial epithelial cell lines and in CF primary bronchial and nasal epithelial cells <em>ex vivo</em>. The expression of key inflammatory proteins involved in CF lung disease, including IL-8, IL-1β, TNF-α and IL-6, was significantly reduced using nanomolar concentrations of GY971. Importantly, GY971 does not interfere with the ETI-mediated rescue of CFTR protein and showed no cytotoxic effects. Lastly, <em>in vivo</em> testing with a zebrafish model confirmed its effectiveness: GY971 decreased neutrophil recruitment in treated larvae across different concentrations, supporting earlier results from murine studies.</div></div><div><h3>Conclusions</h3><div>GY971 appears to be a promising molecule for the future development of combinatorial anti-inflammatory treatments together with ETI.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"25 1","pages":"Pages 135-145"},"PeriodicalIF":6.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145827265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}