Pulmonary pharmacology & therapeutics最新文献

{"title":"Effects of EP395, a novel macrolide, on acute neutrophilic airway inflammation","authors":"Jennifer Ann Kricker ,&nbsp;Virginia Norris ,&nbsp;Clive Page ,&nbsp;Michael John Parnham","doi":"10.1016/j.pupt.2025.102364","DOIUrl":"10.1016/j.pupt.2025.102364","url":null,"abstract":"<div><div>Macrolide antibiotics have been shown to reduce exacerbations of respiratory diseases, including chronic obstructive pulmonary disease (COPD) and asthma. This effect is believed to be due to the immunomodulatory properties of macrolides rather than their antimicrobial activity. However, prolonged use of macrolide antibiotics can result in the development of antimicrobial resistance, which prompted us to develop EP395, a compound with similar pharmacological actions to macrolides, but without antimicrobial activity. We investigated EP395 in several established models of neutrophilic airway inflammation in male BALB/c mice. Oral pretreatment with EP395 for 2 weeks had significant anti-inflammatory effects, reducing cytokines and neutrophil infiltration into bronchoalveolar lavage fluid (BAL) induced by either lipopolysaccharide (LPS), tobacco smoke or respiratory syncytial virus (RSV). EP395 had comparable inhibitory effects to azithromycin in all three models. The PDE4 inhibitor, roflumilast, was also included as a positive control in the LPS model, with comparable effects on neutrophil numbers. In vitro assays on neutrophil function revealed both stimulatory and inhibitory effects of treatment with EP395. These data demonstrate the beneficial pharmacological activity of EP395, a macrolide with negligible antimicrobial activity, in models of acute neutrophilic inflammation and on neutrophil activity and supported its progression into clinical development as a potential treatment for COPD.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"90 ","pages":"Article 102364"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144221986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacovigilance of five commonly used antibiotics in acute exacerbations of COPD (AECOPD): Analysis of the FDA adverse event reporting system database","authors":"Qin Shen ,&nbsp;Suzhen Yang ,&nbsp;Sha Wang","doi":"10.1016/j.pupt.2025.102383","DOIUrl":"10.1016/j.pupt.2025.102383","url":null,"abstract":"<div><h3>Objective</h3><div>Antibiotics are commonly administered during acute exacerbations of chronic obstructive pulmonary disease (AECOPD) to manage infections and alleviate their symptoms. However, their use may result in adverse drug events (ADEs), potentially compromising patient safety and treatment effectiveness. The U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) provides valuable data for identifying such risks. This study aimed to analyze FAERS data to detect ADE signals associated with antibiotic use in patients with AECOPD, thereby supporting safer clinical practices.</div></div><div><h3>Methods</h3><div>Five antibiotics frequently used in AECOPD management, azithromycin, moxifloxacin, meropenem, gentamicin, and minocycline, were selected for analysis. FAERS data from January 1, 2004, to July 30, 2024, were extracted using OpenVigil 2.1 platform. Duplicate and incomplete reports were excluded. ADEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA). Data mining techniques, including the proportional reporting ratio (PRR) and reporting odds ratio (ROR), were used to identify statistically significant ADE signals.</div></div><div><h3>Results</h3><div>111,179 ADE reports involving 100,602 patients were identified, including azithromycin (41,241 reports), moxifloxacin (46,770), meropenem (5,904), gentamicin (4,142), and minocycline (13,122). Serious events comprised 30.6 %–47.1 % of the reported ADEs, with the lowest proportion observed for meropenem, and the highest proportion observed for gentamicin. Females accounted for 57.0 % of the cases with known gender. Data mining identified 1946 ADE signals, including novel associations such as infectious chondromatosis (azithromycin), hemorrhagic obstructive retinal vasculitis (moxifloxacin), elevated procalcitonin (meropenem), Bartter syndrome (gentamicin), and nodular polyarteritis (minocycline).</div></div><div><h3>Conclusion</h3><div>This study identified novel ADE signals associated with antibiotics used in AECOPD treatment, highlighting the importance of continuous pharmacovigilance. Clinicians should be informed of the emerging safety concerns to enhance patient care.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"90 ","pages":"Article 102383"},"PeriodicalIF":2.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144842212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Celebrating the appointment of Mario Cazzola as Honorary Editor of Pulmonary Pharmacology & Therapeutics","authors":"Luigino Calzetta","doi":"10.1016/j.pupt.2025.102378","DOIUrl":"10.1016/j.pupt.2025.102378","url":null,"abstract":"","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"90 ","pages":"Article 102378"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144588023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of Dry Powder Inhaler formulation for site specific delivery of nanoconjugates loaded with Curcumin and BCL2 siRNA in Lung Cancer","authors":"Madhuchandra Lahan ,&nbsp;Trideep Saikia ,&nbsp;Rinku Baishya ,&nbsp;Alakesh Bharali ,&nbsp;Sunayana Baruah ,&nbsp;Shatabdi Ghose ,&nbsp;Nikhil Biswas ,&nbsp;Damiki Laloo ,&nbsp;Subhash Medhi ,&nbsp;Bhanu P Sahu","doi":"10.1016/j.pupt.2025.102361","DOIUrl":"10.1016/j.pupt.2025.102361","url":null,"abstract":"<div><div>Lung cancer remains one of the leading causes of cancer-related deaths, with current chemotherapy limited by poor drug delivery, toxicity, and resistance. To overcome these challenges, we developed a dry powder inhaler (DPI) system incorporating a PLGA-PEG-LHRH (PPL) nanoconjugate (NC) for enhanced delivery. Curcumin (CUR), with known anticancer and P-gp inhibition properties, was co-loaded with bcl2 siRNA (bclsR) to target bcl2 protein and combat resistance mechanisms.</div><div>The CUR and bclsR-loaded PLGA NC (172.12 ± 24.23 nm) were prepared using double emulsion solvent evaporation (DESE) method and converted into DPI using a carbohydrate carrier, showing a mass mean aerodynamic diameter of 4.62 μm and fine particle fraction of 65.39 ± 0.19 %, ideal for lung delivery. Animal studies showed that DPI delivered via tracheal administration in lung cancer models exhibited superior anticancer effects compared to free CUR, particularly in terms of pathological improvements and upregulation of cancer markers like P53 and TNF-α.</div><div><em>In vivo</em> biodistribution studies in tumor-bearing mice revealed higher CUR concentrations in plasma (326.85 ± 6.17 μg) and lungs (207.03 ± 4.11 μg), with enhanced systemic exposure as indicated by higher AUC and Cmax values. These findings suggest that CUR-siRNA loaded DPI could provide an effective therapeutic approach for lung cancer.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"90 ","pages":"Article 102361"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144221985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhaled epoprostenol for management of acute respiratory failure and pulmonary vascular disease","authors":"Daniel Connelly ,&nbsp;Jessica Delahanty ,&nbsp;Shyam Patel ,&nbsp;Kimberly A. Ackerbauer ,&nbsp;Nicholas A. Bosch ,&nbsp;Elizabeth S. Klings ,&nbsp;Justin K. Lui","doi":"10.1016/j.pupt.2025.102374","DOIUrl":"10.1016/j.pupt.2025.102374","url":null,"abstract":"<div><div>Inhaled epoprostenol has remained an attractive and viable option for the delivery of prostacyclin to offset abnormalities in ventilation and perfusion mismatch while minimizing the typical adverse effects associated with systemic administration. There is a need to better understand pharmacologic properties of inhaled epoprostenol and its application to diseases affecting the cardiopulmonary system. The goal of this review is to provide an overview of inhaled epoprostenol and outline its use specifically in the medical management of acute hypoxemic respiratory failure and pulmonary vascular disease. Among patients with acute respiratory distress syndrome who ultimately required invasive ventilation, inhaled epoprostenol has not improved ventilator-free days, intensive care unit length of stay, or mortality. However, it may be beneficial in certain select patient populations. In the management of pulmonary hypertension, inhaled epoprostenol has allowed for continued maintenance of chronic pulmonary arterial hypertension-specific therapy and for possibly improving right ventricular function as an attractive option in the critical care management of pulmonary hypertension.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"90 ","pages":"Article 102374"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144272530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FTO regulates the proliferation and apoptosis of pulmonary artery smooth muscle cells through m6A demethylation modification","authors":"Xinwei Shi ,&nbsp;Yizhou Yang ,&nbsp;Yue Gao ,&nbsp;Chao Yuan ,&nbsp;Xianqun Rao ,&nbsp;Wei Li ,&nbsp;Liting Wu ,&nbsp;Tingting Yu ,&nbsp;Ming Xu ,&nbsp;Baoli Zhu ,&nbsp;Lei Han ,&nbsp;Kai Sun","doi":"10.1016/j.pupt.2025.102382","DOIUrl":"10.1016/j.pupt.2025.102382","url":null,"abstract":"<div><h3>Background</h3><div>To investigate whether FTO-mediated N6-methyladenosine (m6A) demethylation affects the proliferative/apoptotic phenotype of mouse pulmonary artery smooth muscle cells (PASMCs).</div></div><div><h3>Methods</h3><div>The hypoxia model of PASMCs was established to examine changes in FTO protein expression and m6A modification levels. Cell transfection, m6A expression profiling, mRNA stability testing, and protein-RNA binding assays were used to explore the effects of FTO and its downstream target, <em>CACNA1d</em>, on PASMC proliferation and apoptosis.</div></div><div><h3>Results</h3><div>Hypoxia downregulated FTO expression and upregulated m6A modification, leading to enhanced proliferation and reduced apoptosis in PASMCs. Overexpression of FTO reversed these effects, while FTO knockdown under normoxia mimicked the hypoxia-induced \"pro-proliferative and anti-apoptotic\" changes. Genome-wide m6A profiling identified <em>CACNA1d</em> as a potential downstream target of FTO, with YTHDC1 acting as the m6A reader. FTO binds <em>CACNA1d</em> mRNA and reduces its stability via m6A demethylation. CACNA1d knockdown partially mitigated the hypoxia-induced changes in PASMC proliferation and apoptosis. In addition, when the hypoxic culture was returned to normoxic culture, the level of apoptosis in PASMCs was restored to the pre-hypoxic level, and this was still observed after the overexpression of FTO or knockdown of CACNA1d expression.</div></div><div><h3>Conclusion</h3><div>FTO downregulation in hypoxic PASMCs increases m6A modification, promoting proliferation and inhibiting apoptosis by enhancing CACNA1d expression.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"90 ","pages":"Article 102382"},"PeriodicalIF":2.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Experimental modeling of pulmonary fibrosis and combined emphysema in mice using repeated doses of bleomycin and cigarette smoke extract","authors":"Jung Hur ,&nbsp;Chin Kook Rhee ,&nbsp;Joon Young Choi ,&nbsp;Yong Suk Jo","doi":"10.1016/j.pupt.2025.102376","DOIUrl":"10.1016/j.pupt.2025.102376","url":null,"abstract":"<div><h3>Rationale</h3><div>A high prevalence of smoking among idiopathic pulmonary fibrosis (IPF) patients increases the risk of emphysema. Combined pulmonary fibrosis and emphysema (CPFE) occurs predominantly in males, characterized by severe exercise-induced dyspnea, decreased diffusing capacity, and increased lung cancer risk. The exclusion of CPFE patients from clinical studies has limited understanding of its pathophysiology, treatment, and prognosis. This study aimed to close this knowledge gap by comparing CPFE with pure IPF in animal models, with the intent of developing phenotype-directed therapeutic strategies.</div></div><div><h3>Methods</h3><div>Eight-week-old female C57BL/6J mice received biweekly intratracheal bleomycin (BLM, 2 U/kg/100 μL) for 3 doses. For the CPFE model, additional intranasal cigarette smoke extract (CSE) was administered twice weekly. Inflammation and fibrosis were evaluated through bronchoalveolar lavage fluid (BALF), proinflammatory cytokines, fibrosis markers, and lung histology.</div></div><div><h3>Results</h3><div>BALF analysis showed increased cell counts in all BLM-treated groups, primarily macrophages, with elevated interleukin (IL)-6, transforming growth factor (TGF)-β1, and matrix metalloproteinases (MMP 3 and MMP 8). The BLM and CSE treated group displayed higher macrophages and lymphocytes counts than BLM alone. Lung tissue analysis revealed increased hydroxyproline, inflammation scores, Ashcroft scores, and higher α-smooth muscle actin (SMA) and collagen 1 expression in BLM-treated groups. The BLM and CSE treated group demonstrated notably higher emphysema formation as measured by mean linear intercept (MLI).</div></div><div><h3>Conclusions</h3><div>Through repeated BLM administrations and CSE exposure, an effective model for persistent pulmonary fibrosis and emphysema was established, enabling preclinical studies on CPFE and IPF and exploration of phenotype-directed therapeutic strategies for pulmonary fibrosis.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"90 ","pages":"Article 102376"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144523904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of EP395, a novel anti-inflammatory macrolide, in an inhaled lipopolysaccharide challenge model in healthy volunteers: a randomised controlled trial","authors":"Jens M. Hohlfeld ,&nbsp;Philipp Badorrek ,&nbsp;Olof Breuer ,&nbsp;Kate Hanrott ,&nbsp;Jennifer Kricker ,&nbsp;Michael J. Parnham ,&nbsp;Virginia Norris","doi":"10.1016/j.pupt.2025.102365","DOIUrl":"10.1016/j.pupt.2025.102365","url":null,"abstract":"<div><div>EP395, a macrolide with negligible antimicrobial activity but with anti-inflammatory effects in murine lipopolysaccharide (LPS) challenge model, is being developed as a potential treatment to reduce COPD exacerbations. This double-blind, placebo-controlled clinical study evaluated the pharmacodynamics of EP395 in response to inhaled LPS, an established clinical model for assessing anti-inflammatory effects of potential new treatments.</div><div>Forty-nine healthy, non-smoking participants were randomised to oral 375 mg EP395 or placebo, daily for 3 weeks. An inhaled LPS challenge (2 μg) was then given, followed 6 h later by bronchoscopy for bronchoalveolar lavage fluid (BALF) collection. Blood samples were collected pre, 6 and 24 h after LPS challenge.</div><div>BALF concentrations of IL-6, TNF-α, MIP-1α, MIP-1β and MCP-1 were lower with EP395 than placebo, while IL-33, IL-8, and IL-1β were higher with EP395 than placebo (not statistically significant). Neutrophil counts were unaffected, but neutrophil elastase and myeloperoxidase were higher with EP395 than placebo (not statistically significant). Serum concentrations of surfactant protein-D significantly increased in the EP395 group in response to LPS at both 6 and 24 h compared with pre-LPS (mean pre-LPS 148.8 ng/mL; mean 24 h post-LPS 183.0 ng/mL) but not in the placebo group (mean pre-LPS 142.4 ng/mL; mean 24 h post-LPS 142.4 ng/mL). The log₂ transformed fold difference in the EP395 group, before and 24 h after LPS challenge was 0.33 (95 % CI 0.52, 0.14; p = 0.0007).</div><div>EP395 treatment increased the host defence response to inhaled LPS, including the epithelial response, whilst reducing inflammatory site pro-inflammatory mediators.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"90 ","pages":"Article 102365"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144226488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical remission at two years post-diagnosis of asthma and its association with clinical outcomes: A retrospective cohort study in asthma patients with maintenance inhaler therapy","authors":"Hyun-Jun Park ,&nbsp;Chang Hoon Lee ,&nbsp;Jung-Kyu Lee ,&nbsp;Deog Kyeom Kim ,&nbsp;Hyun-Woo Lee","doi":"10.1016/j.pupt.2025.102381","DOIUrl":"10.1016/j.pupt.2025.102381","url":null,"abstract":"<div><div>Clinical remission (CR) has emerged as a potential therapeutic goal in patients with severe asthma eligible for biologic agents. However, its impact on long-term outcomes in asthma patients managed with maintenance inhaler therapy remains unclear. In this retrospective cohort study, we evaluated adult asthma patients on maintenance inhalers to investigate the long-term outcomes associated with achieving CR. CR was defined as at least one year without exacerbations, well-controlled symptoms, no use of systemic corticosteroids, and stable lung function, assessed two years after asthma diagnosis. We compared the trajectory of forced expiratory volume in 1 s (FEV₁) and the annual rate of exacerbations between CR and non-CR groups in a 1:1 propensity score-matched population. Among 549 patients followed for a median of 7 years, 88 (16 %) met the criteria for CR. After matching, 76 patients were included in each group. Compared to the non-CR group, the CR group showed a significantly lower proportion of patients with annual FEV₁ decline exceeding 60 mL (8.6 % vs. 25 %, <em>P</em> = 0.010). A linear mixed-effects model showed that the CR group had a significantly slower rate of FEV1 decline, with an annual difference of 32.7 mL (95 % CI 6.7 to 58.7; <em>P</em> = 0.014) compared with the non-CR group. The CR group also had a lower annual rate of moderate-to-severe exacerbations (0.17 events/year [IQR 0, 0.37] vs. 0.42 events/year [IQR 0, 1], <em>P</em> = 0.007). In conclusion, achieving CR in asthma patients receiving maintenance inhaler therapy was associated with a slower decline in lung function and fewer exacerbations. These findings support the potential role of CR as a long-term therapeutic goal.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"90 ","pages":"Article 102381"},"PeriodicalIF":2.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144779569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel macrolide, EP395, with reduced antibacterial activity and an enhancing effect on respiratory epithelial barrier","authors":"Thorarinn Gudjonsson ,&nbsp;Jon Petur Joelsson ,&nbsp;Ari Jon Arason ,&nbsp;Arni Asbjarnarson ,&nbsp;Fridrik Runar Gardarsson ,&nbsp;Fredrik Lehmann ,&nbsp;Peter Teodorovic ,&nbsp;Saevar Ingthorsson ,&nbsp;Snaevar Sigurdsson ,&nbsp;Bryndis Valdimarsdottir ,&nbsp;Michael John Parnham ,&nbsp;Clive Page ,&nbsp;Jennifer Ann Kricker","doi":"10.1016/j.pupt.2025.102363","DOIUrl":"10.1016/j.pupt.2025.102363","url":null,"abstract":"<div><div>Epithelial barrier failure, a feature of several inflammatory lung diseases, contributes to exacerbations and disease progression. Acute exacerbations are often treated with macrolides, including azithromycin (AZM). In part, this is due to both primary antimicrobial and additional immunomodulatory actions, complemented by recently reported enhanced integrity of respiratory epithelial barriers. However, long-term “off label” use of macrolides is associated with increased bacterial resistance. We now introduce a new class of compounds, “Barriolides” that are analogues of AZM promoting airway epithelial barrier integrity <em>in vitro</em>, with negligible antibacterial activity. The lead compound is EP395 which does not affect cell viability up to 100 μM in VA10 bronchial epithelial cells. Treatment with EP395 for three weeks enhanced epithelial barrier integrity, measured by increased transepithelial electrical resistance, reduced paracellular flux in air-liquid interface culture and increased expression of tight junction proteins. EP395 also induced epidermal differentiation and formation of lamellar bodies, complemented by a relevant genetic footprint. In mice exposed to sulphur dioxide, pre-treatment with EP395 reduced extravasation of human serum albumin into the bronchoalveolar lavage fluid. These data demonstrate epithelial barrier-protecting effects of EP395, a promising candidate for treatment of chronic respiratory diseases without risk of bacterial resistance.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"90 ","pages":"Article 102363"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144230280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}