Pulmonary pharmacology & therapeutics最新文献_第2页

Targeting the immunometabolism interface: A novel strategy for IPF therapy 靶向免疫代谢界面：IPF治疗的新策略

IF 2.8 3区医学 Q2 PHARMACOLOGY & PHARMACY

Pulmonary pharmacology & therapeutics

Pub Date : 2025-12-01 Epub Date: 2025-09-10 DOI: 10.1016/j.pupt.2025.102394

Ganggang Li , Yuzhi Huo , Xiaochuan Pan , Nan Jia , Xuanyu Wu , Xinhui Wu , Fei Wang , Quanyu Du

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by aberrant tissue remodeling and excessive deposition of extracellular matrix components. Emerging evidence underscores the critical role of the immunometabolism in the pathogenesis of IPF, highlighting how dysregulated metabolic pathways modulate immune responses and contribute to fibrotic progression. Key molecular regulators such as PPARG (peroxisome proliferator activated receptor gamma) and SPP1 (secreted phosphoprotein 1), along with signaling pathways including mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and hypoxia-inducible factor 1-alpha (HIF-1α), orchestrate immune cell polarization, fibroblast activation, and extracellular matrix production. These insights reveal promising therapeutic targets at the intersection of metabolism and immunity. This review synthesizes current findings on immunometabolism interactions in IPF, emphasizing the potential of metabolic reprogramming and immune modulation as novel treatment strategies. Despite substantial advances, significant challenges persist in elucidating the precise mechanisms underlying these interactions and translating preclinical insights into effective clinical interventions. Future research should prioritize the identification of actionable metabolic biomarkers, refinement of molecular targets, and development of personalized therapeutic approaches. Addressing these gaps may pave the way for innovative therapies capable of halting or even reversing fibrosis, ultimately improving outcomes for patients with IPF.

特发性肺纤维化（IPF）是一种慢性进行性间质性肺疾病，其特征是异常组织重塑和细胞外基质成分过度沉积。新出现的证据强调了免疫代谢在IPF发病机制中的关键作用，强调了失调的代谢途径如何调节免疫反应并促进纤维化进展。关键的分子调节因子，如PPARG（过氧化物酶体增殖体激活受体γ）和SPP1（分泌磷酸化蛋白1），以及包括哺乳动物雷帕霉素靶点（mTOR）、amp激活蛋白激酶（AMPK）和缺氧诱导因子1- α (HIF-1α)在内的信号通路，协调免疫细胞极化、成纤维细胞激活和细胞外基质的产生。这些见解揭示了代谢和免疫交叉的有希望的治疗靶点。本文综述了IPF中免疫代谢相互作用的最新研究结果，强调了代谢重编程和免疫调节作为新的治疗策略的潜力。尽管取得了重大进展，但在阐明这些相互作用的确切机制以及将临床前见解转化为有效的临床干预措施方面，仍然存在重大挑战。未来的研究应优先确定可操作的代谢生物标志物，改进分子靶点，并开发个性化的治疗方法。解决这些空白可能为能够阻止甚至逆转纤维化的创新疗法铺平道路，最终改善IPF患者的预后。

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引用次数: 0

Effects of EP395, a novel macrolide, on acute neutrophilic airway inflammation 新型大环内酯EP395对急性中性粒细胞性气道炎症的影响

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Pulmonary pharmacology & therapeutics

Pub Date : 2025-09-01 Epub Date: 2025-06-03 DOI: 10.1016/j.pupt.2025.102364

Jennifer Ann Kricker , Virginia Norris , Clive Page , Michael John Parnham

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.

大环内酯类抗生素已被证明可减少呼吸系统疾病的恶化，包括慢性阻塞性肺疾病（COPD）和哮喘。这种作用被认为是由于大环内酯类的免疫调节特性而不是它们的抗菌活性。然而，长期使用大环内酯类抗生素会导致耐药性的发展，这促使我们开发了EP395，一种与大环内酯类药物药理作用相似但没有抗菌活性的化合物。我们在几种已建立的雄性BALB/c小鼠中性粒细胞气道炎症模型中研究了EP395。口服EP395预处理2周具有显著的抗炎作用，可减少脂多糖（LPS）、烟草烟雾或呼吸道合胞病毒（RSV）诱导的支气管肺泡灌洗液（BAL）的细胞因子和中性粒细胞浸润。EP395在三种模型中均具有与阿奇霉素相当的抑制作用。PDE4抑制剂罗氟司特也被纳入LPS模型作为阳性对照，对中性粒细胞数量有类似的影响。体外中性粒细胞功能测定显示EP395对中性粒细胞有刺激和抑制作用。这些数据表明EP395（一种抗菌活性可忽略不计的大环内酯类药物）在急性中性粒细胞炎症模型和中性粒细胞活性中具有有益的药理活性，并支持其作为慢性阻塞性肺疾病的潜在治疗方法进入临床开发。

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引用次数: 0

Pharmacovigilance of five commonly used antibiotics in acute exacerbations of COPD (AECOPD): Analysis of the FDA adverse event reporting system database 慢性阻塞性肺病急性加重期（AECOPD） 5种常用抗生素的药物警戒：FDA不良事件报告系统数据库分析

IF 2.8 3区医学 Q2 PHARMACOLOGY & PHARMACY

Pulmonary pharmacology & therapeutics

Pub Date : 2025-09-01 Epub Date: 2025-08-11 DOI: 10.1016/j.pupt.2025.102383

Qin Shen , Suzhen Yang , Sha Wang

Objective

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.

Methods

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.

Results

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).

Conclusion

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.

目的慢性阻塞性肺疾病（AECOPD）急性加重期通常使用抗生素来控制感染并减轻其症状。然而，它们的使用可能导致药物不良事件（ADEs），潜在地损害患者安全和治疗效果。美国食品和药物管理局不良事件报告系统（FAERS）为识别此类风险提供了有价值的数据。本研究旨在分析FAERS数据，以检测与AECOPD患者抗生素使用相关的ADE信号，从而支持更安全的临床实践。方法选取阿奇霉素、莫西沙星、美罗培南、庆大霉素、米诺环素5种AECOPD常用抗生素进行分析。2004年1月1日至2024年7月30日FAERS数据采用OpenVigil 2.1平台提取。排除了重复和不完整的报告。使用药物调节活动医学词典（MedDRA）对ade进行编码。数据挖掘技术，包括比例报告比（PRR）和报告优势比（ROR），用于识别具有统计学意义的ADE信号。结果共发现111,179例ADE报告，涉及100,602例患者，包括阿奇霉素（41,241例）、莫西沙星（46,770例）、美罗培南（5,904例）、庆大霉素（4,142例）和米诺环素（13,122例）。严重事件发生率为30.6% ~ 47.1%，其中美罗培南发生率最低，庆大霉素发生率最高。已知性别的病例中，女性占57.0%。数据挖掘确定了1946年ADE信号，包括新的关联，如感染性软骨瘤病（阿奇霉素）、出血性阻塞性视网膜血管炎（莫西沙星）、降钙素原升高（美罗培南）、巴氏综合征（庆大霉素）和结节性多动脉炎（米诺环素）。结论本研究发现了与AECOPD治疗中使用的抗生素相关的新型ADE信号，强调了持续药物警戒的重要性。临床医生应了解新出现的安全问题，以加强对患者的护理。

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引用次数: 0

Celebrating the appointment of Mario Cazzola as Honorary Editor of Pulmonary Pharmacology & Therapeutics 庆祝Mario Cazzola被任命为《肺药理学与治疗学》荣誉编辑

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Pulmonary pharmacology & therapeutics

Pub Date : 2025-09-01 Epub Date: 2025-07-07 DOI: 10.1016/j.pupt.2025.102378

Luigino Calzetta

引用次数: 0

Development of Dry Powder Inhaler formulation for site specific delivery of nanoconjugates loaded with Curcumin and BCL2 siRNA in Lung Cancer 用于肺癌中姜黄素和BCL2 siRNA负载纳米偶联物位点特异性递送的干粉吸入剂配方的开发

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Pulmonary pharmacology & therapeutics

Pub Date : 2025-09-01 Epub Date: 2025-06-03 DOI: 10.1016/j.pupt.2025.102361

Madhuchandra Lahan , Trideep Saikia , Rinku Baishya , Alakesh Bharali , Sunayana Baruah , Shatabdi Ghose , Nikhil Biswas , Damiki Laloo , Subhash Medhi , Bhanu P Sahu

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.

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.

In vivo 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.

肺癌仍然是癌症相关死亡的主要原因之一，目前的化疗受到药物输送不良、毒性和耐药性的限制。为了克服这些挑战，我们开发了一种包含PLGA-PEG-LHRH （PPL）纳米偶联物（NC）的干粉吸入器（DPI）系统，以增强给药能力。姜黄素（Curcumin， CUR）具有抗癌和抑制P-gp的特性，与bcl2 siRNA （bclsR）共负载，以bcl2蛋白为靶点，对抗bcl2的耐药机制。采用双乳液溶剂蒸发法（DESE）制备了cnr和bclsr负载的PLGA NC(172.12±24.23 nm)，并通过碳水化合物载体转化为DPI，其质量平均气动直径为4.62 μm，细颗粒分数为65.39±0.19%，适合肺输送。动物研究表明，在肺癌模型中，与游离CUR相比，经气管给药的DPI具有更好的抗癌作用，特别是在病理改善和P53和TNF-α等癌症标志物上调方面。荷瘤小鼠的体内生物分布研究显示，CUR在血浆（326.85±6.17 μg）和肺部（207.03±4.11 μg）中的浓度较高，AUC和Cmax值较高，表明全身暴露增强。这些发现表明，携带CUR-siRNA的DPI可以为肺癌提供有效的治疗方法。

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引用次数: 0

Inhaled epoprostenol for management of acute respiratory failure and pulmonary vascular disease 吸入环氧前列醇治疗急性呼吸衰竭和肺血管疾病

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Pulmonary pharmacology & therapeutics

Pub Date : 2025-09-01 Epub Date: 2025-06-11 DOI: 10.1016/j.pupt.2025.102374

Daniel Connelly , Jessica Delahanty , Shyam Patel , Kimberly A. Ackerbauer , Nicholas A. Bosch , Elizabeth S. Klings , Justin K. Lui

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.

吸入环氧丙烯醇仍然是一种有吸引力和可行的选择，用于输送前列环素，以抵消通气和灌注不匹配的异常，同时最大限度地减少与全身给药相关的典型不良反应。有必要进一步了解吸入型环氧前列醇的药理学特性及其在心肺系统疾病中的应用。本综述的目的是提供吸入性丙烯醇的概述，并概述其在急性低氧性呼吸衰竭和肺血管疾病的医疗管理中的应用。在最终需要有创通气的急性呼吸窘迫综合征患者中，吸入丙烯醇并没有改善无呼吸机天数、重症监护病房住院时间或死亡率。然而，它可能对某些特定的患者群体有益。在肺动脉高压的治疗中，吸入epoprostenol允许持续维持慢性肺动脉高压特异性治疗，并可能改善右心室功能，作为肺动脉高压危重监护管理的一个有吸引力的选择。

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引用次数: 0

FTO regulates the proliferation and apoptosis of pulmonary artery smooth muscle cells through m6A demethylation modification FTO通过m6A去甲基化修饰调控肺动脉平滑肌细胞的增殖和凋亡。

IF 2.8 3区医学 Q2 PHARMACOLOGY & PHARMACY

Pulmonary pharmacology & therapeutics

Pub Date : 2025-09-01 Epub Date: 2025-08-14 DOI: 10.1016/j.pupt.2025.102382

Xinwei Shi , Yizhou Yang , Yue Gao , Chao Yuan , Xianqun Rao , Wei Li , Liting Wu , Tingting Yu , Ming Xu , Baoli Zhu , Lei Han , Kai Sun

Background

To investigate whether FTO-mediated N6-methyladenosine (m6A) demethylation affects the proliferative/apoptotic phenotype of mouse pulmonary artery smooth muscle cells (PASMCs).

Methods

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, CACNA1d, on PASMC proliferation and apoptosis.

Results

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 CACNA1d as a potential downstream target of FTO, with YTHDC1 acting as the m6A reader. FTO binds CACNA1d 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.

Conclusion

FTO downregulation in hypoxic PASMCs increases m6A modification, promoting proliferation and inhibiting apoptosis by enhancing CACNA1d expression.

背景：研究fto介导的n6 -甲基腺苷（m6A）去甲基化是否影响小鼠肺动脉平滑肌细胞（PASMCs）的增殖/凋亡表型。方法：建立PASMCs缺氧模型，检测FTO蛋白表达及m6A修饰水平的变化。通过细胞转染、m6A表达谱、mRNA稳定性测试和蛋白- rna结合实验，探讨FTO及其下游靶点CACNA1d对PASMC增殖和凋亡的影响。结果：缺氧可下调PASMCs FTO表达，上调m6A修饰，导致PASMCs增殖增强，凋亡减少。FTO的过表达逆转了这些作用，而在常氧条件下FTO的敲低模拟了缺氧诱导的“促增殖和抗凋亡”的变化。全基因组m6A分析鉴定了CACNA1d作为FTO的潜在下游靶点，YTHDC1作为m6A读取器。FTO结合CACNA1d mRNA并通过m6A去甲基化降低其稳定性。CACNA1d敲低可部分减轻缺氧诱导的PASMC增殖和凋亡的变化。此外，当缺氧培养恢复到常氧培养时，PASMCs的凋亡水平恢复到缺氧前水平，并且在过表达FTO或敲低CACNA1d表达后仍能观察到这种情况。结论：缺氧PASMCs中FTO下调可增加m6A修饰，通过提高CACNA1d表达促进细胞增殖，抑制细胞凋亡。

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引用次数: 0

Experimental modeling of pulmonary fibrosis and combined emphysema in mice using repeated doses of bleomycin and cigarette smoke extract 使用重复剂量的博来霉素和香烟烟雾提取物对小鼠肺纤维化和合并肺气肿的实验建模

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Pulmonary pharmacology & therapeutics

Pub Date : 2025-09-01 Epub Date: 2025-06-28 DOI: 10.1016/j.pupt.2025.102376

Jung Hur , Chin Kook Rhee , Joon Young Choi , Yong Suk Jo

Rationale

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.

Methods

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.

Results

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).

Conclusions

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.

特发性肺纤维化（IPF）患者中吸烟的高患病率增加了肺气肿的风险。合并肺纤维化和肺气肿（CPFE）主要发生在男性中，其特征是严重的运动性呼吸困难，弥散能力下降，肺癌风险增加。将CPFE患者排除在临床研究之外，限制了对其病理生理、治疗和预后的了解。本研究旨在通过在动物模型中比较CPFE与纯IPF来缩小这一知识差距，旨在开发以表型为导向的治疗策略。方法8周龄雌性C57BL/6J小鼠每2周气管内注射博来霉素（BLM, 2 U/kg/100 μL） 3次。对于CPFE模型，每周两次给予额外的鼻内香烟烟雾提取物（CSE）。通过支气管肺泡灌洗液（BALF）、促炎细胞因子、纤维化标志物和肺组织学来评估炎症和纤维化。结果balf分析显示，所有blm处理组细胞计数增加，主要是巨噬细胞，白细胞介素(IL)-6、转化生长因子(TGF)-β1和基质金属蛋白酶（MMP 3和MMP 8）升高。BLM和CSE治疗组巨噬细胞和淋巴细胞计数高于BLM单独治疗组。肺组织分析显示，blm处理组羟脯氨酸、炎症评分、Ashcroft评分升高，α-平滑肌肌动蛋白（SMA）和胶原蛋白1表达升高。通过平均线性截距（MLI）测量，BLM和CSE治疗组的肺气肿形成明显增加。结论通过反复给予BLM和CSE暴露，建立了持久肺纤维化和肺气肿的有效模型，可以进行CPFE和IPF的临床前研究，并探索以表型为导向的肺纤维化治疗策略。

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引用次数: 0

Effect of EP395, a novel anti-inflammatory macrolide, in an inhaled lipopolysaccharide challenge model in healthy volunteers: a randomised controlled trial 新型抗炎大环内酯EP395在健康志愿者吸入脂多糖刺激模型中的作用：一项随机对照试验

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Pulmonary pharmacology & therapeutics

Pub Date : 2025-09-01 Epub Date: 2025-06-03 DOI: 10.1016/j.pupt.2025.102365

Jens M. Hohlfeld , Philipp Badorrek , Olof Breuer , Kate Hanrott , Jennifer Kricker , Michael J. Parnham , Virginia Norris

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.

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.

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).

EP395 treatment increased the host defence response to inhaled LPS, including the epithelial response, whilst reducing inflammatory site pro-inflammatory mediators.

EP395是一种大环内酯类药物，抗菌活性可忽略不计，但在小鼠脂多糖（LPS）挑战模型中具有抗炎作用，目前正被开发为一种减少COPD恶化的潜在治疗方法。这项双盲、安慰剂对照的临床研究评估了EP395对吸入LPS的药效学反应，这是一种评估潜在新疗法抗炎作用的临床模型。49名健康、不吸烟的参与者被随机分组，每天口服375毫克EP395或安慰剂，持续3周。然后给予吸入LPS (2 μg)， 6小时后进行支气管镜检查收集支气管肺泡灌洗液（BALF）。在LPS刺激前、6和24小时采集血样。EP395组IL-6、TNF-α、MIP-1α、MIP-1β、MCP-1的BALF浓度低于安慰剂组，IL-33、IL-8、IL-1β浓度高于安慰剂组（差异无统计学意义）。中性粒细胞计数未受影响，但EP395组中性粒细胞弹性酶和髓过氧化物酶高于安慰剂组（无统计学意义）。与LPS处理前相比，EP395组在LPS处理后6和24小时血清表面活性剂蛋白d浓度均显著升高(LPS处理前平均148.8 ng/mL；lps后平均24小时183.0 ng/mL)，但安慰剂组没有(lps前平均142.4 ng/mL；lps后平均24 h 142.4 ng/mL)。LPS刺激前和24小时后，EP395组的log2转化倍数差异为0.33 (95% CI 0.52, 0.14；p = 0.0007)。EP395处理增加了宿主对吸入LPS的防御反应，包括上皮反应，同时减少了炎症部位的促炎介质。

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引用次数: 0

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 哮喘诊断后两年的临床缓解及其与临床结果的关联：一项对接受维持性吸入器治疗的哮喘患者的回顾性队列研究

IF 2.8 3区医学 Q2 PHARMACOLOGY & PHARMACY

Pulmonary pharmacology & therapeutics

Pub Date : 2025-09-01 Epub Date: 2025-08-06 DOI: 10.1016/j.pupt.2025.102381

Hyun-Jun Park , Chang Hoon Lee , Jung-Kyu Lee , Deog Kyeom Kim , Hyun-Woo Lee

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 %, P = 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; P = 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], P = 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.

临床缓解（CR）已成为重症哮喘患者有资格使用生物制剂的潜在治疗目标。然而，它对接受维持性吸入器治疗的哮喘患者的长期预后的影响尚不清楚。在这项回顾性队列研究中，我们评估了使用维持性吸入器的成年哮喘患者，以调查与实现CR相关的长期结果。CR的定义是在哮喘诊断两年后，至少一年没有恶化，症状得到良好控制，不使用全身皮质类固醇，肺功能稳定。在1:1倾向评分匹配的人群中，我们比较了1秒内强迫呼气量（FEV1）的轨迹和CR组与非CR组之间的年恶化率。549例患者中位随访7年，88例（16%）患者符合CR标准。匹配后，每组纳入76例。与非CR组相比，CR组患者年FEV1下降超过60 mL的比例明显降低（8.6% vs. 25%, P = 0.010）。线性混合效应模型显示，CR组的FEV1下降速度明显较慢，年差异为32.7 mL (95% CI 6.7至58.7；P = 0.014)。CR组的年中重度加重发生率也较低（0.17事件/年[IQR 0,0.37] vs. 0.42事件/年[IQR 0,1], P = 0.007）。总之，接受维持性吸入器治疗的哮喘患者达到CR与肺功能下降较慢和恶化较少相关。这些发现支持了CR作为长期治疗目标的潜在作用。

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