Pulmonary pharmacology & therapeutics最新文献_第2页

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 : 2025-08-14 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

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 : 2025-08-11 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

Functional interplay between bradykinin receptors and transient receptor potential vanilloid-1 in lipopolysaccharide-induced acute lung injury in mice 缓激肽受体与瞬时受体电位香草素-1在脂多糖诱导的小鼠急性肺损伤中的功能相互作用

IF 2.8 3区医学 Q2 PHARMACOLOGY & PHARMACY

Pulmonary pharmacology & therapeutics

Pub Date : 2025-08-10 DOI: 10.1016/j.pupt.2025.102384

Mayara Alves Amorim , Vitor Hélio Souza Oliveira , João B. Calixto , Eunice André

In this study, we investigated the functional interplay between bradykinin receptors and the transient receptor potential vanilloid-1 (TRPV1) channel in a mouse model of acute lung injury (ALI) induced by lipopolysaccharide (LPS). Lung and bronchoalveolar lavages were collected at 6 and 24 h after the induction of ALI and evaluated for changes in body weight, inflammatory marker levels, lung injury, and TRPV1 expression. Pretreatments with a TRPV1 antagonist (capsazepine) or B₁ and B₂ receptor antagonists, i.e., DALBK and HOE 140, respectively, were evaluated in this ALI mouse model. The histological score revealed higher levels of lung injury in mice treated with LPS (5 and 10 mg/kg), assessed at both 6 and 24 h, compared to the vehicle-treated group. A loss of body weight was observed within 24 h of ALI induction. Furthermore, collagen deposition, pulmonary oedema, leukocyte influx, and increased cytokine levels were also observed following LPS administration. Pretreatment with capsazepine, DALBK, or HOE 140 not only reversed all inflammatory parameters but also prevented the increased expression of TRPV1 observed in the lungs of mice subjected LPS-induced ALI. Our data suggest that, following LPS-induced ALI, bradykinin activates both B₁ and B₂ receptors associated with the subsequent activation of TRPV1. These findings suggest that bradykinin can activate both B₁ and B₂ receptors, which may contribute functionally to TRPV1 upregulation and activation during LPS-induced ALI. This novel pathway appears to sustain inflammation, offering a new therapeutic target for ALI and ARDS.

在本研究中，我们研究了缓激肽受体与瞬时受体电位香草素-1 （TRPV1）通道在脂多糖（LPS）诱导的急性肺损伤（ALI）小鼠模型中的功能相互作用。在ALI诱导后6和24小时收集肺和支气管肺泡灌洗液，评估体重、炎症标志物水平、肺损伤和TRPV1表达的变化。用TRPV1拮抗剂（辣椒平）或B1和B2受体拮抗剂（分别为DALBK和ho140）预处理ALI小鼠模型进行评估。组织学评分显示，LPS（5和10 mg/kg）处理的小鼠在6和24小时的肺损伤水平均高于给药组。在ALI诱导24小时内观察到体重下降。此外，胶原沉积、肺水肿、白细胞内流和细胞因子水平升高也在LPS处理后被观察到。用辣椒平、DALBK或ho140预处理不仅可以逆转所有炎症参数，还可以阻止lps诱导的ALI小鼠肺中TRPV1表达的增加。我们的数据表明，在lps诱导的ALI后，缓激肽激活了与随后激活TRPV1相关的B1和B2受体。这些发现表明，缓激素可以激活B1和B2受体，这可能在功能上有助于lps诱导的ALI中TRPV1的上调和激活。这种新途径似乎可以维持炎症，为ALI和ARDS提供新的治疗靶点。

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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 : 2025-08-06 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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引用次数: 0

Icaritin protects against airway inflammation by inhibiting the TLR4/NF-κB pathway in vivo and in vitro 在体内和体外实验中，淫羊藿苷通过抑制TLR4/NF-κB通路对气道炎症具有保护作用

IF 2.8 3区医学 Q2 PHARMACOLOGY & PHARMACY

Pulmonary pharmacology & therapeutics

Pub Date : 2025-07-29 DOI: 10.1016/j.pupt.2025.102380

Bo Xiao , Guiming Zhou , Lixia Hou , Lihong Yang , Zhimei Li , Yuchun Cai , Ailing Zhao , Biwen Mo , Dong Yao

Icaritin, a bioactive phytomolecule derived from Epimedium flavonoids (EFs), has been shown to have anti-inflammatory, anti-proliferative, and pro-apoptotic properties. However, its potential mechanisms in asthma airway inflammation have not been elucidated. In this study, Ovalbumin (OVA)-induced asthma mouse model and human bronchial epithelial cells (BEAS-2B) were used to illustrate the effects and mechanisms of Icaritin on airway inflammation. Specific airway resistance (sRAW) was used to detect the airway hyperresponsiveness (AHR). Hematoxylin-eosin (H&E) and periodic acid schiff (PAS) were used to detect the pathological changes. Bronchoalveolar lavage fluid (BALF) was used to detect the airway inflammatory cells. Serum and supernatants were used to detect the cytokines. Immunohistochemistry (IHC) and western blotting were used to detect the expression of TLR4, p-65, p-p65, IκBα, and p-IκBα. Cell Counting Kit-8 (CCK-8) was used to detect the cell viability. Icaritin suppressed AHR, attenuated eosinophilic infiltration and mucus hypersecretion, and significantly reduced the levels of OVA-specific cytokines in asthmatic mice. Moreover, Icaritin inhibited TLR4 expression, decreased phosphorylation of IκBα, and reduced NF-κB p65 activation in lung tissue of asthmatic mice. Further mechanistic studies showed that Icaritin reduces TLR4-induced inflammatory factor expression and blocks TLR4-activated NF-κB pathway in BEAS-2B cells. These findings demonstrate for the first time that Icaritin suppresses airway inflammation in asthma by inhibiting the TLR4/NF-κB pathway, suggesting its potential as a therapeutic agent for asthma.

淫羊藿黄酮类化合物淫羊藿苷（Icaritin）是淫羊藿黄酮类化合物中的一种生物活性植物分子，具有抗炎、抗增殖和促细胞凋亡的作用。然而，其在哮喘气道炎症中的潜在机制尚未阐明。本研究通过卵清蛋白（OVA）诱导的哮喘小鼠模型和人支气管上皮细胞（BEAS-2B），探讨了淫羊藿苷对气道炎症的影响及其机制。采用特异性气道阻力（sRAW）检测气道高反应性（AHR）。采用苏木精-伊红（H&；E）和周期性酸席夫（PAS）检测病理变化。支气管肺泡灌洗液（BALF）检测气道炎症细胞。血清和上清液检测细胞因子。采用免疫组化（IHC）和western blotting检测TLR4、p-65、p-p65、i - κ b α、p- i - κ b α的表达。细胞计数试剂盒-8 （CCK-8）检测细胞活力。icartin抑制哮喘小鼠AHR，减轻嗜酸性粒细胞浸润和粘液高分泌，显著降低ova特异性细胞因子水平。此外，淫羊藿苷抑制哮喘小鼠肺组织TLR4表达，降低i -κB α磷酸化，降低NF-κB p65活化。进一步的机制研究表明，Icaritin可降低BEAS-2B细胞中tlr4诱导的炎症因子表达，阻断tlr4激活的NF-κB通路。这些发现首次表明，icartin通过抑制TLR4/NF-κB通路抑制哮喘气道炎症，提示其作为哮喘治疗药物的潜力。

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引用次数: 0

PM2.5 augments cigarette smoke-induced lung inflammation in mice by driving a stronger immune response: Potential beneficial effects of oleanolic acid PM2.5通过驱动更强的免疫反应来增强香烟引起的小鼠肺部炎症：齐墩果酸的潜在有益作用。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Pulmonary pharmacology & therapeutics

Pub Date : 2025-07-16 DOI: 10.1016/j.pupt.2025.102379

Jitender Chandel, Amarjit S. Naura

Though cigarette smoke (CS) is primary risk factor for Chronic obstructive pulmonary disease (COPD), rising air pollution and higher concentrations of particulate matter (PM_2.5) in ambient air contribute substantially to COPD cases, particularly in smokers. However, the pathogenesis of COPD upon dual exposure to CS and PM_2.5 is not entirely known. Therefore, the impact of combined exposure to CS (9 cigarettes/day for 4 days) and PM_2.5 (single dose of 50 μg) on COPD pathogenesis was examined using mouse model in order to understand the key players behind the process. The data suggest that single exposure to PM_2.5 in CS pre-exposed mice triggered a strong inflammatory response, marked by switch from macrophage to neutrophilic inflammation, leading to severe deterioration in lung function compared to single hits. Furthermore, combined exposure led to robust increase in the levels of pro-inflammatory cytokines (G-CSF/KC/MCP-1/TNF-α/IL-1β/IL-6) in BALF as compared to the respective individual exposure. Interestingly, Oleanolic acid (OA) treatment protects against CS + PM_2.5-induced COPD-like pulmonary inflammation potentially by exerting antioxidant properties as reflected by data on BALF inflammatory cells, particularly neutrophils and various oxidative stress markers such as ROS/LPO/GSH/SOD/Catalase in lung tissue. Suppressed inflammation was associated with downregulation of gene expression of pro-inflammatory factors namely IL-1β, TNF-α, MIP-2 and normalization of proteinase-antiproteinase balance by downregulating gene expression of MMP-9 with simultaneous upregulation of its inhibitor TIMP-1. Reduced inflammatory response upon OA treatment correlates well with improved lung function. Overall, PM_2.5 exposure flares up the CS-induced lung inflammation linked to COPD, which is effectively ameliorated by OA.

虽然吸烟（CS）是慢性阻塞性肺病的主要危险因素，但空气污染加剧和环境空气中颗粒物（PM2.5）浓度升高在很大程度上导致了慢性阻塞性肺病病例，特别是对吸烟者而言。然而，双重暴露于CS和PM2.5的COPD发病机制尚不完全清楚。因此，我们通过小鼠模型研究了CS（9支/天，持续4天）和PM2.5（单剂量50μg）联合暴露对COPD发病机制的影响，以了解这一过程背后的关键因素。数据表明，CS预暴露小鼠的PM2.5单次暴露引发了强烈的炎症反应，其特征是从巨噬细胞炎症转变为中性粒细胞炎症，与单次暴露相比，导致肺功能严重恶化。此外，与单独暴露相比，联合暴露导致BALF中促炎细胞因子（G-CSF/KC/MCP-1/TNF-α/IL-1β/IL-6）水平的显著增加。有趣的是，正如肺组织中BALF炎症细胞，特别是中性粒细胞和各种氧化应激标志物（如ROS/LPO/GSH/SOD/过氧化氢酶）的数据所反映的那样，OA治疗可能通过发挥抗氧化特性来保护抗CS+ pm2.5诱导的copd样肺部炎症。抑制炎症与下调促炎因子IL-1β、TNF-α、mmp -2基因表达及蛋白酶-抗蛋白酶平衡正常化有关，其途径是下调MMP-9基因表达，同时上调其抑制剂TIMP-1。OA治疗后炎症反应的减少与肺功能的改善密切相关。总体而言，PM2.5暴露会加剧cs诱导的与COPD相关的肺部炎症，而OA可以有效改善这种炎症。

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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 : 2025-07-07 DOI: 10.1016/j.pupt.2025.102378

Luigino Calzetta

引用次数: 0

A disproportionality analysis of diabetes mellitus in patients treated with biologics for asthma and related conditions using FAERS data 使用FAERS数据对使用生物制剂治疗哮喘及相关疾病的患者中糖尿病的歧化分析

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Pulmonary pharmacology & therapeutics

Pub Date : 2025-07-02 DOI: 10.1016/j.pupt.2025.102377

Maria Gabriella Matera , Luigino Calzetta , Alfredo De Biase , Davide Lauro , Paola Rogliani , Mario Cazzola

Background

Biologics for asthma and related conditions target distinct immunologic pathways but may have differential effects on glucose metabolism. Emerging real-world evidence suggests a need to evaluate potential associations with diabetes mellitus (DM) and related metabolic adverse events (AEs).

Objective

To assess the disproportionality of DM and other metabolic AEs associated with six biologics approved for asthma and related conditions using data from the FDA Adverse Event Reporting System (FAERS).

Methods

Reported odds ratios (RORs) were calculated for metabolic events and DM for omalizumab, mepolizumab, benralizumab, reslizumab, dupilumab, and tezepelumab, comparing drug-specific AE profiles against the FAERS background.

Results

Omalizumab (ROR: 6.10) and benralizumab (ROR: 4.88) exhibited significant disproportionality regarding diabetes AEs, with mepolizumab also demonstrating an elevated ROR (2.80). For metabolic AEs, mepolizumab (ROR: 3.57) and omalizumab (ROR: 2.94) had the highest signals. Dupilumab showed the lowest RORs for both diabetes (0.10) and metabolic AEs (0.21).

Conclusion

This FAERS-based analysis identified a potential pharmacovigilance signal for DM associated with several biologics used to treat asthma and related conditions, most notably omalizumab and benralizumab. Similar patterns were observed for metabolic AEs, which reinforces the need for post-marketing studies and clinical awareness in patients with or at risk for metabolic disorders.

治疗哮喘和相关疾病的生物制剂针对不同的免疫途径，但可能对葡萄糖代谢有不同的影响。越来越多的现实证据表明，有必要评估其与糖尿病（DM）和相关代谢不良事件（ae）的潜在关联。目的利用FDA不良事件报告系统（FAERS）的数据，评估6种批准用于哮喘及相关疾病的生物制剂相关的糖尿病和其他代谢不良事件的不成比例。方法计算omalizumab， mepolizumab, benralizumab, reslizumab， dupilumab和tezepelumab的代谢事件和DM的报告优势比（RORs），将药物特异性AE与FAERS背景进行比较。结果somalizumab （ROR: 6.10）和benralizumab （ROR: 4.88）在糖尿病ae方面表现出显著的歧化，mepolizumab也显示出升高的ROR（2.80）。对于代谢性不良反应，美泊珠单抗（ROR: 3.57）和奥玛珠单抗（ROR: 2.94）的信号最高。Dupilumab在糖尿病（0.10）和代谢ae（0.21）方面均显示最低的RORs。结论：基于faers的分析确定了几种用于治疗哮喘和相关疾病的生物制剂与糖尿病相关的潜在药物警戒信号，最明显的是omalizumab和benralizumab。在代谢性不良反应中也观察到类似的模式，这加强了对代谢性疾病患者或有代谢性疾病风险的患者进行上市后研究和临床意识的必要性。

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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 : 2025-06-28 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

The era of multiple biologics: Is combination and switching an option in the management of severe asthma? 多种生物制剂的时代：联合和转换是治疗严重哮喘的一种选择吗？

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Pulmonary pharmacology & therapeutics

Pub Date : 2025-06-19 DOI: 10.1016/j.pupt.2025.102375

Emmanuel Oshiogwe Okwuofu , Audrey Chee Hui Yong , Jonathan Chee Woei Lim , Johnson Stanslas

Background and objective

The introduction of biologics therapies targeting specific cytokines relevant to asthma pathophysiology has changed the landscape in the treatment of severe asthma in both adults and children. However, the availability of multiple agents, inclusion criteria for randomised control trials (RCTs), variation in national and international guidelines, instances of treatment failures, and the potential of switching or combining biologic therapies, highlight the need for real-world evidence. Data from real-world studies of biologics in severe asthma may complement efficacy data obtained from RCTs and provide important post-marketing safety information. Additionally, these studies may help inform the design of future clinical trials, characterise the natural history of the disease, and support important translational research. This review highlights current evidence for the combination and switching of biologics in severe asthma and comorbid diseases that may serve as pointers for optimal clinical outcomes.

Method

Pubmed, Scopus, and Web of Science were searched using specified search strategies.

Results

Available evidence suggests that patients with severe asthma who received combination or switched biologics (omalizumab, benralizumab, reslizumab, mepolizumab, dupilumab, and Tezepelumab) in real-world settings experienced significant improvement in asthma control, exacerbation, and lung function. Although combining biologics is not currently a common practice, there are cases where biologic therapies were combined, discontinued, or switched.

Conclusion

Patients may benefit from the early and systematic consideration of combination and switching of biologic therapies in severe asthma.

背景与目的：针对哮喘病理生理相关的特定细胞因子的生物制剂疗法的引入已经改变了成人和儿童重度哮喘治疗的格局。然而，多种药物的可用性、随机对照试验（rct）的纳入标准、国家和国际指南的变化、治疗失败的实例以及切换或联合生物治疗的潜力，都突出了对真实证据的需求。来自生物制剂治疗严重哮喘的实际研究数据可以补充随机对照试验获得的疗效数据，并提供重要的上市后安全性信息。此外，这些研究可能有助于为未来临床试验的设计提供信息，描述疾病的自然历史，并支持重要的转化研究。这篇综述强调了目前在严重哮喘和合并症疾病中联合和转换生物制剂的证据，这些证据可能作为最佳临床结果的指针。方法：采用指定的检索策略对Pubmed、Scopus和Web of Science进行检索。结果：现有证据表明，在现实环境中接受联合或转换生物制剂（omalizumab, benralizumab, reslizumab, mepolizumab， dupilumab和Tezepelumab）的严重哮喘患者在哮喘控制，恶化和肺功能方面有显着改善。虽然联合生物制剂目前还不是一种常见的做法，但也有联合、停止或切换生物疗法的情况。结论：在重症哮喘患者早期系统考虑联合和切换生物治疗可能会受益。

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