Pub Date : 2025-10-20DOI: 10.1016/j.pupt.2025.102396
Menghao Li , Bokun Chen , Xinhui Zhang, Tingting Zhuo, Xiuju Liu
IPF is a chronic, progressive interstitial lung disease characterized by irreversible lung scarring, leading to exertional dyspnea and a gradual decline in pulmonary function. Its pathogenesis involves multiple mechanisms, including chronic inflammation, aberrant cytokine signaling, and alveolar epithelial injury. Currently, IPF remains incurable, and treatment primarily aims to slow disease progression and improve survival. This paper systematically reviews recent clinical trials of novel IPF drug therapies that have demonstrated promising efficacy, aiming to inform future drug development.
{"title":"Advances in novel therapeutics for idiopathic pulmonary fibrosis","authors":"Menghao Li , Bokun Chen , Xinhui Zhang, Tingting Zhuo, Xiuju Liu","doi":"10.1016/j.pupt.2025.102396","DOIUrl":"10.1016/j.pupt.2025.102396","url":null,"abstract":"<div><div>IPF is a chronic, progressive interstitial lung disease characterized by irreversible lung scarring, leading to exertional dyspnea and a gradual decline in pulmonary function. Its pathogenesis involves multiple mechanisms, including chronic inflammation, aberrant cytokine signaling, and alveolar epithelial injury. Currently, IPF remains incurable, and treatment primarily aims to slow disease progression and improve survival. This paper systematically reviews recent clinical trials of novel IPF drug therapies that have demonstrated promising efficacy, aiming to inform future drug development.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"91 ","pages":"Article 102396"},"PeriodicalIF":2.8,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145337490","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}
Pub Date : 2025-09-10DOI: 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.
{"title":"Targeting the immunometabolism interface: A novel strategy for IPF therapy","authors":"Ganggang Li , Yuzhi Huo , Xiaochuan Pan , Nan Jia , Xuanyu Wu , Xinhui Wu , Fei Wang , Quanyu Du","doi":"10.1016/j.pupt.2025.102394","DOIUrl":"10.1016/j.pupt.2025.102394","url":null,"abstract":"<div><div>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 <em>PPARG</em> (<em>peroxisome proliferator activated receptor gamma</em>) and <em>SPP1</em> (<em>secreted phosphoprotein 1</em>), along with signaling pathways including mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and <em>hypoxia-inducible factor 1-alpha (HIF-1α)</em>, 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.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"91 ","pages":"Article 102394"},"PeriodicalIF":2.8,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145048269","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}
Pub Date : 2025-08-18DOI: 10.1016/j.pupt.2025.102385
Alessandro Cannavo , Marika Comegna , Alice Castaldo , Caterina Vinciguerra , Anna Lauritano , Giulia Renata Franco , Giovanna Casoria , Graziamaria Corbi , Giuseppe Rengo , Giuseppe Castaldo
Cystic fibrosis (CF) is an autosomal recessive disorder that affects multiple organs, with clinical manifestations, disease progression, and response to therapy varying among individuals. This effect is mainly caused by mutations in the gene encoding for the CF transmembrane conductance regulator (CFTR), a cAMP-regulated chloride channel.
In recent decades, other genes and their allelic variants, beyond CFTR mutations, have been proposed as genetic modifiers of CF phenotype. For instance, different polymorphic β2-adrenergic receptor (β2AR) polymorphic variants have been reported in CF individuals and appear to influence correct receptor function. β2AR belongs to the βAR family, which includes three subtypes: β1AR, β2AR, and β3AR. These receptors are crucial G protein-coupled receptors (GPCRs) expressed in various cell types and serve as key modulators of cAMP production, making their function particularly relevant in CF pathophysiology. β2AR is abundantly expressed in airway epithelial and smooth muscle cells, and studies revealed that it plays a crucial role in modulating CFTR activity and smooth muscle contractility through cAMP signaling. For these reasons, β2-agonists are widely used in clinical healthcare to treat patients with obstructive airway disorders, including CF.
Emerging evidence has also supported a role for β3AR, which is expressed in the canine and human bronchial epithelium and have been reported to enhance ciliary motility and regulate CFTR function, making it a potential therapeutic target in CF.
{"title":"Exploring the role of β2- and β3-adrenergic receptors in cystic fibrosis","authors":"Alessandro Cannavo , Marika Comegna , Alice Castaldo , Caterina Vinciguerra , Anna Lauritano , Giulia Renata Franco , Giovanna Casoria , Graziamaria Corbi , Giuseppe Rengo , Giuseppe Castaldo","doi":"10.1016/j.pupt.2025.102385","DOIUrl":"10.1016/j.pupt.2025.102385","url":null,"abstract":"<div><div>Cystic fibrosis (CF) is an autosomal recessive disorder that affects multiple organs, with clinical manifestations, disease progression, and response to therapy varying among individuals. This effect is mainly caused by mutations in the gene encoding for the CF transmembrane conductance regulator (CFTR), a cAMP-regulated chloride channel.</div><div>In recent decades, other genes and their allelic variants, beyond CFTR mutations, have been proposed as genetic modifiers of CF phenotype. For instance, different polymorphic β2-adrenergic receptor (β2AR) polymorphic variants have been reported in CF individuals and appear to influence correct receptor function. β2AR belongs to the βAR family, which includes three subtypes: β1AR, β2AR, and β3AR. These receptors are crucial G protein-coupled receptors (GPCRs) expressed in various cell types and serve as key modulators of cAMP production, making their function particularly relevant in CF pathophysiology. β2AR is abundantly expressed in airway epithelial and smooth muscle cells, and studies revealed that it plays a crucial role in modulating CFTR activity and smooth muscle contractility through cAMP signaling. For these reasons, β2-agonists are widely used in clinical healthcare to treat patients with obstructive airway disorders, including CF.</div><div>Emerging evidence has also supported a role for β3AR, which is expressed in the canine and human bronchial epithelium and have been reported to enhance ciliary motility and regulate CFTR function, making it a potential therapeutic target in CF.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"90 ","pages":"Article 102385"},"PeriodicalIF":2.8,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144879420","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}
Pub Date : 2025-08-14DOI: 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.
{"title":"FTO regulates the proliferation and apoptosis of pulmonary artery smooth muscle cells through m6A demethylation modification","authors":"Xinwei Shi , Yizhou Yang , Yue Gao , Chao Yuan , Xianqun Rao , Wei Li , Liting Wu , Tingting Yu , Ming Xu , Baoli Zhu , Lei Han , 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":"2025-08-14","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}
Pub Date : 2025-08-11DOI: 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.
{"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 , Suzhen Yang , 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":"2025-08-11","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}
Pub Date : 2025-08-10DOI: 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.
{"title":"Functional interplay between bradykinin receptors and transient receptor potential vanilloid-1 in lipopolysaccharide-induced acute lung injury in mice","authors":"Mayara Alves Amorim , Vitor Hélio Souza Oliveira , João B. Calixto , Eunice André","doi":"10.1016/j.pupt.2025.102384","DOIUrl":"10.1016/j.pupt.2025.102384","url":null,"abstract":"<div><div>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 B<sub>1</sub> and B<sub>2</sub> 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 B<sub>1</sub> and B<sub>2</sub> receptors associated with the subsequent activation of TRPV1. These findings suggest that bradykinin can activate both B<sub>1</sub> and B<sub>2</sub> 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.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"90 ","pages":"Article 102384"},"PeriodicalIF":2.8,"publicationDate":"2025-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144830131","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}
Pub Date : 2025-08-06DOI: 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。
{"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 , Chang Hoon Lee , Jung-Kyu Lee , Deog Kyeom Kim , 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 (FEV<sub>1</sub>) 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 FEV<sub>1</sub> 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":"2025-08-06","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}
Pub Date : 2025-07-29DOI: 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。
{"title":"Icaritin protects against airway inflammation by inhibiting the TLR4/NF-κB pathway in vivo and in vitro","authors":"Bo Xiao , Guiming Zhou , Lixia Hou , Lihong Yang , Zhimei Li , Yuchun Cai , Ailing Zhao , Biwen Mo , Dong Yao","doi":"10.1016/j.pupt.2025.102380","DOIUrl":"10.1016/j.pupt.2025.102380","url":null,"abstract":"<div><div>Icaritin, a bioactive phytomolecule derived from <em>Epimedium</em> 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.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"90 ","pages":"Article 102380"},"PeriodicalIF":2.8,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144723445","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}
Pub Date : 2025-07-16DOI: 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 (PM2.5) in ambient air contribute substantially to COPD cases, particularly in smokers. However, the pathogenesis of COPD upon dual exposure to CS and PM2.5 is not entirely known. Therefore, the impact of combined exposure to CS (9 cigarettes/day for 4 days) and PM2.5 (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 PM2.5 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 + PM2.5-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, PM2.5 exposure flares up the CS-induced lung inflammation linked to COPD, which is effectively ameliorated by OA.
{"title":"PM2.5 augments cigarette smoke-induced lung inflammation in mice by driving a stronger immune response: Potential beneficial effects of oleanolic acid","authors":"Jitender Chandel, Amarjit S. Naura","doi":"10.1016/j.pupt.2025.102379","DOIUrl":"10.1016/j.pupt.2025.102379","url":null,"abstract":"<div><div>Though cigarette smoke (CS) is primary risk factor for Chronic obstructive pulmonary disease (COPD), rising air pollution and higher concentrations of particulate matter (PM<sub>2.5</sub>) in ambient air contribute substantially to COPD cases, particularly in smokers. However, the pathogenesis of COPD upon dual exposure to CS and PM<sub>2.5</sub> is not entirely known. Therefore, the impact of combined exposure to CS (9 cigarettes/day for 4 days) and PM<sub>2.5</sub> (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<sub>2.5</sub> 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<sub>2.5</sub>-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<sub>2.5</sub> exposure flares up the CS-induced lung inflammation linked to COPD, which is effectively ameliorated by OA.</div></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"90 ","pages":"Article 102379"},"PeriodicalIF":3.3,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668139","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}
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