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Localized delivery of therapeutics impact laryngeal mechanics, local inflammatory response, and respiratory microbiome following upper airway intubation injury in swine. 局部给药对猪上气道插管损伤后喉力学、局部炎症反应和呼吸道微生物组的影响。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-09-28 DOI: 10.1186/s12931-024-02973-1
Gabriela Gonzales, Ronit Malka, Lisa M Marinelli, Christine M Lee, Stacy Cook, Solaleh Miar, Gregory R Dion, Teja Guda

Background: Laryngeal injury associated with traumatic or prolonged intubation may lead to voice, swallow, and airway complications. The interplay between inflammation and microbial population shifts induced by intubation may relate to clinical outcomes. The objective of this study was to investigate laryngeal mechanics, tissue inflammatory response, and local microbiome changes with laryngotracheal injury and localized delivery of therapeutics via drug-eluting endotracheal tube.

Methods: A simulated traumatic intubation injury was created in Yorkshire crossbreed swine under direct laryngoscopy. Endotracheal tubes electrospun with roxadustat or valacyclovir- loaded polycaprolactone (PCL) fibers were placed in the injured airway for 3, 7, or 14 days (n = 3 per group/time and ETT type). Vocal fold stiffness was then evaluated with normal indentation and laryngeal tissue sections were histologically examined. Immunohistochemistry and inflammatory marker profiling were conducted to evaluate the inflammatory response associated with injury and ETT placement. Additionally, ETT biofilm formation was visualized using scanning electron microscopy and micro-computed tomography, while changes in the airway microbiome were profiled through 16S rRNA sequencing.

Results: Laryngeal tissue with roxadustat ETT placement had increasing localized stiffness outcomes over time and histological assessment indicated minimal epithelial ulceration and fibrosis, while inflammation remained severe across all timepoints. In contrast, vocal fold tissue with valacyclovir ETT placement showed no significant changes in stiffness over time; histological analysis presented a reduction in epithelial ulceration and inflammation scores along with increased fibrosis observed at 14 days. Immunohistochemistry revealed a decline in M1 and M2 macrophage markers over time for both ETT types. Among the cytokines, IL-8 levels differed significantly between the roxadustat and valacyclovir ETT groups, while no other cytokines showed statistically significant differences. Additionally, increased biofilm formation was observed in the coated ETTs with notable alterations in microbiota distinctive to each ETT type and across time.

Conclusion: The injured and intubated airway resulted in increased laryngeal stiffness. Local inflammation and the type of therapeutic administered impacted the bacterial composition within the upper respiratory microbiome, which in turn mediated local tissue healing and recovery.

背景:与创伤性或长时间插管相关的喉损伤可能会导致嗓音、吞咽和气道并发症。插管引起的炎症和微生物群变化之间的相互作用可能与临床结果有关。本研究的目的是调查喉力学、组织炎症反应以及喉气管损伤和通过药物洗脱气管导管局部给药引起的局部微生物群变化:方法:在直接喉镜检查下,对约克郡杂交猪进行模拟创伤性插管损伤。将电纺有罗沙司他(roxadustat)或伐昔洛韦(valacyclovir- loaded polycaprolactone (PCL))纤维的气管导管置于受伤气道中 3、7 或 14 天(每组/时间和 ETT 类型 n = 3)。然后用正常压痕法评估声带僵硬度,并对喉组织切片进行组织学检查。免疫组化和炎症标记物分析用于评估与损伤和 ETT 置入相关的炎症反应。此外,还使用扫描电子显微镜和微型计算机断层扫描观察了 ETT 生物膜的形成,并通过 16S rRNA 测序分析了气道微生物组的变化:结果:放置了罗沙司他 ETT 的喉组织的局部僵硬度随时间推移而增加,组织学评估显示上皮溃疡和纤维化极少,而炎症在所有时间点上都很严重。与此相反,放置了伐昔洛韦 ETT 的声带组织的僵硬度没有随着时间的推移而发生显著变化;组织学分析表明,上皮溃疡和炎症评分降低,14 天后观察到纤维化增加。免疫组化显示,两种 ETT 的 M1 和 M2 巨噬细胞标记物均随时间推移而下降。在细胞因子中,罗沙司他和伐昔洛韦 ETT 组的 IL-8 水平差异显著,而其他细胞因子则没有统计学意义上的显著差异。此外,在有涂层的 ETT 中观察到生物膜形成增加,每种 ETT 类型和不同时间段的微生物群发生了明显变化:结论:受伤和插管气道导致喉部僵硬度增加。局部炎症和治疗类型影响了上呼吸道微生物群中的细菌组成,进而促进了局部组织的愈合和恢复。
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引用次数: 0
Role of β-adrenergic signaling and the NLRP3 inflammasome in chronic intermittent hypoxia-induced murine lung cancer progression. β-肾上腺素能信号传导和 NLRP3 炎性体在慢性间歇性缺氧诱导的小鼠肺癌进展中的作用
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-09-28 DOI: 10.1186/s12931-024-02969-x
Jianxia Sun, Xinyun Jia, Zhiqiang Zhang, Yang Yang, Chuntao Zhai, Baosheng Zhao, Yuzhen Liu

Background: Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH), is a prevalent condition that has been associated with various forms of cancer. Although some clinical studies suggest a potential link between OSA and lung cancer, this association remains uncertain, and the underlying mechanisms are not fully understood. This study investigated the role of the catecholamine-β-adrenergic receptor (βAR) and the NLRP3 inflammasome in mediating the effects of CIH on lung cancer progression in mice.

Methods: Male C57BL/6 N mice were subjected to CIH for four weeks, with Lewis lung carcinoma cells seeded subcutaneously. Propranolol (a βAR blocker) or nepicastat (an inhibitor of catecholamine production) was administered during this period. Tumor volume and tail artery blood pressure were monitored. Immunohistochemical staining and immunofluorescence staining were employed to assess protein expression of Ki-67, CD31, VEGFR2, PD-1, PD-L1, and ASC specks in tumor tissues. ELISA was used to detect catecholamine and various cytokines, while western blot assessed the expression of cyclin D1, caspase-1, and IL-1β. In vitro tube formation assay investigated angiogenesis. NLRP3 knockout mice were used to determine the mechanism of NLRP3 in CIH.

Results: CIH led to an increase in catecholamine. Catecholamine-βAR inhibitor drugs prevented the increase in blood pressure caused by CIH. Notably, the drugs inhibited CIH-induced murine lung tumor growth, and the expression of Ki-67, cyclin D1, CD31, VEGFR2, PD-1 and PD-L1 in tumor decreased. In vitro, propranolol inhibits tube formation induced by CIH mouse serum. Moreover, CIH led to an increase in TNF-α, IL-6, IL-1β, IFN-γ and sPD-L1 levels and a decrease in IL-10 in peripheral blood, accompanied by activation of NLRP3 inflammasomes in tumor, but these effects were also stopped by drugs. In NLRP3-knockout mice, CIH-induced upregulation of PD-1/PD-L1 in tumor was inhibited.

Conclusions: Our study underscores the significant contribution of β-adrenergic signaling and the NLRP3 inflammasome to CIH-induced lung cancer progression. These pathways represent potential therapeutic targets for mitigating the impact of OSA on lung cancer.

背景:以慢性间歇性缺氧(CIH)为特征的阻塞性睡眠呼吸暂停(OSA)是一种普遍存在的疾病,与各种形式的癌症有关。尽管一些临床研究表明 OSA 与肺癌之间存在潜在联系,但这种联系仍不确定,其潜在机制也不完全清楚。本研究探讨了儿茶酚胺-β-肾上腺素能受体(βAR)和NLRP3炎性体在介导CIH对小鼠肺癌进展的影响中的作用:雄性 C57BL/6 N 小鼠接受为期四周的 CIH 治疗,并在皮下播种 Lewis 肺癌细胞。在此期间给予普萘洛尔(一种βAR阻断剂)或奈皮司他(一种儿茶酚胺分泌抑制剂)。监测肿瘤体积和尾动脉血压。免疫组化染色和免疫荧光染色用于评估肿瘤组织中 Ki-67、CD31、VEGFR2、PD-1、PD-L1 和 ASC斑点的蛋白表达。ELISA 检测儿茶酚胺和各种细胞因子,Western 印迹评估细胞周期蛋白 D1、caspase-1 和 IL-1β 的表达。体外血管形成试验研究血管生成。用 NLRP3 基因敲除小鼠来确定 NLRP3 在 CIH 中的作用机制:结果:CIH导致儿茶酚胺增加。结果:CIH导致儿茶酚胺增加,儿茶酚胺-βAR抑制剂药物阻止了CIH引起的血压升高。值得注意的是,这些药物抑制了 CIH 诱导的小鼠肺肿瘤的生长,肿瘤中 Ki-67、细胞周期蛋白 D1、CD31、血管内皮生长因子受体 2、PD-1 和 PD-L1 的表达均有所下降。在体外,普萘洛尔能抑制 CIH 小鼠血清诱导的管形成。此外,CIH导致外周血中TNF-α、IL-6、IL-1β、IFN-γ和sPD-L1水平升高,IL-10水平降低,并伴随着肿瘤中NLRP3炎性体的激活,但这些效应也被药物所阻止。在NLRP3基因敲除的小鼠中,CIH诱导的肿瘤中PD-1/PD-L1的上调受到抑制:我们的研究强调了β肾上腺素能信号传导和NLRP3炎性体对CIH诱导的肺癌进展的重要作用。这些通路是减轻 OSA 对肺癌影响的潜在治疗靶点。
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引用次数: 0
It takes two peroxisome proliferator-activated receptors (PPAR-β/δ and PPAR-γ) to tango idiopathic pulmonary fibrosis. 特发性肺纤维化需要两种过氧化物酶体增殖激活受体(PPAR-β/δ 和 PPAR-γ)的共同作用。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-09-23 DOI: 10.1186/s12931-024-02935-7
Eistine Boateng, Rocio Bonilla-Martinez, Barbara Ahlemeyer, Vannuruswamy Garikapati, Mohammad Rashedul Alam, Omelyan Trompak, Gani Oruqaj, Natalia El-Merhie, Michael Seimetz, Clemens Ruppert, Andreas Günther, Bernhard Spengler, Srikanth Karnati, Eveline Baumgart-Vogt

Background: Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant lung epithelial phenotypes, fibroblast activation, and increased extracellular matrix deposition. Transforming growth factor-beta (TGF-β)1-induced Smad signaling and downregulation of peroxisomal genes are involved in the pathogenesis and can be inhibited by peroxisome proliferator-activated receptor (PPAR)-α activation. However, the three PPARs, that is PPAR-α, PPAR-β/δ, and PPAR-γ, are known to interact in a complex crosstalk.

Methods: To mimic the pathogenesis of lung fibrosis, primary lung fibroblasts from control and IPF patients with comparable levels of all three PPARs were treated with TGF-β1 for 24 h, followed by the addition of PPAR ligands either alone or in combination for another 24 h. Fibrosis markers (intra- and extracellular collagen levels, expression and activity of matrix metalloproteinases) and peroxisomal biogenesis and metabolism (gene expression of peroxisomal biogenesis and matrix proteins, protein levels of PEX13 and catalase, targeted and untargeted lipidomic profiles) were analyzed after TGF-β1 treatment and the effects of the PPAR ligands were investigated.

Results: TGF-β1 induced the expected phenotype; e.g. it increased the intra- and extracellular collagen levels and decreased peroxisomal biogenesis and metabolism. Agonists of different PPARs reversed TGF-β1-induced fibrosis even when given 24 h after TGF-β1. The effects included the reversals of (1) the increase in collagen production by repressing COL1A2 promoter activity (through PPAR-β/δ activation); (2) the reduced activity of matrix metalloproteinases (through PPAR-β/δ activation); (3) the decrease in peroxisomal biogenesis and lipid metabolism (through PPAR-γ activation); and (4) the decrease in catalase protein levels in control (through PPAR-γ activation) and IPF (through a combined activation of PPAR-β/δ and PPAR-γ) fibroblasts. Further experiments to explore the role of catalase showed that an overexpression of catalase protein reduced collagen production. Additionally, the beneficial effect of PPAR-γ but not of PPAR-β/δ activation on collagen synthesis depended on catalase activity and was thus redox-sensitive.

Conclusion: Our data provide evidence that IPF patients may benefit from a combined activation of PPAR-β/δ and PPAR-γ.

背景:特发性肺纤维化(IPF)的特点是肺上皮表型异常、成纤维细胞活化和细胞外基质沉积增加。转化生长因子-β(TGF-β)1 诱导的 Smad 信号转导和过氧化物酶体基因下调参与了发病机制,过氧化物酶体增殖激活受体(PPAR)-α 的激活可抑制这种信号转导。然而,已知三种 PPAR(即 PPAR-α、PPAR-β/δ 和 PPAR-γ)之间存在复杂的相互作用:方法:为了模拟肺纤维化的发病机制,用 TGF-β1 处理来自对照组和 IPF 患者的原代肺成纤维细胞 24 小时,然后单独或联合添加 PPAR 配体 24 小时。分析了TGF-β1处理后的纤维化标志物(细胞内和细胞外胶原蛋白水平、基质金属蛋白酶的表达和活性)和过氧化物酶体生物生成和代谢(过氧化物酶体生物生成和基质蛋白的基因表达、PEX13和过氧化氢酶的蛋白水平、靶向和非靶向脂质组图谱),并研究了PPAR配体的影响:结果:TGF-β1诱导了预期的表型,如增加了细胞内和细胞外胶原蛋白水平,减少了过氧化物酶体的生物生成和代谢。不同 PPARs 的激动剂可逆转 TGF-β1 诱导的纤维化,即使在 TGF-β1 24 小时后给药也是如此。这些效应包括:(1)通过抑制 COL1A2 启动子的活性(通过 PPAR-β/δ 激活)逆转胶原蛋白生成的增加;(2)降低基质金属蛋白酶的活性(通过 PPAR-β/δ 激活);(4)对照组(通过 PPAR-γ 激活)和 IPF(通过 PPAR-β/δ 和 PPAR-γ)成纤维细胞中过氧化氢酶蛋白水平的下降。进一步探索过氧化氢酶作用的实验表明,过氧化氢酶蛋白的过量表达减少了胶原蛋白的生成。此外,PPAR-γ 而非 PPAR-β/δ 激活对胶原合成的有益影响取决于过氧化氢酶的活性,因此对氧化还原反应敏感:我们的数据提供了 IPF 患者可能从 PPAR-β/δ 和 PPAR-γ 的联合激活中获益的证据。
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引用次数: 0
Associations between vitamin D status and biomarkers linked with inflammation in patients with asthma: a systematic review and meta-analysis of interventional and observational studies. 哮喘患者维生素 D 状态与炎症相关生物标志物之间的关系:对干预性和观察性研究的系统回顾和荟萃分析。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-09-19 DOI: 10.1186/s12931-024-02967-z
Asmae El Abd, Harika Dasari, Philippe Dodin, Helen Trottier, Francine M Ducharme

Background: Numerous studies indicate an association between vitamin D status and inflammatory biomarkers in patients with asthma, but findings are inconsistent. This review aims to summarize the relationship between serum vitamin D status, assessed by 25-hydroxyvitamin D (25(OH)D) level, and inflammatory biomarkers in children and adults with asthma.

Methods: A literature search of interventional and observational studies on 25(OH)D up to November 2022 was conducted across six electronic databases. Outcomes of interest included a range of inflammatory biomarkers classified in four categories: T helper 2 (Th2) pro-inflammatory, non-Th2 pro-inflammatory, anti-inflammatory, and non-specific biomarkers. Study characteristics were extracted and risk of bias was evaluated using the American Academy of Nutrition and Dietetics tool. Meta-analysis was conducted on studies with a low risk of bias, while narrative reporting was used to present the direction of associations (positive, no association, or negative) for each biomarker, overall and within the low-risk studies.

Results: We included 71 studies (3 interventional, 68 observational) involving asthma patients. These studies investigated the association between serum 25(OH)D and Th2 pro-inflammatory biomarkers (N = 58), non-Th2 pro-inflammatory biomarkers (N = 18), anti-inflammatory biomarkers (N = 16), and non-specific biomarkers (N = 10). Thirteen (18.3%) studies, 50 (70.4%), and 8 (11.3%) were at high, moderate, and low risk of bias, respectively. In all studies, irrespective of risk of bias, the most frequently reported finding was no significant association, followed by a negative association between 25(OH)D and pro-inflammatory biomarkers and a positive association with anti-inflammatory biomarkers. In low-risk studies, one biomarker could be meta-analysed. The pooled estimate for 25(OH)D and serum IgE showed a negative association (β (95% CI)= - 0.33 (-0.65 to - 0.01); I2 = 88%; N = 4 studies). A negative association between 25(OH)D and blood eosinophils was also observed in the largest of three studies, as well as with cathelicidin (LL-37) in the only study reporting it. For other biomarkers, most low-risk studies revealed no significant association with 25(OH)D.

Conclusion: Serum 25(OH)D is negatively associated with serum IgE and possibly with blood eosinophils and LL-37, supporting an in vivo immunomodulatory effect of 25(OH)D. Future research should employ rigorous methodologies and standardized reporting for meta-analysis aggregation to further elucidate these associations.

背景:大量研究表明,哮喘患者的维生素 D 状态与炎症生物标志物之间存在关联,但研究结果并不一致。本综述旨在总结以25-羟基维生素D(25(OH)D)水平评估的儿童和成人哮喘患者血清维生素D状态与炎症生物标志物之间的关系:在六个电子数据库中检索了截至 2022 年 11 月有关 25(OH)D 的干预性和观察性研究文献。感兴趣的结果包括一系列炎症生物标志物,分为四类:T辅助2(Th2)促炎、非Th2促炎、抗炎和非特异性生物标志物。使用美国营养与饮食学会工具提取了研究特征并评估了偏倚风险。对偏倚风险较低的研究进行了荟萃分析,同时使用叙述性报告来说明总体和低风险研究中每种生物标志物的关联方向(正相关、无关联或负相关):我们纳入了 71 项涉及哮喘患者的研究(3 项干预性研究,68 项观察性研究)。这些研究调查了血清 25(OH)D 与 Th2 促炎生物标志物(58 项)、非 Th2 促炎生物标志物(18 项)、抗炎生物标志物(16 项)和非特异性生物标志物(10 项)之间的关系。分别有 13 项(18.3%)、50 项(70.4%)和 8 项(11.3%)研究存在高、中和低偏倚风险。在所有研究中,无论偏倚风险如何,最常报告的发现是无显著关联,其次是 25(OH)D 与促炎症生物标志物呈负相关,与抗炎症生物标志物呈正相关。在低风险研究中,可以对一种生物标志物进行荟萃分析。25(OH)D与血清IgE的汇总估计值呈负相关(β (95% CI)= - 0.33 (-0.65 to - 0.01);I2 = 88%;N = 4项研究)。在三项最大的研究中,也观察到 25(OH)D 与血液中的嗜酸性粒细胞呈负相关;在唯一一项报告中,也观察到 25(OH)D 与 cathelicidin(LL-37)呈负相关。至于其他生物标志物,大多数低风险研究显示与 25(OH)D 没有显著关联:结论:血清 25(OH)D 与血清 IgE 呈负相关,可能还与血液中的嗜酸性粒细胞和 LL-37 呈负相关,这支持了 25(OH)D 的体内免疫调节作用。未来的研究应采用严格的方法和标准化报告进行荟萃分析,以进一步阐明这些关联。
{"title":"Associations between vitamin D status and biomarkers linked with inflammation in patients with asthma: a systematic review and meta-analysis of interventional and observational studies.","authors":"Asmae El Abd, Harika Dasari, Philippe Dodin, Helen Trottier, Francine M Ducharme","doi":"10.1186/s12931-024-02967-z","DOIUrl":"10.1186/s12931-024-02967-z","url":null,"abstract":"<p><strong>Background: </strong>Numerous studies indicate an association between vitamin D status and inflammatory biomarkers in patients with asthma, but findings are inconsistent. This review aims to summarize the relationship between serum vitamin D status, assessed by 25-hydroxyvitamin D (25(OH)D) level, and inflammatory biomarkers in children and adults with asthma.</p><p><strong>Methods: </strong>A literature search of interventional and observational studies on 25(OH)D up to November 2022 was conducted across six electronic databases. Outcomes of interest included a range of inflammatory biomarkers classified in four categories: T helper 2 (Th2) pro-inflammatory, non-Th2 pro-inflammatory, anti-inflammatory, and non-specific biomarkers. Study characteristics were extracted and risk of bias was evaluated using the American Academy of Nutrition and Dietetics tool. Meta-analysis was conducted on studies with a low risk of bias, while narrative reporting was used to present the direction of associations (positive, no association, or negative) for each biomarker, overall and within the low-risk studies.</p><p><strong>Results: </strong>We included 71 studies (3 interventional, 68 observational) involving asthma patients. These studies investigated the association between serum 25(OH)D and Th2 pro-inflammatory biomarkers (N = 58), non-Th2 pro-inflammatory biomarkers (N = 18), anti-inflammatory biomarkers (N = 16), and non-specific biomarkers (N = 10). Thirteen (18.3%) studies, 50 (70.4%), and 8 (11.3%) were at high, moderate, and low risk of bias, respectively. In all studies, irrespective of risk of bias, the most frequently reported finding was no significant association, followed by a negative association between 25(OH)D and pro-inflammatory biomarkers and a positive association with anti-inflammatory biomarkers. In low-risk studies, one biomarker could be meta-analysed. The pooled estimate for 25(OH)D and serum IgE showed a negative association (β (95% CI)= - 0.33 (-0.65 to - 0.01); I<sup>2</sup> = 88%; N = 4 studies). A negative association between 25(OH)D and blood eosinophils was also observed in the largest of three studies, as well as with cathelicidin (LL-37) in the only study reporting it. For other biomarkers, most low-risk studies revealed no significant association with 25(OH)D.</p><p><strong>Conclusion: </strong>Serum 25(OH)D is negatively associated with serum IgE and possibly with blood eosinophils and LL-37, supporting an in vivo immunomodulatory effect of 25(OH)D. Future research should employ rigorous methodologies and standardized reporting for meta-analysis aggregation to further elucidate these associations.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11423515/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Mask side-effects are related to gender in long-term CPAP: results from the InterfaceVent real-life study. 长期使用 CPAP 时面罩的副作用与性别有关:InterfaceVent 真实生活研究的结果。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-09-06 DOI: 10.1186/s12931-024-02965-1
Celia Vidal, Fanny Bertelli, Jean-Pierre Mallet, Raphael Gilson, Jean-Christian Borel, Frédéric Gagnadoux, Arnaud Bourdin, Nicolas Molinari, Dany Jaffuel

Background: Over the past three decades, our understanding of sleep apnea in women has advanced, revealing disparities in pathophysiology, diagnosis, and treatment compared to men. However, no real-life study to date has explored the relationship between mask-related side effects (MRSEs) and gender in the context of long-term CPAP.

Methods: The InterfaceVent-CPAP study is a prospective real-life cross-sectional study conducted in an apneic adult cohort undergoing at least 3 months of CPAP with unrestricted mask-access (34 different masks, no gender specific mask series). MRSE were assessed by the patient using visual analog scales (VAS). CPAP-non-adherence was defined as a mean CPAP-usage of less than 4 h per day. The primary objective of this ancillary study was to investigate the impact of gender on the prevalence of MRSEs reported by the patient. Secondary analyses assessed the impact of MRSEs on CPAP-usage and CPAP-non-adherence depending on the gender.

Results: A total of 1484 patients treated for a median duration of 4.4 years (IQ25-75: 2.0-9.7) were included in the cohort, with women accounting for 27.8%. The prevalence of patient-reported mask injury, defined as a VAS score ≥ 5 (p = 0.021), was higher in women than in men (9.6% versus 5.3%). For nasal pillow masks, the median MRSE VAS score for dry mouth was higher in women (p = 0.039). For oronasal masks, the median MRSE VAS score for runny nose was higher in men (p = 0.039). Multivariable regression analyses revealed that, for both women and men, dry mouth was independently and negatively associated with CPAP-usage, and positively associated with CPAP-non-adherence.

Conclusion: In real-life patients treated with long-term CPAP, there are gender differences in patient reported MRSEs. In the context of personalized medicine, these results suggest that the design of future masks should consider these gender differences if masks specifically for women are developed. However, only dry mouth, a side effect not related to mask design, impacts CPAP-usage and non-adherence.

Trial registration: INTERFACEVENT IS REGISTERED WITH CLINICALTRIALS.GOV (NCT03013283).FIRST REGISTRATION DATE IS 2016-12-23.

背景:在过去的三十年中,我们对女性睡眠呼吸暂停的认识有了很大的进步,发现了与男性相比,女性在病理生理学、诊断和治疗方面的差异。然而,迄今为止还没有一项真实的研究探讨了在长期使用 CPAP 的情况下,面罩相关副作用(MRSE)与性别之间的关系:InterfaceVent-CPAP 研究是一项前瞻性真实横断面研究,研究对象是接受至少 3 个月不受限制面罩使用(34 种不同面罩,无特定性别面罩系列)CPAP 治疗的呼吸暂停成人。患者使用视觉模拟量表(VAS)对 MRSE 进行评估。不坚持使用 CPAP 的定义是平均每天使用 CPAP 少于 4 小时。这项辅助研究的主要目的是调查性别对患者报告的 MRSE 发生率的影响。辅助分析评估了不同性别的 MRSE 对使用 CPAP 和不坚持使用 CPAP 的影响:共有 1484 名患者被纳入队列,治疗时间中位数为 4.4 年(IQ25-75:2.0-9.7),其中女性占 27.8%。患者报告的面罩损伤(定义为 VAS 评分≥ 5(P = 0.021))发生率女性高于男性(9.6% 对 5.3%)。就鼻枕式口罩而言,女性口干的 MRSE VAS 评分中位数更高(p = 0.039)。对于口鼻面罩,男性流鼻涕的 MRSE VAS 中位数得分更高(p = 0.039)。多变量回归分析表明,对于女性和男性而言,口干与使用 CPAP 存在独立的负相关关系,而与不坚持使用 CPAP 存在正相关关系:结论:在现实生活中,长期使用 CPAP 治疗的患者在报告的 MRSE 方面存在性别差异。在个性化医疗的背景下,这些结果表明,如果开发出专门针对女性的面罩,未来面罩的设计应考虑这些性别差异。不过,只有口干这种与面罩设计无关的副作用会影响 CPAP 的使用和不依从性:interfacevent已在clinicaltrials.gov(nct03013283)注册。首次注册日期为2016-12-23。
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引用次数: 0
Recombinant thrombomodulin and recombinant antithrombin attenuate pulmonary endothelial glycocalyx degradation and neutrophil extracellular trap formation in ventilator-induced lung injury in the context of endotoxemia. 重组血栓调节蛋白和重组抗凝血酶可减轻呼吸机诱导的内毒素血症肺损伤中的肺内皮细胞糖萼降解和中性粒细胞胞外陷阱的形成。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-09-03 DOI: 10.1186/s12931-024-02958-0
Kenichiro Kikuchi, Satoshi Kazuma, Michiaki Yamakage

Background: Vascular endothelial damage is involved in the development and exacerbation of ventilator-induced lung injury (VILI). Pulmonary endothelial glycocalyx and neutrophil extracellular traps (NETs) are endothelial protective and damaging factors, respectively; however, their dynamics in VILI and the effects of recombinant thrombomodulin and antithrombin on these dynamics remain unclear. We hypothesized that glycocalyx degradation and NETs are induced by VILI and suppressed by recombinant thrombomodulin, recombinant antithrombin, or their combination.

Methods: VILI was induced in male C57BL/6J mice by intraperitoneal lipopolysaccharide injection (20 mg/kg) and high tidal volume ventilation (20 mL/kg). In the intervention groups, recombinant thrombomodulin, recombinant antithrombin, or their combination was administered at the start of mechanical ventilation. Glycocalyx degradation was quantified by measuring serum syndecan-1, fluorescence-labeled lectin intensity, and glycocalyx-occupied area in the pulmonary vascular lumen. Double-stranded DNA in the bronchoalveolar fluid and fluorescent areas of citrullinated histone H3 and myeloperoxidase were quantified as NET formation.

Results: Serum syndecan-1 increased, and lectin fluorescence intensity decreased in VILI. Electron microscopy revealed decreases in glycocalyx-occupied areas within pulmonary microvessels in VILI. Double-stranded DNA levels in the bronchoalveolar lavage fluid and the fluorescent area of citrullinated histone H3 and myeloperoxidase in lung tissues increased in VILI. Recombinant thrombomodulin, recombinant antithrombin, and their combination reduced glycocalyx injury and NET marker levels. There was little difference in glycocalyx injury and NET makers between the intervention groups.

Conclusion: VILI induced glycocalyx degradation and NET formation. Recombinant thrombomodulin and recombinant antithrombin attenuated glycocalyx degradation and NETs in our VILI model. The effect of their combination did not differ from that of either drug alone. Recombinant thrombomodulin and antithrombin have the potential to be therapeutic agents for biotrauma in VILI.

背景:血管内皮损伤参与了呼吸机诱发肺损伤(VILI)的发生和加重。肺内皮糖萼和中性粒细胞胞外捕获物(NET)分别是内皮保护因子和损伤因子;然而,它们在 VILI 中的动态变化以及重组凝血酶原和抗凝血酶对这些动态变化的影响仍不清楚。我们假设,VILI 会诱导糖萼降解和 NET,而重组凝血酶原、重组抗凝血酶或它们的组合会抑制糖萼降解和 NET:方法:通过腹腔注射脂多糖(20 毫克/千克)和高潮气量通气(20 毫升/千克)诱导雄性 C57BL/6J 小鼠 VILI。在干预组中,机械通气开始时给予重组血栓调节蛋白、重组抗凝血酶或它们的组合。通过测量血清辛迪加-1、荧光标记凝集素强度和肺血管腔内糖萼占位面积来量化糖萼降解情况。支气管肺泡液中的双链DNA以及瓜氨酸组蛋白H3和髓过氧化物酶的荧光区域被量化为NET的形成:结果:VILI患者血清辛迪加-1增加,凝集素荧光强度降低。电子显微镜显示,VILI 患者肺微血管中糖萼占据的区域减少。VILI 患者支气管肺泡灌洗液中的双链 DNA 含量以及肺组织中瓜氨酸化组蛋白 H3 和髓过氧化物酶的荧光面积均有所增加。重组血栓调节蛋白、重组抗凝血酶和它们的组合可减少糖萼损伤和 NET 标记物水平。干预组之间的糖萼损伤和NET标记物差异不大:结论:VILI诱导糖萼降解和NET形成。在我们的 VILI 模型中,重组血栓调节蛋白和重组抗凝血酶减轻了糖萼降解和 NET 的形成。这两种药物联合使用的效果与单独使用两种药物的效果没有区别。重组血栓调节蛋白和抗凝血酶有可能成为治疗 VILI 生物创伤的药物。
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引用次数: 0
CT-based whole lung radiomics nomogram for identification of PRISm from non-COPD subjects. 基于 CT 的全肺放射组学提名图,用于从非慢性阻塞性肺病受试者中识别 PRISm。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-09-03 DOI: 10.1186/s12931-024-02964-2
TaoHu Zhou, Yu Guan, XiaoQing Lin, XiuXiu Zhou, Liang Mao, YanQing Ma, Bing Fan, Jie Li, ShiYuan Liu, Li Fan

Background: Preserved Ratio Impaired Spirometry (PRISm) is considered to be a precursor of chronic obstructive pulmonary disease. Radiomics nomogram can effectively identify the PRISm subjects from non-COPD subjects, especially when during large-scale CT lung cancer screening.

Methods: Totally 1481 participants (864, 370 and 247 in training, internal validation, and external validation cohorts, respectively) were included. Whole lung on thin-section computed tomography (CT) was segmented with a fully automated segmentation algorithm. PyRadiomics was adopted for extracting radiomics features. Clinical features were also obtained. Moreover, Spearman correlation analysis, minimum redundancy maximum relevance (mRMR) feature ranking and least absolute shrinkage and selection operator (LASSO) classifier were adopted to analyze whether radiomics features could be used to build radiomics signatures. A nomogram that incorporated clinical features and radiomics signature was constructed through multivariable logistic regression. Last, calibration, discrimination and clinical usefulness were analyzed using validation cohorts.

Results: The radiomics signature, which included 14 stable features, was related to PRISm of training and validation cohorts (p < 0.001). The radiomics nomogram incorporating independent predicting factors (radiomics signature, age, BMI, and gender) well discriminated PRISm from non-COPD subjects compared with clinical model or radiomics signature alone for training cohort (AUC 0.787 vs. 0.675 vs. 0.778), internal (AUC 0.773 vs. 0.682 vs. 0.767) and external validation cohorts (AUC 0.702 vs. 0.610 vs. 0.699). Decision curve analysis suggested that our constructed radiomics nomogram outperformed clinical model.

Conclusions: The CT-based whole lung radiomics nomogram could identify PRISm to help decision-making in clinic.

背景:肺活量保留比值受损(PRISm)被认为是慢性阻塞性肺病的前兆。放射组学提名图能有效地从非慢性阻塞性肺病受试者中识别出 PRISm 受试者,尤其是在大规模 CT 肺癌筛查中:方法:共纳入 1481 名受试者(分别有 864 人、370 人和 247 人参加训练队列、内部验证队列和外部验证队列)。采用全自动分割算法对薄层计算机断层扫描(CT)上的全肺进行分割。采用 PyRadiomics 提取放射组学特征。同时还获得了临床特征。此外,还采用了斯皮尔曼相关性分析、最小冗余度最大相关性(mRMR)特征排序和最小绝对收缩和选择算子(LASSO)分类器来分析放射组学特征是否可用于建立放射组学特征。通过多变量逻辑回归,构建了包含临床特征和放射组学特征的提名图。最后,利用验证队列分析了校准、区分度和临床实用性:结果:包括 14 个稳定特征的放射组学特征与训练队列和验证队列的 PRISm 相关(p 结论:训练队列和验证队列的 PRISm 均高于训练队列和验证队列的 PRISm:基于 CT 的全肺放射组学提名图可以识别 PRISm,帮助临床决策。
{"title":"CT-based whole lung radiomics nomogram for identification of PRISm from non-COPD subjects.","authors":"TaoHu Zhou, Yu Guan, XiaoQing Lin, XiuXiu Zhou, Liang Mao, YanQing Ma, Bing Fan, Jie Li, ShiYuan Liu, Li Fan","doi":"10.1186/s12931-024-02964-2","DOIUrl":"10.1186/s12931-024-02964-2","url":null,"abstract":"<p><strong>Background: </strong>Preserved Ratio Impaired Spirometry (PRISm) is considered to be a precursor of chronic obstructive pulmonary disease. Radiomics nomogram can effectively identify the PRISm subjects from non-COPD subjects, especially when during large-scale CT lung cancer screening.</p><p><strong>Methods: </strong>Totally 1481 participants (864, 370 and 247 in training, internal validation, and external validation cohorts, respectively) were included. Whole lung on thin-section computed tomography (CT) was segmented with a fully automated segmentation algorithm. PyRadiomics was adopted for extracting radiomics features. Clinical features were also obtained. Moreover, Spearman correlation analysis, minimum redundancy maximum relevance (mRMR) feature ranking and least absolute shrinkage and selection operator (LASSO) classifier were adopted to analyze whether radiomics features could be used to build radiomics signatures. A nomogram that incorporated clinical features and radiomics signature was constructed through multivariable logistic regression. Last, calibration, discrimination and clinical usefulness were analyzed using validation cohorts.</p><p><strong>Results: </strong>The radiomics signature, which included 14 stable features, was related to PRISm of training and validation cohorts (p < 0.001). The radiomics nomogram incorporating independent predicting factors (radiomics signature, age, BMI, and gender) well discriminated PRISm from non-COPD subjects compared with clinical model or radiomics signature alone for training cohort (AUC 0.787 vs. 0.675 vs. 0.778), internal (AUC 0.773 vs. 0.682 vs. 0.767) and external validation cohorts (AUC 0.702 vs. 0.610 vs. 0.699). Decision curve analysis suggested that our constructed radiomics nomogram outperformed clinical model.</p><p><strong>Conclusions: </strong>The CT-based whole lung radiomics nomogram could identify PRISm to help decision-making in clinic.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373438/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142127122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Unraveling the Mfn2-Warburg effect nexus: a therapeutic strategy to combat pulmonary arterial hypertension arising from catch-up growth after IUGR. 揭示 Mfn2-Warburg 效应关系:应对 IUGR 后追赶生长引起的肺动脉高压的治疗策略。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-09-02 DOI: 10.1186/s12931-024-02957-1
Lingling Yan, Xiaofei Luo, Chengcheng Hang, YuWang, Ziming Zhang, Shanshan Xu, Lizhong Du

Background: The interplay between intrauterine and early postnatal environments has been associated with an increased risk of cardiovascular diseases in adulthood, including pulmonary arterial hypertension (PAH). While emerging evidence highlights the crucial role of mitochondrial pathology in PAH, the specific mechanisms driving fetal-originated PAH remain elusive.

Methods and results: To elucidate the role of mitochondrial dynamics in the pathogenesis of fetal-originated PAH, we established a rat model of postnatal catch-up growth following intrauterine growth restriction (IUGR) to induce pulmonary arterial hypertension (PAH). RNA-seq analysis of pulmonary artery samples from the rats revealed dysregulated mitochondrial metabolic genes and pathways associated with increased pulmonary arterial pressure and pulmonary arterial remodeling in the RC group (postnatal catch-up growth following IUGR). In vitro experiments using pulmonary arterial smooth muscle cells (PASMCs) from the RC group demonstrated elevated proliferation, migration, and impaired mitochondrial functions. Notably, reduced expression of Mitofusion 2 (Mfn2), a mitochondrial outer membrane protein involved in mitochondrial fusion, was observed in the RC group. Reconstitution of Mfn2 resulted in enhanced mitochondrial fusion and improved mitochondrial functions in PASMCs of RC group, effectively reversing the Warburg effect. Importantly, Mfn2 reconstitution alleviated the PAH phenotype in the RC group rats.

Conclusions: Imbalanced mitochondrial dynamics, characterized by reduced Mfn2 expression, plays a critical role in the development of fetal-originated PAH following postnatal catch-up growth after IUGR. Mfn2 emerges as a promising therapeutic strategy for managing IUGR-catch-up growth induced PAH.

背景:宫内环境和出生后早期环境之间的相互作用与成年后心血管疾病(包括肺动脉高压(PAH))风险的增加有关。虽然新出现的证据强调了线粒体病理学在 PAH 中的关键作用,但驱动胎儿源性 PAH 的具体机制仍然难以捉摸:为了阐明线粒体动力学在胎儿源性 PAH 发病机制中的作用,我们建立了宫内生长受限(IUGR)后出生后追赶生长的大鼠模型,诱发肺动脉高压(PAH)。对大鼠肺动脉样本进行的 RNA-seq 分析发现,线粒体代谢基因和通路失调与 RC 组(IUGR 后的产后追赶生长)肺动脉压力升高和肺动脉重塑有关。使用 RC 组的肺动脉平滑肌细胞(PASMCs)进行的体外实验表明,RC 组的肺动脉平滑肌细胞增殖、迁移和线粒体功能受损。值得注意的是,在 RC 组中观察到线粒体外膜蛋白 Mitofusion 2(Mfn2)的表达减少。重建 Mfn2 可增强线粒体融合,改善 RC 组 PASMC 的线粒体功能,有效逆转沃伯格效应。重要的是,Mfn2重组减轻了RC组大鼠的PAH表型:结论:线粒体动力学失衡(以 Mfn2 表达减少为特征)在 IUGR 出生后追赶生长过程中胎儿源 PAH 的发展中起着关键作用。Mfn2是治疗IUGR-追赶生长诱发的PAH的一种有前景的治疗策略。
{"title":"Unraveling the Mfn2-Warburg effect nexus: a therapeutic strategy to combat pulmonary arterial hypertension arising from catch-up growth after IUGR.","authors":"Lingling Yan, Xiaofei Luo, Chengcheng Hang, YuWang, Ziming Zhang, Shanshan Xu, Lizhong Du","doi":"10.1186/s12931-024-02957-1","DOIUrl":"10.1186/s12931-024-02957-1","url":null,"abstract":"<p><strong>Background: </strong>The interplay between intrauterine and early postnatal environments has been associated with an increased risk of cardiovascular diseases in adulthood, including pulmonary arterial hypertension (PAH). While emerging evidence highlights the crucial role of mitochondrial pathology in PAH, the specific mechanisms driving fetal-originated PAH remain elusive.</p><p><strong>Methods and results: </strong>To elucidate the role of mitochondrial dynamics in the pathogenesis of fetal-originated PAH, we established a rat model of postnatal catch-up growth following intrauterine growth restriction (IUGR) to induce pulmonary arterial hypertension (PAH). RNA-seq analysis of pulmonary artery samples from the rats revealed dysregulated mitochondrial metabolic genes and pathways associated with increased pulmonary arterial pressure and pulmonary arterial remodeling in the RC group (postnatal catch-up growth following IUGR). In vitro experiments using pulmonary arterial smooth muscle cells (PASMCs) from the RC group demonstrated elevated proliferation, migration, and impaired mitochondrial functions. Notably, reduced expression of Mitofusion 2 (Mfn2), a mitochondrial outer membrane protein involved in mitochondrial fusion, was observed in the RC group. Reconstitution of Mfn2 resulted in enhanced mitochondrial fusion and improved mitochondrial functions in PASMCs of RC group, effectively reversing the Warburg effect. Importantly, Mfn2 reconstitution alleviated the PAH phenotype in the RC group rats.</p><p><strong>Conclusions: </strong>Imbalanced mitochondrial dynamics, characterized by reduced Mfn2 expression, plays a critical role in the development of fetal-originated PAH following postnatal catch-up growth after IUGR. Mfn2 emerges as a promising therapeutic strategy for managing IUGR-catch-up growth induced PAH.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11370119/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142120938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Employing a synergistic bioinformatics and machine learning framework to elucidate biomarkers associating asthma with pyrimidine metabolism genes. 采用协同生物信息学和机器学习框架,阐明哮喘与嘧啶代谢基因相关的生物标志物。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-08-31 DOI: 10.1186/s12931-024-02954-4
Dihui Zhang, Xiaowei Pu, Man Zheng, Guanghui Li, Jia Chen

Background: Asthma, a prevalent chronic inflammatory disorder, is shaped by a multifaceted interplay between genetic susceptibilities and environmental exposures. Despite strides in deciphering its pathophysiological landscape, the intricate molecular underpinnings of asthma remain elusive. The focus has increasingly shifted toward the metabolic aberrations accompanying asthma, particularly within the domain of pyrimidine metabolism (PyM)-a critical pathway in nucleotide synthesis and degradation. While the therapeutic relevance of PyM has been recognized across various diseases, its specific contributions to asthma pathology are yet underexplored. This study employs sophisticated bioinformatics approaches to delineate and confirm the involvement of PyM genes (PyMGs) in asthma, aiming to bridge this significant gap in knowledge.

Methods: Employing cutting-edge bioinformatics techniques, this research aimed to elucidate the role of PyMGs in asthma. We conducted a detailed examination of 31 PyMGs to assess their differential expression. Through Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA), we explored the biological functions and pathways linked to these genes. We utilized Lasso regression and Support Vector Machine-Recursive Feature Elimination (SVM-RFE) to pinpoint critical hub genes and to ascertain the diagnostic accuracy of eight PyMGs in distinguishing asthma, complemented by an extensive correlation study with the clinical features of the disease. Validation of the gene expressions was performed using datasets GSE76262 and GSE147878.

Results: Our analyses revealed that eleven PyMGs-DHODH, UMPS, NME7, NME1, POLR2B, POLR3B, POLR1C, POLE, ENPP3, RRM2B, TK2-are significantly associated with asthma. These genes play crucial roles in essential biological processes such as RNA splicing, anatomical structure maintenance, and metabolic processes involving purine compounds.

Conclusions: This investigation identifies eleven PyMGs at the core of asthma's pathogenesis, establishing them as potential biomarkers for this disease. Our findings enhance the understanding of asthma's molecular mechanisms and open new avenues for improving diagnostics, monitoring, and progression evaluation. By providing new insights into non-cancerous pathologies, our work introduces a novel perspective and sets the stage for further studies in this field.

背景:哮喘是一种常见的慢性炎症性疾病,是由遗传易感性和环境暴露之间的多方面相互作用形成的。尽管在破译其病理生理结构方面取得了长足进步,但哮喘错综复杂的分子基础仍然难以捉摸。人们越来越关注哮喘伴随的代谢畸变,尤其是嘧啶代谢(PyM)领域--核苷酸合成和降解的关键途径。虽然 PyM 在各种疾病中的治疗意义已得到认可,但其对哮喘病理学的具体贡献尚未得到充分探索。本研究采用先进的生物信息学方法来描述和确认 PyM 基因(PyMGs)参与哮喘的病理过程,旨在弥补这一知识空白:本研究采用最先进的生物信息学技术,旨在阐明 PyMGs 在哮喘中的作用。我们对 31 个 PyMGs 进行了详细研究,以评估它们的差异表达。通过基因组富集分析(Gene Set Enrichment Analysis,GSEA)和基因组变异分析(Gene Set Variation Analysis,GSVA),我们探索了与这些基因相关的生物学功能和通路。我们利用拉索回归(Lasso regression)和支持向量机-递归特征消除(SVM-RFE)来确定关键的枢纽基因,并确定八个 PyMGs 在鉴别哮喘方面的诊断准确性,同时辅以与疾病临床特征的广泛相关性研究。利用数据集 GSE76262 和 GSE147878 对基因表达进行了验证:我们的分析表明,11 个 PyMGs-DHODH、UMPS、NME7、NME1、POLR2B、POLR3B、POLR1C、POLE、ENPP3、RRM2B、TK2 与哮喘显著相关。这些基因在 RNA 剪接、解剖结构维持和涉及嘌呤化合物的代谢过程等重要生物过程中发挥着关键作用:这项研究发现了 11 个处于哮喘发病机制核心的 PyMGs,并将它们确立为该疾病的潜在生物标记物。我们的研究结果加深了人们对哮喘分子机制的了解,为改进诊断、监测和病情发展评估开辟了新途径。通过提供对非癌症病理的新见解,我们的工作引入了一个新的视角,为这一领域的进一步研究奠定了基础。
{"title":"Employing a synergistic bioinformatics and machine learning framework to elucidate biomarkers associating asthma with pyrimidine metabolism genes.","authors":"Dihui Zhang, Xiaowei Pu, Man Zheng, Guanghui Li, Jia Chen","doi":"10.1186/s12931-024-02954-4","DOIUrl":"10.1186/s12931-024-02954-4","url":null,"abstract":"<p><strong>Background: </strong>Asthma, a prevalent chronic inflammatory disorder, is shaped by a multifaceted interplay between genetic susceptibilities and environmental exposures. Despite strides in deciphering its pathophysiological landscape, the intricate molecular underpinnings of asthma remain elusive. The focus has increasingly shifted toward the metabolic aberrations accompanying asthma, particularly within the domain of pyrimidine metabolism (PyM)-a critical pathway in nucleotide synthesis and degradation. While the therapeutic relevance of PyM has been recognized across various diseases, its specific contributions to asthma pathology are yet underexplored. This study employs sophisticated bioinformatics approaches to delineate and confirm the involvement of PyM genes (PyMGs) in asthma, aiming to bridge this significant gap in knowledge.</p><p><strong>Methods: </strong>Employing cutting-edge bioinformatics techniques, this research aimed to elucidate the role of PyMGs in asthma. We conducted a detailed examination of 31 PyMGs to assess their differential expression. Through Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA), we explored the biological functions and pathways linked to these genes. We utilized Lasso regression and Support Vector Machine-Recursive Feature Elimination (SVM-RFE) to pinpoint critical hub genes and to ascertain the diagnostic accuracy of eight PyMGs in distinguishing asthma, complemented by an extensive correlation study with the clinical features of the disease. Validation of the gene expressions was performed using datasets GSE76262 and GSE147878.</p><p><strong>Results: </strong>Our analyses revealed that eleven PyMGs-DHODH, UMPS, NME7, NME1, POLR2B, POLR3B, POLR1C, POLE, ENPP3, RRM2B, TK2-are significantly associated with asthma. These genes play crucial roles in essential biological processes such as RNA splicing, anatomical structure maintenance, and metabolic processes involving purine compounds.</p><p><strong>Conclusions: </strong>This investigation identifies eleven PyMGs at the core of asthma's pathogenesis, establishing them as potential biomarkers for this disease. Our findings enhance the understanding of asthma's molecular mechanisms and open new avenues for improving diagnostics, monitoring, and progression evaluation. By providing new insights into non-cancerous pathologies, our work introduces a novel perspective and sets the stage for further studies in this field.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11365277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142113936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Ubiquitination of angiotensin-converting enzyme 2 contributes to the development of pulmonary arterial hypertension mediated by neural precursor cell-expressed developmentally down-regulated gene 4-Like. 血管紧张素转换酶2的泛素化有助于神经前体细胞表达的发育下调基因4-Like介导的肺动脉高压的发病。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-08-29 DOI: 10.1186/s12931-024-02953-5
Rui Wang, Rui Wang, Siqi Zhou, Tianya Liu, Jingjing Dang, Qianmin Chen, Jingyu Chen, Zhiping Wang

Objectives: In this study, we investigated whether neural precursor cell-expressed developmentally down-regulated gene 4-like (NEDD4L) is the E3 enzyme of angiotensin-converting enzyme 2 (ACE2) and whether NEDD4L degrades ACE2 via ubiquitination, leading to the progression of pulmonary arterial hypertension (PAH).

Methods: Bioinformatic analyses were used to explore the E3 ligase that ubiquitinates ACE2. Cultured pulmonary arterial smooth muscle cells (PASMCs) and specimens from patients with PAH were used to investigate the crosstalk between NEDD4L and ACE2 and its ubiquitination in the context of PAH.

Results: The inhibition of ubiquitination attenuated hypoxia-induced proliferation of PASMCs. The levels of NEDD4L were increased, and those of ACE2 were decreased in lung tissues from patients with PAH and in PASMCs. NEDD4L, the E3 ligase of ACE2, inhibited the expression of ACE2 in PASMCs, possibly through ubiquitination-mediated degradation. PAH was associated with upregulation of NEDD4L expression and downregulation of ACE2 expression.

Conclusions: NEDD4L, the E3 ubiquitination enzyme of ACE2, promotes the proliferation of PASMCs, ultimately leading to PAH.

研究目的本研究探讨了神经前体细胞表达的发育下调基因4样(NEDD4L)是否是血管紧张素转换酶2(ACE2)的E3酶,以及NEDD4L是否通过泛素化降解ACE2,从而导致肺动脉高压(PAH)的进展:方法:利用生物信息学分析探索泛素化 ACE2 的 E3 连接酶。培养的肺动脉平滑肌细胞(PASMCs)和 PAH 患者的标本被用来研究 PAH 背景下 NEDD4L 和 ACE2 之间的串联及其泛素化:结果:泛素化的抑制减轻了缺氧诱导的PASMCs增殖。在 PAH 患者的肺组织和 PASMCs 中,NEDD4L 的水平升高,ACE2 的水平降低。NEDD4L是ACE2的E3连接酶,可能通过泛素化介导的降解抑制了ACE2在PASMCs中的表达。PAH 与 NEDD4L 表达上调和 ACE2 表达下调有关:结论:ACE2 的 E3 泛素化酶 NEDD4L 可促进 PASMC 的增殖,最终导致 PAH。
{"title":"Ubiquitination of angiotensin-converting enzyme 2 contributes to the development of pulmonary arterial hypertension mediated by neural precursor cell-expressed developmentally down-regulated gene 4-Like.","authors":"Rui Wang, Rui Wang, Siqi Zhou, Tianya Liu, Jingjing Dang, Qianmin Chen, Jingyu Chen, Zhiping Wang","doi":"10.1186/s12931-024-02953-5","DOIUrl":"10.1186/s12931-024-02953-5","url":null,"abstract":"<p><strong>Objectives: </strong>In this study, we investigated whether neural precursor cell-expressed developmentally down-regulated gene 4-like (NEDD4L) is the E3 enzyme of angiotensin-converting enzyme 2 (ACE2) and whether NEDD4L degrades ACE2 via ubiquitination, leading to the progression of pulmonary arterial hypertension (PAH).</p><p><strong>Methods: </strong>Bioinformatic analyses were used to explore the E3 ligase that ubiquitinates ACE2. Cultured pulmonary arterial smooth muscle cells (PASMCs) and specimens from patients with PAH were used to investigate the crosstalk between NEDD4L and ACE2 and its ubiquitination in the context of PAH.</p><p><strong>Results: </strong>The inhibition of ubiquitination attenuated hypoxia-induced proliferation of PASMCs. The levels of NEDD4L were increased, and those of ACE2 were decreased in lung tissues from patients with PAH and in PASMCs. NEDD4L, the E3 ligase of ACE2, inhibited the expression of ACE2 in PASMCs, possibly through ubiquitination-mediated degradation. PAH was associated with upregulation of NEDD4L expression and downregulation of ACE2 expression.</p><p><strong>Conclusions: </strong>NEDD4L, the E3 ubiquitination enzyme of ACE2, promotes the proliferation of PASMCs, ultimately leading to PAH.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11363581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142113937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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Respiratory Research
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