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Quantitative micro-CT-derived biomarkers elucidate age-related lung fibrosis in elder mice. 定量微计算机断层扫描生物标志物阐明了老年小鼠与年龄相关的肺纤维化。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-30 DOI: 10.1186/s12931-024-03006-7
Davide Buseghin, Andrea Grandi, Erica Ferrini, Gino Villetti, Roberta Ciccimarra, Nicola Sverzellati, Andrea Aliverti, Francesca Pennati, Franco Fabio Stellari

Background: Idiopathic Pulmonary Fibrosis (IPF), prevalently affecting individuals over 60 years of age, has been mainly studied in young mouse models. The limited efficacy of current treatments underscores the need for animal models that better mimic an aged patient population. We addressed this by inducing pulmonary fibrosis in aged mice, using longitudinal micro-CT imaging as primary readout, with special attention to animal welfare.

Methods: A double bleomycin dose was administered to 18-24 months-old male C57Bl/6j mice to induce pulmonary fibrosis. Bleomycin dosage was reduced to as low as 75% compared to that commonly administered to young (8-12 weeks-old) mice, resulting in long-term lung fibrosis without mortality, complying with animal welfare guidelines. After fibrosis induction, animals received Nintedanib once-daily for two weeks and longitudinally monitored by micro-CT, which provided structural and functional biomarkers, followed by post-mortem histological analysis as terminal endpoint.

Results: Compared to young mice, aged animals displayed increased volume, reduced tissue density and function, and marked inflammation. This increased vulnerability imposed a bleomycin dosage reduction to the lowest tested level (2.5 µg/mouse), inducing a milder, yet persistent, fibrosis, while preserving animal welfare. Nintedanib treatment reduced fibrotic lesions and improved pulmonary function.

Conclusions: Our data identify a downsized bleomycin treatment that allows to achieve the best trade-off between fibrosis induction and animal welfare, a requirement for antifibrotic drug testing in aged lungs. Nintedanib displayed significant efficacy in this lower-severity disease model, suggesting potential patient stratification strategies. Lung pathology was quantitatively assessed by micro-CT, pointing to the value of longitudinal endpoints in clinical trials.

背景:特发性肺纤维化(IPF)主要影响 60 岁以上的人群,目前主要通过年轻的小鼠模型进行研究。目前的治疗方法疗效有限,因此需要能更好地模拟老年患者群体的动物模型。为此,我们通过诱导老年小鼠肺纤维化,以纵向显微 CT 成像为主要读数,并特别关注动物福利:方法:给 18-24 个月大的雄性 C57Bl/6j 小鼠注射双倍博莱霉素,诱导肺纤维化。与幼鼠(8-12周大)的常用剂量相比,博莱霉素剂量降低至75%,从而使小鼠长期肺纤维化而不死亡,符合动物福利准则。诱导肺纤维化后,动物连续两周每天一次服用宁替达尼,并通过显微CT进行纵向监测,提供结构和功能生物标志物,然后进行死后组织学分析作为终点:结果:与年轻小鼠相比,老年小鼠的体积增大,组织密度和功能降低,炎症明显。这种脆弱性的增加迫使博莱霉素剂量减少到最低测试水平(2.5微克/只小鼠),从而诱发了较轻微但持续的纤维化,同时保护了动物福利。宁替达尼治疗可减少纤维化病变并改善肺功能:我们的数据确定了一种缩小博莱霉素剂量的治疗方法,它能在纤维化诱导和动物福利之间实现最佳权衡,而这正是在老年肺中进行抗纤维化药物试验的要求。在这种低严重程度的疾病模型中,Nintedanib显示出了显著的疗效,提示了潜在的患者分层策略。通过显微CT对肺部病理进行了定量评估,显示了临床试验中纵向终点的价值。
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引用次数: 0
Six clinical phenotypes with prognostic implications were identified by unsupervised machine learning in children and adolescents with SARS-CoV-2 infection: results from a German nationwide registry. 通过无监督机器学习在感染 SARS-CoV-2 的儿童和青少年中识别出六种具有预后意义的临床表型:来自德国全国范围登记的结果。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-30 DOI: 10.1186/s12931-024-03018-3
Yanyan Shi, Ralf Strobl, Reinhard Berner, Jakob Armann, Simone Scheithauer, Eva Grill

Objective: Phenotypes are important for patient classification, disease prognostication, and treatment customization. We aimed to identify distinct clinical phenotypes of children and adolescents hospitalized with SARS-CoV-2 infection, and to evaluate their prognostic differences.

Methods: The German Society of Pediatric Infectious Diseases (DGPI) registry is a nationwide, prospective registry for children and adolescents hospitalized with a SARS-CoV-2 infection in Germany. We applied hierarchical clustering for phenotype identification with variables including sex, SARS-CoV-2-related symptoms on admission, pre-existing comorbidities, clinically relevant coinfection, and SARS-CoV-2 risk factors. Outcomes of this study were: discharge status and ICU admission. Discharge status was categorized as: full recovery, residual symptoms, and unfavorable prognosis (including consequential damage that has already been identified as potentially irreversible at the time of discharge and SARS-CoV-2-related death). After acquiring the phenotypes, we evaluated their correlation with discharge status by multinomial logistic regression model, and correlation with ICU admission by binary logistic regression model. We conducted an analogous subgroup analysis for those aged < 1 year (infants) and those aged ⩾ 1 year (non-infants).

Results: The DGPI registry enrolled 6983 patients, through which we identified six distinct phenotypes for children and adolescents with SARS-CoV-2 which can be characterized by their symptom pattern: phenotype A had a range of symptoms, while predominant symptoms of patients with other phenotypes were gastrointestinal (95.9%, B), asymptomatic (95.9%, C), lower respiratory tract (49.8%, D), lower respiratory tract and ear, nose and throat (86.2% and 41.7%, E), and neurological (99.2%, F). Regarding discharge status, patients with D and E phenotype had the highest odds of having residual symptoms (OR: 1.33 [1.11, 1.59] and 1.91 [1.65, 2.21], respectively) and patients with phenotype D were significantly more likely (OR: 4.00 [1.95, 8.19]) to have an unfavorable prognosis. Regarding ICU, patients with phenotype D had higher possibility of ICU admission than staying in normal ward (OR: 4.26 [3.06, 5.98]), compared to patients with phenotype A. The outcomes observed in the infants and non-infants closely resembled those of the entire registered population, except infants did not exhibit typical neurological/neuromuscular phenotypes.

Conclusions: Phenotypes enable pediatric patient stratification by risk and thus assist in personalized patient care. Our findings in SARS-CoV-2-infected population might also be transferable to other infectious diseases.

目的:表型对于患者分类、疾病预后和定制治疗非常重要。我们旨在确定感染 SARS-CoV-2 住院儿童和青少年的不同临床表型,并评估其预后差异:方法:德国儿科传染病学会(DGPI)登记处是一个全国性的前瞻性登记处,登记对象为德国因感染 SARS-CoV-2 而住院的儿童和青少年。我们采用分层聚类的方法进行表型识别,变量包括性别、入院时的 SARS-CoV-2 相关症状、入院前的合并症、临床相关的合并感染以及 SARS-CoV-2 风险因素。本研究的结果包括:出院情况和入住重症监护室情况。出院状态分为:完全康复、残留症状和预后不良(包括出院时已被确定为潜在不可逆的后遗症和与 SARS-CoV-2 相关的死亡)。获得表型后,我们通过多项式逻辑回归模型评估了它们与出院状态的相关性,并通过二元逻辑回归模型评估了它们与入住重症监护室的相关性。我们还对年龄较大的患者进行了类似的亚组分析:DGPI 登记了 6983 名患者,通过这些患者,我们确定了儿童和青少年 SARS-CoV-2 患者的六种不同表型,这些表型可根据症状模式来描述:表型 A 患者有一系列症状,而其他表型患者的主要症状是胃肠道症状(95.9%,B)、无症状(95.9%,C)、下呼吸道(49.8%,D)、下呼吸道和耳鼻喉(86.2%和 41.7%,E)以及神经系统(99.2%,F)。在出院状态方面,表型为 D 和 E 的患者出现残留症状的几率最高(OR:分别为 1.33 [1.11, 1.59] 和 1.91 [1.65, 2.21]),表型为 D 的患者预后不良的几率明显更高(OR:4.00 [1.95, 8.19])。在重症监护室方面,与表型为 A 的患者相比,表型为 D 的患者入住重症监护室的可能性高于普通病房(OR:4.26 [3.06,5.98])。除了婴儿没有表现出典型的神经/神经肌肉表型外,在婴儿和非婴儿中观察到的结果与所有登记人群的结果非常相似:表型有助于根据风险对儿科病人进行分层,从而帮助对病人进行个性化治疗。我们在 SARS-CoV-2 感染人群中的发现也可用于其他传染病。
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引用次数: 0
A novel Non-rodent animal model of hydrochloric acid-induced acute and chronic lung injury. 盐酸诱发急性和慢性肺损伤的新型非啮齿动物模型
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-29 DOI: 10.1186/s12931-024-03022-7
Pavel A Solopov, Ruben Manuel Luciano Colunga Biancatelli, Tierney Day, Christiana Dimitropoulou, John D Catravas

Hydrochloric acid is one of the most prevalent and hazardous chemicals. Accidental spills occur in industrial plants or during transportation. Exposure to HCl can induce severe health impairment, including acute and chronic pulmonary diseases. We have previously described the molecular, structural, and functional aspects of the development of chronic lung injury and pulmonary fibrosis caused by intratracheal instillation of HCl in mice. Although mouse models of human disease have many advantages, rodents are evolutionary far from human and exhibit significant anatomical and physiological differences. Genetic and anatomic similarities between rabbits and humans are significantly higher. Rabbit models of HCl-induced lung injury have been used sparsely to evaluate acute lung injury. In this study, for the first time, we utilized rabbits as a model of HCl-induced pulmonary fibrosis and chronic lung injury. We present molecular, histological, and functional evidence that demonstrate the utility of using this model for studying new pharmaceutics against pulmonary fibrosis.

盐酸是最常见的危险化学品之一。工业厂房或运输过程中会发生意外泄漏。接触盐酸会导致严重的健康损害,包括急性和慢性肺部疾病。我们以前曾描述过气管内灌注盐酸导致小鼠慢性肺损伤和肺纤维化的分子、结构和功能方面的发展。虽然人类疾病的小鼠模型有很多优点,但啮齿类动物在进化过程中与人类相差甚远,而且在解剖学和生理学方面也有显著差异。兔子与人类在遗传和解剖方面的相似性要高得多。HCl 诱导的肺损伤兔模型很少用于评估急性肺损伤。在本研究中,我们首次利用兔子作为 HCl 诱导的肺纤维化和慢性肺损伤的模型。我们提出了分子、组织学和功能方面的证据,证明了使用该模型研究抗肺纤维化新药的实用性。
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引用次数: 0
Automatic lung cancer subtyping using rapid on-site evaluation slides and serum biological markers. 利用现场快速评估切片和血清生物标记物自动进行肺癌亚型分析。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-29 DOI: 10.1186/s12931-024-03021-8
Junxiang Chen, Chunxi Zhang, Jun Xie, Xuebin Zheng, Pengchen Gu, Shuaiyang Liu, Yongzheng Zhou, Jie Wu, Ying Chen, Yanli Wang, Chuan He, Jiayuan Sun

Background: Rapid on-site evaluation (ROSE) plays an important role during transbronchial sampling, providing an intraoperative cytopathologic evaluation. However, the shortage of cytopathologists limits its wide application. This study aims to develop a deep learning model to automatically analyze ROSE cytological images.

Methods: The hierarchical multi-label lung cancer subtyping (HMLCS) model that combines whole slide images of ROSE slides and serum biological markers was proposed to discriminate between benign and malignant lesions and recognize different subtypes of lung cancer. A dataset of 811 ROSE slides and paired serum biological markers was retrospectively collected between July 2019 and November 2020, and randomly divided to train, validate, and test the HMLCS model. The area under the curve (AUC) and accuracy were calculated to assess the performance of the model, and Cohen's kappa (κ) was calculated to measure the agreement between the model and the annotation. The HMLCS model was also compared with professional staff.

Results: The HMLCS model achieved AUC values of 0.9540 (95% confidence interval [CI]: 0.9257-0.9823) in malignant/benign classification, 0.9126 (95% CI: 0.8756-0.9365) in malignancy subtyping (non-small cell lung cancer [NSCLC], small cell lung cancer [SCLC], or other malignancies), and 0.9297 (95% CI: 0.9026-0.9603) in NSCLC subtyping (lung adenocarcinoma [LUAD], lung squamous cell carcinoma [LUSC], or NSCLC not otherwise specified [NSCLC-NOS]), respectively. In total, the model achieved an AUC of 0.8721 (95% CI: 0.7714-0.9258) and an accuracy of 0.7184 in the six-class classification task (benign, LUAD, LUSC, NSCLC-NOS, SCLC, or other malignancies). In addition, the model demonstrated a κ value of 0.6183 with the annotation, which was comparable to cytopathologists and superior to trained bronchoscopists and technicians.

Conclusion: The HMLCS model showed promising performance in the multiclassification of lung lesions or intrathoracic lymphadenopathy, with potential application to provide real-time feedback regarding preliminary diagnoses of specimens during transbronchial sampling procedures.

Clinical trial number: Not applicable.

背景:快速现场评估(ROSE)在经支气管取样过程中发挥着重要作用,可提供术中细胞病理学评估。然而,细胞病理学家的短缺限制了它的广泛应用。本研究旨在开发一种深度学习模型,用于自动分析 ROSE 细胞学图像:方法:研究人员提出了分层多标签肺癌亚型分析(HMLCS)模型,该模型结合了ROSE切片的全切片图像和血清生物标记物,用于区分良性和恶性病变,并识别肺癌的不同亚型。研究人员于2019年7月至2020年11月期间回顾性收集了811张ROSE切片和配对的血清生物学标志物数据集,并随机划分数据集进行HMLCS模型的训练、验证和测试。计算曲线下面积(AUC)和准确率来评估模型的性能,计算科恩卡帕(κ)来衡量模型与注释之间的一致性。HMLCS 模型还与专业人员进行了比较:结果:HMLCS 模型在恶性/良性分类中的 AUC 值为 0.9540(95% 置信区间 [CI]:0.9257-0.9823),在恶性肿瘤亚型(非小细胞肺癌 [NSCLC]、小细胞肺癌 [SCLC] 或其他恶性肿瘤)中的 AUC 值为 0.9126(95% 置信区间 [CI]:0.8756-0.9365),在恶性肿瘤分类中的 AUC 值为 0.9297(95% CI:0.9026-0.9603)。在六级分类任务(良性、LUAD、LUSC、NSCLC-NOS、SCLC 或其他恶性肿瘤)中,该模型的 AUC 为 0.8721(95% CI:0.7714-0.9258),准确率为 0.7184。此外,该模型的注释κ值为0.6183,与细胞病理学家相当,优于训练有素的支气管镜医师和技术人员:HMLCS模型在肺部病变或胸腔内淋巴结病的多分类中表现出良好的性能,有望在经支气管取样过程中为标本的初步诊断提供实时反馈:临床试验编号:不适用。
{"title":"Automatic lung cancer subtyping using rapid on-site evaluation slides and serum biological markers.","authors":"Junxiang Chen, Chunxi Zhang, Jun Xie, Xuebin Zheng, Pengchen Gu, Shuaiyang Liu, Yongzheng Zhou, Jie Wu, Ying Chen, Yanli Wang, Chuan He, Jiayuan Sun","doi":"10.1186/s12931-024-03021-8","DOIUrl":"10.1186/s12931-024-03021-8","url":null,"abstract":"<p><strong>Background: </strong>Rapid on-site evaluation (ROSE) plays an important role during transbronchial sampling, providing an intraoperative cytopathologic evaluation. However, the shortage of cytopathologists limits its wide application. This study aims to develop a deep learning model to automatically analyze ROSE cytological images.</p><p><strong>Methods: </strong>The hierarchical multi-label lung cancer subtyping (HMLCS) model that combines whole slide images of ROSE slides and serum biological markers was proposed to discriminate between benign and malignant lesions and recognize different subtypes of lung cancer. A dataset of 811 ROSE slides and paired serum biological markers was retrospectively collected between July 2019 and November 2020, and randomly divided to train, validate, and test the HMLCS model. The area under the curve (AUC) and accuracy were calculated to assess the performance of the model, and Cohen's kappa (κ) was calculated to measure the agreement between the model and the annotation. The HMLCS model was also compared with professional staff.</p><p><strong>Results: </strong>The HMLCS model achieved AUC values of 0.9540 (95% confidence interval [CI]: 0.9257-0.9823) in malignant/benign classification, 0.9126 (95% CI: 0.8756-0.9365) in malignancy subtyping (non-small cell lung cancer [NSCLC], small cell lung cancer [SCLC], or other malignancies), and 0.9297 (95% CI: 0.9026-0.9603) in NSCLC subtyping (lung adenocarcinoma [LUAD], lung squamous cell carcinoma [LUSC], or NSCLC not otherwise specified [NSCLC-NOS]), respectively. In total, the model achieved an AUC of 0.8721 (95% CI: 0.7714-0.9258) and an accuracy of 0.7184 in the six-class classification task (benign, LUAD, LUSC, NSCLC-NOS, SCLC, or other malignancies). In addition, the model demonstrated a κ value of 0.6183 with the annotation, which was comparable to cytopathologists and superior to trained bronchoscopists and technicians.</p><p><strong>Conclusion: </strong>The HMLCS model showed promising performance in the multiclassification of lung lesions or intrathoracic lymphadenopathy, with potential application to provide real-time feedback regarding preliminary diagnoses of specimens during transbronchial sampling procedures.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"391"},"PeriodicalIF":5.8,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11523640/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142548505","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
Impact of HHIP gene polymorphisms on phenotypes, serum IL-17 and IL-18 in COPD patients of the Chinese Han population. HHIP基因多态性对中国汉族慢性阻塞性肺病患者表型、血清IL-17和IL-18的影响
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-28 DOI: 10.1186/s12931-024-03020-9
Jiajun Zhang, Di Zhao, Lili Zhang, Xueyan Feng, Beibei Li, Hui Dong, Yanchao Qi, Zun Jia, Fuyun Liu, Shaohui Zhao, Jin Zhang

Background: Genetic factors, including the Hedgehog Interacting Protein (HHIP) gene, play a crucial role in Chronic Obstructive Pulmonary Disease (COPD) susceptibility. This study examines the association between HHIP gene polymorphisms and COPD susceptibility, phenotypes, and serum IL-17 and IL-18 levels in a Han Chinese population.

Methods: A case-control study was conducted with 300 COPD patients and 300 healthy controls in Chinese Han population. Participants underwent genotyping for HHIP gene polymorphisms, pulmonary function tests, and quantitative CT scans. DNA samples were sequenced using a custom chip targeting the HHIP gene. Serum IL-17 and IL-18 levels were measured by enzyme-linked immunosorbent assay. Associations between SNPs, COPD susceptibility, and phenotypes were analyzed using logistic and multiple linear regression models, adjusting for confounders.

Results: Our study identified the rs11100865 polymorphism in the HHIP gene as significantly associated with COPD susceptibility (OR 2.479, 95% CI 1.527-4.024, P = 2.39E-04) after screening 114 SNPs through rigorous quality control. Stratified analyses further indicated this association was particularly in individuals aged 60 or older. Serum levels of IL-17 and IL-18 were significantly elevated in COPD patients compared to controls, with rs11100865 showing a notable association with IL-18 levels (B = 49.654, SE = 19.627, P = 0.012). However, no significant associations were observed between rs11100865 and serum IL-17 levels, COPD-related imaging parameters, or clinical phenotypes.

Conclusion: This study identified a significant association between HHIP gene polymorphisms and COPD susceptibility in a Han Chinese population, with connections to inflammation, but found no significant associations between this SNP and COPD-related imaging or clinical phenotypes.

Trial registration: www.chictr.org.cn ID: ChiCTR2300071579 2023-05-18.

背景:包括刺猬互作蛋白(HHIP)基因在内的遗传因素在慢性阻塞性肺病(COPD)易感性中起着至关重要的作用。本研究探讨了汉族人群中 HHIP 基因多态性与 COPD 易感性、表型以及血清 IL-17 和 IL-18 水平之间的关系:方法:对中国汉族人群中的 300 名慢性阻塞性肺病患者和 300 名健康对照者进行了病例对照研究。参与者接受了 HHIP 基因多态性基因分型、肺功能测试和定量 CT 扫描。使用针对 HHIP 基因的定制芯片对 DNA 样本进行测序。血清IL-17和IL-18水平通过酶联免疫吸附试验测定。使用逻辑和多元线性回归模型分析了SNPs、慢性阻塞性肺病易感性和表型之间的关联,并对混杂因素进行了调整:结果:通过严格的质量控制筛选出 114 个 SNPs 后,我们的研究发现 HHIP 基因中的 rs11100865 多态性与 COPD 易感性显著相关(OR 2.479,95% CI 1.527-4.024,P = 2.39E-04)。分层分析进一步表明,这种关联在 60 岁或以上的人群中尤为明显。与对照组相比,慢性阻塞性肺病患者血清中的IL-17和IL-18水平明显升高,其中rs11100865与IL-18水平有显著关联(B = 49.654,SE = 19.627,P = 0.012)。然而,在rs11100865与血清IL-17水平、COPD相关影像学参数或临床表型之间没有观察到明显的关联:本研究发现,在汉族人群中,HHIP 基因多态性与慢性阻塞性肺病易感性之间存在显著关联,且与炎症有关,但未发现该 SNP 与慢性阻塞性肺病相关影像学或临床表型之间存在显著关联。试验注册:www.chictr.org.cn ID:ChiCTR2300071579 2023-05-18.
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引用次数: 0
Kiss1 receptor knockout exacerbates airway hyperresponsiveness and remodeling in a mouse model of allergic asthma. 在过敏性哮喘小鼠模型中,Kiss1 受体敲除会加剧气道高反应性和重塑。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-28 DOI: 10.1186/s12931-024-03017-4
Nilesh Sudhakar Ambhore, Premanand Balraj, Ashish Kumar, Mohammad Irshad Reza, Yogaraj S Ramakrishnan, Jacob Tesch, Sahil Lohana, Venkatachalem Sathish

Background: In asthma, sex-steroids signaling is recognized as a critical regulator of disease pathophysiology. However, the paradoxical role of sex-steroids, especially estrogen, suggests that an upstream mechanism or even independent of estrogen plays an important role in regulating asthma pathophysiology. In this context, in our previous studies, we explored kisspeptin (Kp) and its receptor Kiss1R's signaling in regulating human airway smooth muscle cell remodeling in vitro and airway hyperresponsiveness (AHR) in vivo in a mouse (wild-type, WT) model of asthma. In this study, we evaluated the effect of endogenous Kp in regulating AHR and remodeling using Kiss1R knockout (Kiss1R-/-) mice.

Methods: C57BL/6J WT (Kiss1R+/+) and Kiss1R-/- mice, both male and female, were intranasally challenged with mixed-allergen (MA) and/or phosphate-buffered saline (PBS). We used flexiVent analysis to assess airway resistance (Rrs), elastance (Ers), and compliance (Crs). Following this, broncho-alveolar lavage (BAL) was performed for differential leukocyte count (DLC) and cytokine analysis. Histology staining was performed using hematoxylin and eosin (H&E) for morphological analysis and Masson's Trichrome (MT) for collagen deposition. Additionally, lung sections were processed for immunofluorescence (IF) of Ki-67, α-smooth muscle actin (α-SMA), and tenascin-c.

Results: Interestingly, the loss of Kiss1R exacerbated lung function and airway contractility in mice challenged with MA, with more profound effects in Kiss1R-/- female mice. MA-challenged Kiss1R-/- mice showed a significant increase in immune cell infiltration and proinflammatory cytokine levels. Importantly, the loss of Kiss1R aggravated Th2/Th17 biased cytokines in MA-challenged mice. Furthermore, histology of lung sections from Kiss1R-/- mice showed increased collagen deposition on airway walls and mucin production in airway cells compared to Kiss1R+/+ mice. In addition, immunofluorescence analysis showed loss of Kiss1R significantly aggravated airway remodeling and subsequently AHR.

Conclusions: These findings demonstrate the importance of inherent Kiss1R signaling in regulating airway inflammation, AHR, and remodeling in the pathophysiology of asthma.

背景:在哮喘中,性类固醇信号被认为是疾病病理生理学的关键调节因子。然而,性激素(尤其是雌激素)的矛盾作用表明,上游机制甚至独立于雌激素的机制在调节哮喘病理生理学方面发挥着重要作用。在此背景下,我们在之前的研究中探讨了吻肽(Kp)及其受体 Kiss1R 在体外调节人气道平滑肌细胞重塑和体内调节小鼠(野生型,WT)哮喘模型中气道高反应性(AHR)的信号传导。在本研究中,我们利用 Kiss1R 基因敲除(Kiss1R-/-)小鼠评估了内源性 Kp 在调节 AHR 和重塑中的作用:雌雄C57BL/6J WT(Kiss1R+/+)和Kiss1R-/-小鼠经鼻内注射混合过敏原(MA)和/或磷酸盐缓冲盐水(PBS)。我们使用 flexiVent 分析方法评估气道阻力 (Rrs)、弹性 (Ers) 和顺应性 (Crs)。然后进行支气管肺泡灌洗(BAL),以进行白细胞计数差异(DLC)和细胞因子分析。组织学染色采用苏木精和伊红(H&E)进行形态学分析,采用马森三色染色法(MT)进行胶原沉积分析。此外,还对肺部切片进行了免疫荧光(IF),以检测Ki-67、α-平滑肌肌动蛋白(α-SMA)和tenascin-c:结果:有趣的是,Kiss1R缺失会加剧MA挑战小鼠的肺功能和气道收缩力,对Kiss1R-/-雌性小鼠的影响更深。受到 MA 挑战的 Kiss1R-/- 小鼠的免疫细胞浸润和促炎细胞因子水平显著增加。重要的是,Kiss1R 的缺失加剧了 MA 攻击小鼠体内 Th2/Th17 偏向细胞因子的水平。此外,与 Kiss1R+/+ 小鼠相比,Kiss1R-/- 小鼠肺切片的组织学显示气道壁上的胶原沉积和气道细胞中的粘蛋白生成增加。此外,免疫荧光分析表明,Kiss1R 的缺失会显著加重气道重塑,进而导致 AHR:这些研究结果表明,在哮喘的病理生理学过程中,固有的 Kiss1R 信号在调节气道炎症、AHR 和重塑方面起着重要作用。
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引用次数: 0
Quantitative texture analysis using machine learning for predicting interpretable pulmonary perfusion from non-contrast computed tomography in pulmonary embolism patients. 利用机器学习进行定量纹理分析,从肺栓塞患者的非对比计算机断层扫描中预测可解释的肺灌注。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-28 DOI: 10.1186/s12931-024-03004-9
Zihan Li, Meixin Zhao, Zhichun Li, Yu-Hua Huang, Zhi Chen, Yao Pu, Mayang Zhao, Xi Liu, Meng Wang, Kun Wang, Martin Ho Yin Yeung, Lisheng Geng, Jing Cai, Weifang Zhang, Ruijie Yang, Ge Ren

Background: Pulmonary embolism (PE) is life-threatening and requires timely and accurate diagnosis, yet current imaging methods, like computed tomography pulmonary angiography, present limitations, particularly for patients with contraindications to iodinated contrast agents. We aimed to develop a quantitative texture analysis pipeline using machine learning (ML) based on non-contrast thoracic computed tomography (CT) scans to discover intensity and textural features correlated with regional lung perfusion (Q) physiology and pathology and synthesize voxel-wise Q surrogates to assist in PE diagnosis.

Methods: We retrospectively collected 99mTc-labeled macroaggregated albumin Q-SPECT/CT scans from patients suspected of PE, including an internal dataset of 76 patients (64 for training, 12 for testing) and an external testing dataset of 49 patients. Quantitative CT features were extracted from segmented lung subregions and underwent a two-stage feature selection pipeline. The prior-knowledge-driven preselection stage screened for robust and non-redundant perfusion-correlated features, while the data-driven selection stage further filtered features by fitting ML models for classification. The final classification model, trained with the highest-performing PE-associated feature combination, was evaluated in the testing cohorts based on the Area Under the Curve (AUC) for subregion-level predictability. The voxel-wise Q surrogate was then synthesized using the final selected feature maps (FMs) and model score maps (MSMs) to investigate spatial distributions. The Spearman correlation coefficient (SCC) and Dice similarity coefficient (DSC) were used to assess the spatial consistency between FMs or MSMs and Q-SPECT scans.

Results: The optimal model performance achieved an AUC of 0.863 during internal testing and 0.828 on the external testing cohort. The model identified a combination containing 14 intensity and textural features that were non-redundant, robust, and capable of distinguishing between high- and low-functional lung regions. Spatial consistency assessment in the internal testing cohort showed moderate-to-high agreement between MSMs and reference Q-SPECT scans, with median SCC of 0.66, median DSCs of 0.86 and 0.64 for high- and low-functional regions, respectively.

Conclusions: This study validated the feasibility of using quantitative texture analysis and a data-driven ML pipeline to generate voxel-wise lung perfusion surrogates, providing a radiation-free, widely accessible alternative to functional lung imaging in managing pulmonary vascular diseases.

Clinical trial number: Not applicable.

背景:肺栓塞(PE)危及生命,需要及时、准确的诊断,但目前的成像方法,如计算机断层扫描肺血管造影术,存在局限性,尤其是对有碘造影剂禁忌症的患者。我们的目标是基于非对比胸部计算机断层扫描(CT),利用机器学习(ML)技术开发一种定量纹理分析管道,以发现与区域肺灌注(Q)生理和病理相关的强度和纹理特征,并合成体素Q替代物来协助PE诊断:我们回顾性地收集了疑似 PE 患者的 99mTc 标记大聚集白蛋白 Q-SPECT/CT 扫描图像,包括 76 例患者的内部数据集(64 例用于训练,12 例用于测试)和 49 例患者的外部测试数据集。从分割的肺部亚区提取定量 CT 特征,并进行两阶段特征选择。先验知识驱动的预选阶段筛选稳健、非冗余的灌注相关特征,而数据驱动的选择阶段则通过拟合 ML 模型进行分类,进一步筛选特征。最终的分类模型是用表现最好的 PE 相关特征组合训练出来的,在测试队列中根据曲线下面积(AUC)评估子区域级预测性。然后使用最终选定的特征图(FM)和模型得分图(MSM)合成体素Q代用值,以研究空间分布。斯皮尔曼相关系数(SCC)和骰子相似性系数(DSC)用于评估 FMs 或 MSMs 与 Q-SPECT 扫描之间的空间一致性:在内部测试中,最佳模型的 AUC 为 0.863,在外部测试队列中为 0.828。该模型确定了包含 14 个强度和纹理特征的组合,这些特征是非冗余的、稳健的,能够区分高功能和低功能肺区。内部测试队列的空间一致性评估显示,MSM 与参考 Q-SPECT 扫描之间的一致性为中度到高度一致,高功能区和低功能区的 SCC 中位数分别为 0.66,DSC 中位数分别为 0.86 和 0.64:这项研究验证了使用定量纹理分析和数据驱动的ML管道生成体素肺灌注替代物的可行性,为管理肺血管疾病提供了一种无辐射、可广泛使用的肺功能成像替代方法:临床试验编号:不适用。
{"title":"Quantitative texture analysis using machine learning for predicting interpretable pulmonary perfusion from non-contrast computed tomography in pulmonary embolism patients.","authors":"Zihan Li, Meixin Zhao, Zhichun Li, Yu-Hua Huang, Zhi Chen, Yao Pu, Mayang Zhao, Xi Liu, Meng Wang, Kun Wang, Martin Ho Yin Yeung, Lisheng Geng, Jing Cai, Weifang Zhang, Ruijie Yang, Ge Ren","doi":"10.1186/s12931-024-03004-9","DOIUrl":"10.1186/s12931-024-03004-9","url":null,"abstract":"<p><strong>Background: </strong>Pulmonary embolism (PE) is life-threatening and requires timely and accurate diagnosis, yet current imaging methods, like computed tomography pulmonary angiography, present limitations, particularly for patients with contraindications to iodinated contrast agents. We aimed to develop a quantitative texture analysis pipeline using machine learning (ML) based on non-contrast thoracic computed tomography (CT) scans to discover intensity and textural features correlated with regional lung perfusion (Q) physiology and pathology and synthesize voxel-wise Q surrogates to assist in PE diagnosis.</p><p><strong>Methods: </strong>We retrospectively collected <sup>99m</sup>Tc-labeled macroaggregated albumin Q-SPECT/CT scans from patients suspected of PE, including an internal dataset of 76 patients (64 for training, 12 for testing) and an external testing dataset of 49 patients. Quantitative CT features were extracted from segmented lung subregions and underwent a two-stage feature selection pipeline. The prior-knowledge-driven preselection stage screened for robust and non-redundant perfusion-correlated features, while the data-driven selection stage further filtered features by fitting ML models for classification. The final classification model, trained with the highest-performing PE-associated feature combination, was evaluated in the testing cohorts based on the Area Under the Curve (AUC) for subregion-level predictability. The voxel-wise Q surrogate was then synthesized using the final selected feature maps (FMs) and model score maps (MSMs) to investigate spatial distributions. The Spearman correlation coefficient (SCC) and Dice similarity coefficient (DSC) were used to assess the spatial consistency between FMs or MSMs and Q-SPECT scans.</p><p><strong>Results: </strong>The optimal model performance achieved an AUC of 0.863 during internal testing and 0.828 on the external testing cohort. The model identified a combination containing 14 intensity and textural features that were non-redundant, robust, and capable of distinguishing between high- and low-functional lung regions. Spatial consistency assessment in the internal testing cohort showed moderate-to-high agreement between MSMs and reference Q-SPECT scans, with median SCC of 0.66, median DSCs of 0.86 and 0.64 for high- and low-functional regions, respectively.</p><p><strong>Conclusions: </strong>This study validated the feasibility of using quantitative texture analysis and a data-driven ML pipeline to generate voxel-wise lung perfusion surrogates, providing a radiation-free, widely accessible alternative to functional lung imaging in managing pulmonary vascular diseases.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"389"},"PeriodicalIF":5.8,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11520386/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142523402","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
GSK3179106 ameliorates lipopolysaccharide-induced inflammation and acute lung injury by targeting P38 MAPK. GSK3179106 通过靶向 P38 MAPK 改善脂多糖诱导的炎症和急性肺损伤。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-28 DOI: 10.1186/s12931-024-03012-9
Bin Zheng, Mengying Li, Enhong Lan, Wenting Ding, Lijiao Gao, Yue Tang, Xinyi Wu, Bing Zhang, Yali Zhang, Xiaona Zhu, Hui Zhang

Acute lung injury (ALI) is a serious acute respiratory disease that can cause alveolar-capillary barrier disruption and pulmonary edema, respiratory failure and multiple organ dysfunction syndrome. However, there is no effective drugs in clinic until now. GSK3179106 has been reported can alleviate intestinal stress syndrome, but the protective effect of GSK3179106 on ALI has not been elucidated. The present study will evaluate the pharmacological activity of GSK3179106 on lipopolysaccharide (LPS)-induced inflammation and lung injury and clarify its underlying mechanism. We found that GSK3179106 significantly attenuated LPS-induced lung injury in vivo, accompanied by inhibited infiltration of inflammatory cells and reduced expression of inflammatory cytokines. Meanwhile, GSK3179106 dose-dependently reduced the LPS-induced IL-6 expression both in protein and gene levels in macrophages. Mechanistically, GSK3179106 could inhibited the phosphorylation of P38 MAPK induced by LPS. Importantly, results showed that there is a direct combination between GSK3179106 and P38 MAPK. Together, our findings not only clarified the anti-inflammatory activity of GSK3179106 but also discovered its new clinical indications. Therefore, compound GSK3179106 may be a potential candidate for the treatment of acute inflammatory diseases.

急性肺损伤(ALI)是一种严重的急性呼吸道疾病,可导致肺泡-毛细血管屏障破坏和肺水肿、呼吸衰竭及多器官功能障碍综合征。然而,到目前为止,临床上还没有有效的药物。有报道称GSK3179106能缓解肠应激综合征,但GSK3179106对ALI的保护作用尚未阐明。本研究将评估 GSK3179106 对脂多糖(LPS)诱导的炎症和肺损伤的药理活性,并阐明其潜在机制。我们发现,GSK3179106能显著减轻LPS诱导的体内肺损伤,同时抑制炎症细胞的浸润,降低炎症细胞因子的表达。同时,GSK3179106剂量依赖性地降低了LPS诱导的IL-6在巨噬细胞中的蛋白和基因表达。从机理上讲,GSK3179106 可抑制 LPS 诱导的 P38 MAPK 磷酸化。重要的是,研究结果表明 GSK3179106 与 P38 MAPK 之间存在直接的结合。综上所述,我们的研究结果不仅阐明了 GSK3179106 的抗炎活性,还发现了其新的临床适应症。因此,化合物 GSK3179106 可能是治疗急性炎症性疾病的潜在候选药物。
{"title":"GSK3179106 ameliorates lipopolysaccharide-induced inflammation and acute lung injury by targeting P38 MAPK.","authors":"Bin Zheng, Mengying Li, Enhong Lan, Wenting Ding, Lijiao Gao, Yue Tang, Xinyi Wu, Bing Zhang, Yali Zhang, Xiaona Zhu, Hui Zhang","doi":"10.1186/s12931-024-03012-9","DOIUrl":"10.1186/s12931-024-03012-9","url":null,"abstract":"<p><p>Acute lung injury (ALI) is a serious acute respiratory disease that can cause alveolar-capillary barrier disruption and pulmonary edema, respiratory failure and multiple organ dysfunction syndrome. However, there is no effective drugs in clinic until now. GSK3179106 has been reported can alleviate intestinal stress syndrome, but the protective effect of GSK3179106 on ALI has not been elucidated. The present study will evaluate the pharmacological activity of GSK3179106 on lipopolysaccharide (LPS)-induced inflammation and lung injury and clarify its underlying mechanism. We found that GSK3179106 significantly attenuated LPS-induced lung injury in vivo, accompanied by inhibited infiltration of inflammatory cells and reduced expression of inflammatory cytokines. Meanwhile, GSK3179106 dose-dependently reduced the LPS-induced IL-6 expression both in protein and gene levels in macrophages. Mechanistically, GSK3179106 could inhibited the phosphorylation of P38 MAPK induced by LPS. Importantly, results showed that there is a direct combination between GSK3179106 and P38 MAPK. Together, our findings not only clarified the anti-inflammatory activity of GSK3179106 but also discovered its new clinical indications. Therefore, compound GSK3179106 may be a potential candidate for the treatment of acute inflammatory diseases.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"388"},"PeriodicalIF":5.8,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11520791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142523399","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
Multi-drug resistant Pseudomonas aeruginosa isolation is an independent risk factor for recurrent hemoptysis after bronchial artery embolization in patients with idiopathic bronchiectasis: a retrospective cohort study. 特发性支气管扩张症患者支气管动脉栓塞术后复发咯血的独立风险因素:一项回顾性队列研究。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-26 DOI: 10.1186/s12931-024-03019-2
Jibo Sun, Xiang Tong, Dongguang Wang, Lian Wang, Shijie Zhang, Sitong Liu, Xiu Li, Qingqing Jia, Jiehao Chen, Yao Ma, Hong Fan

Background: Currently, there is a lack of research on multi-drug resistant Pseudomonas aeruginosa (MDR-PA) isolation in bronchiectasis-related hemoptysis. The aim of this study to analyze the risk factors for recurrent hemoptysis following bronchial artery embolization (BAE) and compare the recurrent hemoptysis-free rates between MDR-PA, non-MDR-PA, and non-PA isolation.

Methods: A retrospective study was performed of patients diagnosed with idiopathic bronchiectasis-related recurrent hemoptysis who underwent BAE at an university-affiliated hospital. Patients were categorized based on PA susceptibility tests into non-PA, non-MDR-PA, and MDR-PA groups. Univariate and multivariate Cox regression were conducted to identify independent risk factors for recurrent hemoptysis. The Kaplan-Meier curves was conducted to compare recurrent hemoptysis-free rates after BAE for non-PA, non-MDR-PA, and MDR-PA.

Results: A total of 432 patients were included. 181 (41.90%) patients experienced recurrent hemoptysis during a median follow-up period of 25 months. MDR-PA isolation (adjusted hazard ratio (aHR) 2.120; 95% confidence interval (CI) [1.249, 3.597], p = 0.005) was identified as an independent risk factor for recurrent hemoptysis. Antibiotic treatment (aHR 0.666; 95% CI [0.476, 0.932], p = 0.018) reduced the risk of recurrent hemoptysis. The cumulative recurrent hemoptysis-free rates for non-PA, non-MDR-PA, and MDR-PA were as follows: at 3 months, 88.96%, 88.24%, and 75.86%, respectively; at 1 year, 73.13%, 69.10%, and 51.72%; and at 3 years, 61.91%, 51.69%, and 41.10% (p = 0.034).

Conclusion: MDR-PA isolation was an independent risk factor of recurrent hemoptysis post-BAE. Reducing the occurrence of MDR-PA may effectively decrease the recurrence rates of hemoptysis.

背景:目前,缺乏对支气管扩张相关咯血中多重耐药铜绿假单胞菌(MDR-PA)分离的研究。本研究旨在分析支气管动脉栓塞术(BAE)后复发性咯血的风险因素,并比较MDR-PA、非MDR-PA和非PA分离术的无复发性咯血率:一项回顾性研究针对在大学附属医院接受 BAE 的特发性支气管扩张相关复发性咯血患者。根据 PA 药敏试验将患者分为非 PA 组、非 MDR-PA 组和 MDR-PA 组。通过单变量和多变量考克斯回归来确定复发性咯血的独立风险因素。采用 Kaplan-Meier 曲线比较非 PA、非 MDR-PA 和 MDR-PA 患者 BAE 后的无复发性咯血率:结果:共纳入 432 例患者。181例(41.90%)患者在中位 25 个月的随访期间出现复发性咯血。MDR-PA 分离(调整后危险比 (aHR) 2.120; 95% 置信区间 (CI) [1.249, 3.597], p = 0.005)被确定为复发性咯血的独立危险因素。抗生素治疗(aHR 0.666;95% CI [0.476,0.932],p = 0.018)降低了复发性咯血的风险。非 MDR-PA、非 MDR-PA 和 MDR-PA 的累计无复发性咯血率如下:3 个月时,分别为 88.96%、88.24% 和 75.86%;1 年时,分别为 73.13%、69.10% 和 51.72%;3 年时,分别为 61.91%、51.69% 和 41.10%(P = 0.034):结论:MDR-PA 分离是急性呼吸衰竭后复发性咯血的独立风险因素。减少 MDR-PA 的发生可有效降低咯血的复发率。
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引用次数: 0
Reinitiating lung development: a novel approach in the management of bronchopulmonary dysplasia. 重启肺部发育:治疗支气管肺发育不良的新方法。
IF 5.8 2区 医学 Q1 Medicine Pub Date : 2024-10-24 DOI: 10.1186/s12931-024-02996-8
Xuewei Cui, Jianhua Fu

Bronchopulmonary dysplasia (BPD) is the predominant chronic lung disease in preterm infants, linked with various adverse long-term outcomes. Multiple prenatal and postnatal risk factors can impede lung development, leading to BPD. Current management of BPD relies heavily on pharmacotherapies and alterations in ventilatory strategies. However, these interventions only mitigate BPD symptoms without addressing underlying alveolar, vascular, structural, and functional deficiencies. Given the retarded lung development in infants with BPD and the limitations of existing modalities, new therapeutic approaches are imperative. The induced differentiation of stem/progenitor cells and the spatiotemporal expression patterns of growth factors associated with lung developmental processes are critical for lung development reactivation in BPD, which focuses on stimulating pulmonary vasculogenesis and alveolarization. This review summarizes the process of lung development and offers a comprehensive overview of advancements in therapies designed to reinitiate lung development in BPD. Furthermore, we assessed the potential of these therapies for maintaining lung homeostasis and effectively restoring pulmonary structure and function through stem/progenitor cells and growth factors, which have been widely researched.

支气管肺发育不良(BPD)是早产儿最主要的慢性肺部疾病,与各种不良的长期预后有关。多种产前和产后风险因素会阻碍肺部发育,从而导致 BPD。目前对 BPD 的治疗主要依赖于药物疗法和通气策略的改变。然而,这些干预措施只能缓解 BPD 的症状,却无法解决潜在的肺泡、血管、结构和功能缺陷。鉴于BPD婴儿肺部发育迟缓以及现有模式的局限性,新的治疗方法势在必行。干细胞/祖细胞的诱导分化以及与肺部发育过程相关的生长因子的时空表达模式对 BPD 的肺部发育再激活至关重要,其重点在于刺激肺血管生成和肺泡化。本综述总结了肺发育过程,并全面概述了旨在重启 BPD 肺发育的疗法的进展。此外,我们还评估了这些疗法通过干细胞/祖细胞和生长因子维持肺稳态并有效恢复肺结构和功能的潜力。
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引用次数: 0
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Respiratory Research
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