American Journal of Pathology最新文献_第9页

This Month in AJP 本月 AJP。

IF 4.7 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2024-09-05 DOI: 10.1016/j.ajpath.2024.09.001

引用次数: 0

Histopathologic Differential Diagnosis and Estrogen Receptor/Progesterone Receptor Immunohistochemical Evaluation of Breast Carcinoma Using a Deep Learning–Based Artificial Intelligence Architecture 使用基于深度学习的人工智能架构对乳腺癌进行组织病理学鉴别诊断和雌激素受体/孕激素受体免疫组化评估。

IF 4.7 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2024-09-04 DOI: 10.1016/j.ajpath.2024.08.011

Zhi Han , Shihong Ding , Baichen Liu , Yandong Tang , Xueshan Qiu , Enhua Wang , Huanyu Zhao

In breast carcinoma, invasive ductal carcinoma (IDC) is the most common histopathologic subtype, and ductal carcinoma in situ (DCIS) is a precursor of IDC. These two often occur concomitantly. The immunohistochemical staining of estrogen receptor (ER)/progesterone receptor (PR) in IDC/DCIS on histopathologic whole slide images (WSIs) can predict the prognosis of patients. Artificial intelligence (AI) technology has the potential to substantially reduce the interobserver variability among pathologists reading WSIs. Herein, IDC/DCIS detection was conducted by a deep learning approach, including faster region-based convolutional neural network (Faster R-CNN), RetinaNet, single-shot multibox detector 300 (SSD300), you only look once (YOLO) v3, YOLOv5, YOLOv7, YOLOv8, and Swin transformer. Their performance was estimated by mean average precision (mAP) values. Cell recognition and counting were performed using AI technology to evaluate the intensity and proportion of ER/PR-immunostained cancer cells in IDC/DCIS. A three-round ring study (RS) was conducted to assess WSIs. A database for modelling the underlying probability distribution of a data set with labels was established. YOLOv8 exhibited the highest detection performance with an mAP at 0.5 of 0.944 and an mAP at 0.5 to 0.95 of 0.790. With the assistance of YOLOv8, the scoring concordance across all pathologists was boosted to excellent in RS3 (0.970) from moderate in RS1 (0.724) and good in RS2 (0.812). Deep learning detection can be applied in the clinicopathologic field. Herein, a novel AI architecture and well-organized data set were developed to facilitate the histopathologic diagnosis of IDC/DCIS and immunostaining scoring of ER/PR.

在乳腺癌中，浸润性导管癌（IDC）是最常见的组织病理学亚型，而导管原位癌（DCIS）则是 IDC 的前身。它们常常同时存在。全切片组织病理学图像（WSI）上 IDC/DCIS 中雌激素受体（ER）/孕酮受体（PR）的免疫组化染色可预测患者的预后。然而，病理学家在阅读 WSIs 时难免存在观察者之间的差异。因此，人工智能（AI）技术至关重要。本文采用深度学习方法进行 IDC/DCIS 检测，包括 Faster R-CNN、RetinaNet、SSD300、YOLOv3、YOLOv5、YOLOv7、YOLOv8 和 Swin transformer。它们的性能是通过平均精度 (mAP) 值来估算的。使用人工智能技术进行细胞识别和计数，以评估 IDC/DCIS 中 ER/PR 免疫染色癌细胞的强度和比例。为评估 WSI，进行了三轮环形研究（RS）。建立了一个数据库，用于模拟带有标签的数据集的基本概率分布。YOLOv8 的检测性能最高，mAP@0.5 为 0.944，mAP@0.5-0.95 为 0.790。在 YOLOv8 的帮助下，所有病理学家的评分一致性从 RS1 的中等（0.724）和 RS2 的良好（0.812）提高到了 RS3 的优秀（0.970）。深度学习检测可应用于临床病理领域。为了促进IDC/DCIS的组织病理学诊断和ER/PR的免疫染色评分，我们开发了一种新型的人工智能架构和组织良好的数据集。

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引用次数: 0

Tumor-Derived Immunoglobulin-Like Transcript 4 Promotes Postoperative Relapse via Inducing Vasculogenic Mimicry through MAPK/ERK Signaling in Hepatocellular Carcinoma 肿瘤源性免疫球蛋白样转录物4通过MAPK/ERK信号转导诱导肝细胞癌的血管生成模拟，从而促进术后复发。

IF 4.7 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2024-09-02 DOI: 10.1016/j.ajpath.2024.08.010

Jiayan Li , Xiaofeng Ding , Wanping Yan , Ke Liu , Wei Ye , Huali Wang , Lili Wang

The efficacy of conventional anti-angiogenesis drugs is usually low in treating hepatocellular carcinoma (HCC). Therefore, there is an urgent need to find new precise therapeutic targets and to develop more effective drugs for the treatment of HCC. Vasculogenic mimicry (VM) is different from classic endothelium-dependent angiogenesis and is associated with a poor prognosis in patients with malignant tumor. However, the mechanism underlying VM is complex and not fully defined. Ig-like transcript (ILT)-4, as a negative regulator of immune response, is expressed in many solid tumors. However, whether and how ILT4 regulates VM remains unclear. This study found VM enriched in HCC tissues, especially in tissues from patients with relapse within 5 years after surgery. Similarly, ILT4 expression level was also higher in HCC tissues from patients with relapse within 5 years after surgery. Linear regression analysis revealed a positive correlation between the expression of ILT4 and VM density. Furthermore, overexpression/knockdown of ILT4 expression upregulated/down-regulated VM-related marker, three-dimensional tube formation, and migration and invasion in HCC cell lines in vitro. In mechanistic studies, ILT4 promoted VM formation via mitogen-activated protein kinase (MAPK)/ERK signaling. This study provides a rationale and mechanism for ILT4-mediated postoperative relapse via inducing VM in HCC. The related molecular pathways can be used as novel therapeutic targets for the inhibition of HCC angiogenesis and postoperative relapse.

传统的抗血管生成药物在肝细胞癌（HCC）治疗中的效果通常并不理想。因此，寻找新的精确治疗靶点并进一步开发更有效的药物来治疗 HCC 迫在眉睫。血管生成模拟（VM）不同于传统的内皮依赖性血管生成，与恶性肿瘤患者的不良预后有关。然而，VM发生的机制十分复杂，尚未完全明确。免疫球蛋白样转录物（ILT）4 是免疫反应的负调控因子，最近发现它在许多实体瘤中都有表达。然而，ILT4 是否以及如何调控 VM 仍不清楚。在本研究中，我们发现 VM 在 HCC 组织中富集，尤其是在术后 5 年内复发的患者组织中。同样，术后 5 年内复发患者的 HCC 组织中 ILT4 的表达水平也较高。线性回归分析表明，ILT4 的表达与 VM 密度呈正相关。此外，ILT4的过表达/敲除会上调/下调VM相关标记物、三维管形成、HCC细胞株在体外的迁移和侵袭。机理研究表明，ILT4 通过 MAPK/ERK 信号转导促进了 VM 的形成。总之，本研究为 ILT4 通过诱导 HCC VM 而介导术后复发提供了理论依据和机制。相关分子通路可作为抑制 HCC 血管生成和术后复发的新型治疗靶点。

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引用次数: 0

Spatial Transcriptomics Reveals the Transcriptomic Signatures in a Mouse Model of Pediatric Metabolic Dysfunction–Associated Steatohepatitis 空间转录组学揭示了小儿代谢功能障碍相关性脂肪性肝炎小鼠模型的转录组特征。

IF 4.7 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2024-08-31 DOI: 10.1016/j.ajpath.2024.08.008

Lu Jiang , Qing-Yang Xu , Yong-Chang Zhou , Juan Xu , Jian-Gao Fan

Metabolic dysfunction–associated steatohepatitis (MASH) is considered the progressive form of metabolic dysfunction–associated steatotic liver disease, which is the leading cause of chronic liver disease in children. However, the pathogenesis of pediatric MASH remains poorly understood because of the lack of animal models. In this study, a mouse model of pediatric MASH was developed and its hepatic transcriptomic profile was characterized using spatial transcriptomics technology. C57BL/6J mice were fed a Western diet (WD) along with weekly injections of carbon tetrachloride (CCl₄) from the age of 3 weeks and lasting up to 8 weeks. After 5 weeks of feeding, WD + CCl₄–treated mice showed significant liver injury without the development of insulin resistance. Histologically, WD + CCl₄ induced key features of type 2 MASH, the most common type observed in children, characterized by liver steatosis, portal inflammation, and portal fibrosis. Spatial transcriptomics analysis of liver tissues indicated that cluster 0 in the mouse from the WD + CCl₄ group was enriched in pathways associated with lipid metabolism. Further investigation revealed that cytochrome p450 2E1 was the top marker gene of cluster 0, and its expression was increased in the periportal area of mice from the WD + CCl₄ group. These findings suggest that this mouse model of pediatric MASH mirrors the histologic features of human MASH, and the up-regulation of cytochrome p450 2E1 may be linked to the disease pathogenesis.

代谢功能障碍相关性脂肪性肝炎（MASH）被认为是代谢功能障碍相关性脂肪性肝病（MASLD）的进展形式，是儿童慢性肝病的主要病因。然而，由于缺乏动物模型，人们对小儿 MASH 的发病机制仍然知之甚少。在这项研究中，我们建立了小儿 MASH 的小鼠模型，并利用空间转录组学（ST）技术描述了肝脏转录组的特征。C57BL/6J 小鼠从 3 周大到 8 周大期间，在喂食西式饮食（WD）的同时每周注射四氯化碳（CCl4）。喂养5周后，WD+CCl4处理的小鼠出现了明显的肝损伤，但没有出现胰岛素抵抗。从组织学角度看，WD+CCl4诱导了2型MASH的主要特征，这是儿童中最常见的类型，其特征是肝脏脂肪变性、门静脉炎症和门静脉纤维化。通过对肝组织的 ST 分析，我们发现 WD+CCl4 组小鼠的第 0 簇富含与脂质代谢相关的通路。进一步研究发现，细胞色素 p450 2E1 (CYP2E1) 是第 0 组的首要标记基因，其在 WD+CCl4 组小鼠肝周围区域的表达增加。这些发现表明，我们的小儿MASH小鼠模型反映了人类MASH的组织学特征，而CYP2E1的上调可能与疾病的发病机制有关。

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引用次数: 0

Lipopolysaccharide Triggers Luminal Acidification to Promote Defense Against Bacterial Infection in Vaginal Epithelium 脂多糖引发腔内酸化，促进阴道上皮对细菌感染的防御。

IF 4.7 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2024-08-31 DOI: 10.1016/j.ajpath.2024.08.009

Yi-Lin Zhang , Yu-Yun Zhou , Li-Jiao Ke , Jie Sheng , Dan-Yang Zou , Ting-Ting Tang , Zi-Ying Yang , Lei Chen , Xiao-Chun Hou , Jie Zhu , Jian-Bang Xu , Yun-Xin Zhu , Wen-Liang Zhou

The vaginal epithelium plays pivotal roles in host defense against pathogen invasion, contributing to the maintenance of an acidic microenvironment within the vaginal lumen through the activity of acid-base transport proteins. However, the precise defense mechanisms of the vaginal epithelium after a bacterial infection remain incompletely understood. This study showed that bacterial lipopolysaccharide (LPS) potentiated net proton efflux by up-regulating the expression of Na⁺-H⁺ exchanger 1 (NHE1) in vaginal epithelial cells. Pharmacologic inhibition or genetic knockdown of Toll-like receptor-4 and the extracellular signal–regulated protein kinase signaling pathway effectively counteracted the up-regulation of NHE1 and the enhanced proton efflux triggered by LPS in vaginal epithelial cells. In vivo studies revealed that LPS administration led to luminal acidification through the up-regulation of NHE1 expression in the rat vagina. Moreover, inhibition of NHE exhibited an impaired defense against acute bacterial infection in the rat vagina. These findings collectively indicate the active involvement of vaginal epithelial cells in facilitating luminal acidification during acute bacterial infection, offering potential insights into the treatment of bacterial vaginosis.

阴道上皮在宿主抵御病原体入侵的过程中发挥着关键作用，它通过酸碱转运蛋白的活性来维持阴道腔内的酸性微环境。然而，人们对细菌感染后阴道上皮所采用的精确防御机制仍不甚了解。本研究表明，细菌脂多糖（LPS）通过上调 Na+-H+ 交换子 1（NHE1）的表达来增强净质子外流，而不影响阴道上皮细胞中的其他酸碱转运蛋白。药理抑制或基因敲除 Toll 样受体-4（TLR4）和细胞外信号调节蛋白激酶（ERK）信号通路可有效抵消 LPS 在阴道上皮细胞中引发的 NHE1 上调和质子外流增强。体内研究显示，LPS 通过上调大鼠阴道中 NHE1 的表达导致管腔酸化。此外，抑制 NHE 会削弱大鼠阴道对急性细菌感染的防御能力。这些发现共同表明，阴道上皮细胞在急性细菌感染期间积极参与促进管腔酸化，为治疗细菌性阴道病提供了潜在的启示。

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引用次数: 0

Glucose-Regulated Protein 78, via Releasing β-Catenin from Adherens Junctions, Facilitates Its Interaction with STAT3 in Mediating Retinal Neovascularization GRP78 通过释放粘连接头中的β-catenin，促进其与 STAT3 的相互作用，从而介导视网膜新生血管的形成。

IF 4.7 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2024-08-31 DOI: 10.1016/j.ajpath.2024.08.005

Raj Kumar, Gadiparthi N. Rao

Retinopathy due to neovascularization is one of the major causes of vision loss. To understand the mechanisms underlying retinal neovascularization the oxygen-induced retinopathy (OIR) model was used. Two-dimensional gel matrix-assisted laser desorption/ionization time-of-flight/time-of-flight analysis of normoxic and 24-hour post-OIR mice pups' retinas revealed that glucose-regulated protein 78 (GRP78) was one of the several molecules induced by OIR in the retinal endothelial cells (ECs). Vascular endothelial growth factor A (VEGFA) also induced GRP78 expression independent of endoplasmic reticulum stress response in human retinal microvascular endothelial cells, and its depletion reduced VEGFA-induced EC angiogenic responses. Consistent with these observations, EC-specific deletion of GRP78 inhibited OIR-induced retinal neovascularization. GRP78 bound with vascular endothelial–cadherin and released adherens junction, but not Wnt-mediated, β-catenin. β-catenin, in turn, via interacting with STAT3, triggered cyclin D1 expression. Furthermore, depletion of β-catenin or cyclin D1 levels negated VEGFA-induced EC angiogenic responses and OIR-induced retinal neovascularization. EC-specific deletion of GRP78 also suppressed OIR-induced vascular leakage. Studies of upstream signaling indicated that activating transcription factor 6 mediated GRP78 induction in the modulation of VEGFA-induced EC angiogenic responses and OIR-induced retinal neovascularization. Together, these observations revealed that GRP78, independent of its response to endoplasmic reticulum stress, is involved in mediating EC angiogenic responses by VEGFA and retinal neovascularization by OIR. In view of these findings, GRP78 emerges as a desirable target for drug development against diabetic retinopathy.

新血管形成导致的视网膜病变是视力丧失的主要原因之一。为了了解视网膜新生血管形成的机制，我们利用氧诱导视网膜病变（OIR）模型，对正常缺氧和OIR后24小时的幼鼠视网膜进行了二维凝胶-MALDI-TOF/TOF分析。二维凝胶分析表明，GRP78 是 OIR 在视网膜 EC 中诱导的几种分子之一。在 HRMVECs 中，VEGFA 也会诱导 GRP78 的表达，而不依赖于 ER 应激反应，消耗 GRP78 的水平会降低 VEGFA 诱导的 EC 血管生成反应。与这些观察结果相一致的是，特异性地删除 EC 中的 GRP78 可抑制 OIR 诱导的视网膜新生血管。在探索其机制时，我们发现 GRP78 与 VE-cadherin 结合并释放粘连接头的β-catenin，而不是 Wnt 介导的β-catenin，β-catenin 反过来又通过与 STAT3 相互作用触发细胞周期蛋白 D1 的表达。此外，β-catenin或细胞周期蛋白D1水平的缺失会抑制VEGFA诱导的EC血管生成反应和OIR诱导的视网膜新生血管。细胞因子特异性缺失 GRP78 也抑制了 OIR 诱导的血管渗漏。在阐明上游信号传导时，我们发现 ATF6 在调节 VEGFA 诱导的 EC 血管生成反应和 OIR 诱导的视网膜新生血管的过程中介导了 GRP78 的诱导。总之，这些观察结果表明，GRP78 与其对 ER 应激的反应无关，参与了 VEGFA 对 EC 血管生成反应和 OIR 对视网膜新生血管生成的介导。鉴于这些发现，GRP78似乎可以成为糖尿病视网膜病变药物开发的理想靶点。

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引用次数: 0

Methyltransferase-Like 3–Driven N6-Methyladenosine Modification of Recombination Signal Binding Protein for Immunoglobulin Kappa J Region Promotes Vascular Remodeling in Pulmonary Hypertension METTL3 驱动的 RBPJ m6A 修饰促进肺动脉高压的血管重塑

IF 4.7 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2024-08-31 DOI: 10.1016/j.ajpath.2024.08.007

Qiang Du , Chun Zhang , Tianyu Qu , Xiao Zhou , Yingying Liu , Zhixuan Chen , Ziling Shen , Pingsheng Chen , Ruifeng Zhang

The dysregulation of N6-methyladenosine (m6A) RNA modification is widely recognized for its crucial roles in various diseases, including pulmonary hypertension (PH). Prior studies have highlighted the significant role of methyltransferase-like 3 (METTL3) in the pathogenesis of PH. Nevertheless, the potential and underlying mechanisms of METTL3 and its inhibitors as targets for PH treatment require further elucidation. In this study, increased levels of METTL3 were observed in various rodent models of PH. In vitro studies revealed that METTL3 silencing or treatment with STM2457, a specific METTL3 inhibitor, attenuated the proliferation and migration of pulmonary artery smooth muscle cells stimulated by platelet-derived growth factor-BB or hypoxia. Moreover, in vivo experiments using adeno-associated virus 9–mediated METTL3 silencing or STM2457 inhibition demonstrated improvement in SU5416/hypoxia-induced PH in mice. Additionally, m6A RNA immunoprecipitation analysis identified recombination signal binding protein for immunoglobulin kappa J region (RBPJ) regulated by METTL3 in rodent models of PH. Loss-of-function studies showed that silencing RBPJ could attenuate the changes in the proliferation and migration of pulmonary artery smooth muscle cells induced by platelet-derived growth factor-BB or hypoxia. Further studies indicated that METTL3 and YTH N6-methyladenosine RNA binding protein F1 (YTHDF1) regulated RBPJ mRNA expression in an m6A-dependent manner. These findings indicated that targeting METTL3 may be a promising therapeutic strategy for treating PH, and modulation of RBPJ could offer a potential intervention mechanism.

N6-甲基腺苷（m6A）RNA修饰失调在包括肺动脉高压（PH）在内的各种疾病中的关键作用已得到广泛认可。先前的研究强调了 METTL3 在 PH 发病机制中的重要作用。然而，METTL3及其抑制剂作为PH治疗靶点的潜力和潜在机制还需要进一步阐明。在本研究中，我们观察到各种啮齿动物 PH 模型中 METTL3 水平的升高。体外研究发现，沉默 METTL3 或用 STM2457（一种特异性 METTL3 抑制剂）治疗可减轻肺动脉平滑肌细胞（PASMC）在血小板衍生生长因子-BB（PDGF-BB）或缺氧刺激下的增殖和迁移。此外，使用 AAV9 介导的 METTL3 沉默或 STM2457 抑制剂进行的体内实验表明，SU5416/缺氧诱导的小鼠 PH 有所改善。此外，m6A RNA 免疫沉淀分析确定 RBPJ 是啮齿动物 PH 模型中受 METTL3 调节的基因。功能缺失研究表明，沉默 RBPJ 可减轻 PDGF-BB 或缺氧诱导的 PASMC 增殖和迁移的变化。进一步的研究表明，METTL3 和 YTHDF1 以 m6A 依赖性的方式调控 RBPJ mRNA 的表达。这些研究结果表明，靶向 METTL3 可能是治疗 PH 的一种有前景的治疗策略，而调节 RBPJ 则可能提供一种潜在的干预机制。

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引用次数: 0

A Deep Learning Approach for the Identification of the Molecular Subtypes of Pancreatic Ductal Adenocarcinoma Based on Whole Slide Pathology Images 基于全切片病理图像的胰腺导管腺癌分子亚型鉴定深度学习方法。

IF 4.7 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2024-08-31 DOI: 10.1016/j.ajpath.2024.08.006

Pouya Ahmadvand , Hossein Farahani , David Farnell , Amirali Darbandsari , James Topham , Joanna Karasinska , Jessica Nelson , Julia Naso , Steven J.M. Jones , Daniel Renouf , David F. Schaeffer , Ali Bashashati

Delayed diagnosis and treatment resistance result in high pancreatic ductal adenocarcinoma (PDAC) mortality rates. Identifying molecular subtypes can improve treatment, but current methods are costly and time-consuming. In this study, deep learning models were used to identify histologic features that classify PDAC molecular subtypes based on routine hematoxylin-eosin–stained histopathologic slides. A total of 97 histopathology slides associated with resectable PDAC from The Cancer Genome Atlas project were used to train a deep learning model and test the performance on 44 needle biopsy material (110 slides) from a local annotated patient cohort. The model achieved balanced accuracy of 96.19% and 83.03% in identifying the classical and basal subtypes of PDAC in The Cancer Genome Atlas and the local cohort, respectively. This study provides a promising method to cost-effectively and rapidly classify PDAC molecular subtypes based on routine hematoxylin-eosin–stained slides, potentially leading to more effective clinical management of this disease.

延迟诊断和耐药性使胰腺导管腺癌（PDAC）的死亡率居高不下。识别分子亚型可以改善治疗，但目前的方法成本高、耗时长。本研究利用深度学习模型，基于常规苏木精-伊红（H&E）染色的组织病理切片，识别可对 PDAC 分子亚型进行分类的组织学特征。利用癌症基因组图谱（TCGA）项目中与可切除PDAC相关的97张组织病理切片来训练深度学习模型，并在本地注释患者队列中的44份针刺活检材料（110张切片）上测试其性能。该模型在 TCGA 和本地队列中识别 PDAC 经典亚型和基底亚型的均衡准确率分别达到 96.19% 和 83.03%。这项研究为基于常规 H&E 切片对 PDAC 分子亚型进行经济有效的快速分类提供了一种很有前景的方法，有可能为这种疾病带来更有效的临床治疗。

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引用次数: 0

Sex Differences in Impacts of Early Gestational and Peri-Adolescent Ozone Exposure on Lung Development in Rats 妊娠早期和青春期暴露于臭氧对大鼠肺发育影响的性别差异：对人类后天疾病的影响

IF 4.7 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2024-08-23 DOI: 10.1016/j.ajpath.2024.05.013

Janice A. Dye , Helen H. Nguyen , Erica J. Stewart , Mette C.J. Schladweiler , Colette N. Miller

Air pollution exposure during pregnancy may affect fetal growth. Fetal growth restriction (FGR) is associated with reduced lung function in children that can persist into adulthood. Using an established model of asymmetrical FGR in Long-Evans rats, this study investigated sex differences in effects of early life ozone exposure on lung development and maturation. Adverse health effects for i) gestational exposure (with impacts on primary alveolarization), ii) peri-adolescent exposure (with impacts on secondary alveolarization), and iii) cumulative exposure across both periods were evaluated. Notably, female offspring were most affected by gestational ozone exposure, likely because of impaired angiogenesis and corresponding decreases in primary alveolarization. Females had diminished lung capacity, fewer mature alveoli, and medial hypertrophy of small and large pulmonary arteries. Males, especially FGR-prone offspring, were more affected by peri-adolescent ozone exposure. Males had increased ductal areas, likely due to disrupted secondary alveolarization. Altered lung development may increase risk of developing diseases, such as pulmonary arterial hypertension or chronic obstructive pulmonary disease. Pulmonary arterial hypertension disproportionately affects women. In the United States, chronic obstructive pulmonary disease prevalence is increasing, especially in women; and prevalence for both men and women is highest in urbanized areas. This investigation underlines the importance of evaluating results separately by sex, and provides biologic plausibility for later consequences of early-life exposure to ozone, a ubiquitous urban air pollutant.

孕期接触空气污染可能会影响胎儿生长。胎儿生长受限（FGR）与儿童肺功能下降有关，这种情况可能会持续到成年。本研究利用已建立的长-埃文斯大鼠非对称 FGR 模型，调查了生命早期接触臭氧对肺发育和成熟影响的性别差异。研究评估了 i）妊娠期暴露（对初级肺泡化的影响）、ii）青春期暴露（对次级肺泡化的影响）和 iii）两个时期的累积暴露对健康的不利影响。值得注意的是，雌性后代受妊娠期臭氧暴露的影响最大，这可能是由于血管生成受损和初级肺泡化相应减少。雌性后代的肺活量减小，成熟肺泡减少，大小肺动脉内侧肥大。男性，尤其是容易发生胎儿畸形的后代，受到围青春期臭氧暴露的影响更大。男性肺导管面积增大，可能是由于继发性肺泡化受到破坏。肺部发育的改变可能会增加罹患肺动脉高压或慢性阻塞性肺病等疾病的风险。肺动脉高压对女性的影响尤为严重。在美国，慢性阻塞性肺病的发病率正在上升，尤其是女性；在城市化地区，男性和女性的发病率都最高。这项调查强调了按性别分别评估结果的重要性，并为早年暴露于臭氧--一种无处不在的城市空气污染物--的日后后果提供了生物学上的合理性。

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引用次数: 0

Retraction notice to “Pharmacologic Blockade of 5-Lipoxygenase Improves the Amyloidotic Phenotype of an Alzheimer's Disease Transgenic Mouse Model: Involvement of γ-Secretase” [Am J Pathol 178 (2011) 1762–1769] 药物阻断 5-脂氧合酶可改善阿尔茨海默病转基因小鼠模型的淀粉样表型：γ-分泌酶的参与" [Am J Pathol 178 (2011) 1762-1769]。

IF 4.7 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2024-08-23 DOI: 10.1016/j.ajpath.2024.07.006

Jin Chu, Domenico Praticò

引用次数: 0