American Journal of Pathology最新文献_第6页

Loss of Aquaporin-1 in Tumor Cells Fosters Intrahepatic Cholangiocarcinoma Progression 肿瘤细胞中水通道蛋白-1的缺失促进肝内胆管癌的进展。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-11-07 DOI: 10.1016/j.ajpath.2025.10.007

César I. Gaspari , Carine Beaupere , Seth Richard , Estanislao Peixoto , Bouchra Lekbaby , Mirko Minini , Branko Dubravcic , Javier Vaquero , Marie Vallette , Ander Arbelaiz , Marion Janona , Corentin Louis , Pauline Le Gall , Cédric Coulouarn , Julieta Marrone , Juan E. Abrahante , Raúl A. Marinelli , Sergio A. Gradilone , Laura Fouassier

Aquaporin-1 (AQP1) is a water channel expressed by cholangiocytes described to modulate cell proliferation and invasion in several cancers. But the role of AQP1 in cholangiocarcinoma (CCA) remains unknown. The aim was to study the function of AQP1 in CCA. AQP1 expression was evaluated in 39 intrahepatic CCA (iCCA) specimens from transcriptomic data. AQP1-knockout in HuCCT1 iCCA cells was achieved by clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9). Next-generation sequencing (RNA sequencing) was performed to study the consequences of AQP1 inhibition on cell phenotype. Epithelial-mesenchymal transition (EMT), cell migration and proliferation, and signaling pathways were evaluated by live-cell imaging system, quantitative RT-PCR, Western blot, and immunostaining. In vivo experiments were performed using a xenograft CCA model. In human iCCA, low AQP1 expression correlated with reduced overall survival. In vivo, CCA cells depleted for AQP1 displayed a higher tumorigenic potential than control cells. In vitro, RNA-sequencing analysis of AQP1-depleted CCA cells showed signatures of tumor progression, including EMT. Indeed, AQP1-depleted cells showed a cell dispersion phenotype, loss of the junction protein E-cadherin, and higher expression of vimentin and zinc finger E-box binding homeobox 1 (ZEB1), along with stemness traits. Functionally, loss of AQP1 is associated with increased cell migration and proliferation. Moreover, an activation of the insulin-like growth factor 2/insulin-like growth factor 1 receptor/insulin receptor pathway was found in AQP1-depleted CCA cells. The data suggest that AQP1 acts as a tumor suppressor in iCCA.

水通道蛋白-1 （AQP1）是一种由胆管细胞表达的水通道，在多种癌症中被描述为调节细胞增殖和侵袭。但AQP1在胆管癌（CCA）中的作用尚不清楚。我们的目的是研究AQP1在CCA中的功能。通过转录组学数据评估39例肝内CCA （iCCA）标本中AQP1的表达。通过CRISPR-Cas9在HuCCT1 iCCA细胞中实现AQP1-KO。下一代测序（RNAseq）研究AQP1抑制对细胞表型的影响。采用诱导细胞活细胞成像系统、RT-qPCR、western-blot和免疫染色评价上皮-间质转化（Epithelial-mesenchymal transition， EMT）、细胞迁移增殖和信号通路。体内实验采用异种移植CCA模型。在人类iCCA中，AQP1的低表达与总生存率降低相关。在体内，AQP1缺失的CCA细胞比对照细胞表现出更高的致瘤潜能和肿瘤负荷。体外，aqp1缺失的CCA细胞的RNA-seq分析显示肿瘤进展的特征，包括EMT。事实上，aqp1缺失的细胞表现出表型变化，诱导细胞分散，细胞-细胞连接蛋白E-cadherin的缺失，vimentin和ZEB1的高表达，以及干性性状。功能上，AQP1的缺失与细胞迁移和增殖增加有关。此外，我们发现在aqp1缺失的CCA细胞中IGF2/IGF1R/IR通路被激活。我们的数据表明AQP1在iCCA中起肿瘤抑制作用。

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引用次数: 0

Selective Depletion of Gut Gram-Negative Bacteria Attenuates Alcohol Binge-Induced Cardiovascular Dysfunction by Lowering Cardiac Anandamide Levels 选择性消耗肠道革兰氏阴性菌通过降低心脏Anandamide水平减轻酗酒引起的心血管功能障碍。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-11-06 DOI: 10.1016/j.ajpath.2025.10.010

Sarah E. Cohen , Meagan E. Donovan , Davin J. Gardner , Danielle Sambo , Seray B. Karagoz , Resat Cinar , David Goldman , Jason D. Gardner , Pal Pacher , Janos Paloczi

Binge drinking contributes to an increasing number of emergency department visits in the United States. Previous work demonstrated that an alcohol binge impairs cardiac performance and exerts complex hemodynamic effects through the activation of the endocannabinoid-mediated cannabinoid type 1 receptor (CB1R) signaling pathway. Anandamide (AEA), an endogenous CB1R agonist, is synthesized in response to various stressors and tissue injury. However, the role of binge drinking in increasing myocardial AEA levels, which leads to CB1R-dependent cardiodepression, remains unclear. This work studied how endotoxins from intestinal Gram-negative bacteria affect myocardial AEA levels, which further induce CB1R-dependent cardiac dysfunction following acute alcohol intoxication. Using a murine model of a single alcohol binge (5 g/kg orally), reduced mesenteric microcirculation concurrent with elevated circulating endotoxin levels was observed. Selective depletion of gut Gram-negative bacteria by antibiotics partially ameliorated alcohol-induced gut barrier dysfunction, significantly lowered circulating endotoxins, coinciding with reduced cardiac AEA levels at 3 hours after binge. These changes were paralleled with moderately improved cardiac performance and vascular tone. Cardiac RNA levels of genes involved in AEA synthesis increased after alcohol binge, but not in antibiotic-pretreated mice. However, acute alcohol-induced cardiac AEA formation was unrelated to toll-like receptor-4 signaling. These findings provide novel insights that highlight the pivotal role of intestinal Gram-negative bacteria in modulating cardiac AEA levels after an alcohol binge, leading to cardiovascular dysfunction.

在美国，酗酒导致急诊室就诊人数不断上升。我们之前的研究表明，酗酒会损害心脏功能，并通过激活内源性大麻素介导的大麻素受体1 （CB1R）信号通路产生复杂的血流动力学影响。阿南达胺（Anandamide， AEA）是一种内源性CB1R激动剂，在各种应激源和组织损伤的作用下合成。然而，酗酒在增加心肌AEA水平（导致cb1r依赖性心脏抑郁）中的作用尚不清楚。在这里，我们研究了肠道革兰氏阴性菌内毒素如何影响心肌AEA水平，从而进一步诱导急性酒精中毒后cb1r依赖性心功能障碍。使用单次酒精暴饮（5 g/kg口服）的小鼠模型，我们观察到肠系膜微循环减少同时循环内毒素水平升高。抗生素选择性消耗肠道革兰氏阴性菌部分改善了酒精诱导的肠道屏障功能障碍，显著降低了循环内毒素，与暴食后3小时心脏AEA水平降低相一致。这些变化与心脏功能和血管张力的中度改善是平行的。酗酒后，参与AEA合成的基因的心脏RNA水平增加，但在抗生素预处理的小鼠中没有。然而，急性酒精诱导的心脏AEA形成与toll样受体-4信号传导无关。这些发现提供了新的见解，强调了肠道革兰氏阴性菌在酗酒后调节心脏AEA水平的关键作用，导致心血管功能障碍。

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引用次数: 0

PathViT Model for Automated Disease Classification from Skeletal Muscle Histopathology PathViT：骨骼肌组织病理学自动疾病分类。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-11-06 DOI: 10.1016/j.ajpath.2025.10.009

Taymaz Akan , Sait Alp , Richa Aishwarya , Diensn G. Xing , Destyn Dicharry , Md. Shenuarin Bhuiyan , Mohammad Alfrad Nobel Bhuiyan

Analyzing skeletal muscle pathology from histological images is labor intensive (requiring manual cell counting, segmentation, and thresholding), time consuming, and prone to inter- and intrauser variability, influencing the accuracy and consistency of diagnoses. To address these difficulties, PathViT, a transformer-based deep-learning model, was designed to automatically distinguish between healthy and diseased muscle fibers, with the aims of reducing human intervention, minimizing subjectivity and variability, and significantly decreasing analysis time compared to conventional manual methods. Skeletal muscle pathology is characterized by changes in myofiber cross-sectional area, increased central nuclei, and structural disruptions in sarcomeres. To investigate these changes in myofiber size, wheat germ agglutinin staining and digital histopathology of skeletal muscle (quadriceps, gastrocnemius, tibialis anterior, extensor digitorum longus, and soleus) was utilized to classify diseased tissue [amyotrophic lateral sclerosis (SOD1∗G93A) and type 1 diabetes (Akita)] versus nondiseased controls. The performance of PathViT in distinguishing diseased versus nondiseased muscle fibers was compared with that of state-of-the-art deep-learning models. PathViT classified healthy and diseased muscle fibers with 96% accuracy, outperforming the other models. This approach enhanced scalability and diagnostic accuracy and decreased variability, making PathViT a potentially powerful biomedical research and clinical tool.

从组织学图像中分析骨骼肌病理是一个劳动密集型的过程，容易受到用户之间和用户内部差异的影响，从而影响诊断的准确性和一致性——传统的技术，如基于imagej的工具，需要手动进行细胞计数、分割和阈值设置。因此，它们既耗时又会产生不同的结果。为了解决这些困难，我们开发了PathViT，这是一种基于转换器的深度学习模型，用于病理图像的自动分类。骨骼肌病理的特点是肌纤维横截面积改变，中央核增加，肌节结构破坏。为了研究这些肌纤维大小的变化，我们使用小麦胚芽凝集素（WGA）染色的不同骨骼肌（股四头肌、腓肠肌、胫骨前肌、指长伸肌和比目鱼肌）的组织病理学图像来对肌萎缩性侧索硬化症（ALS）、糖尿病和健康对照进行分类。PathVit可以自动区分健康和病变肌纤维，减少人为干预，最大限度地减少主观性和可变性，与传统的人工方法相比，显著减少分析时间。我们使用野生型和疾病模型（ALS为G93A*SOD1, 1型糖尿病为Akita）的wga染色骨骼肌图像，对PathViT与最先进的深度学习模型进行了评估。PathViT对健康和病变肌纤维的分类准确率为96%，优于所有其他模型。与人工方法相比，PathVit减少了人为干预、主观性、可变性和分析时间。这种方法提高了可扩展性、诊断准确性和可变性，使PathViT成为强大的生物医学研究和临床工具。

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引用次数: 0

Silencing Ubiquitin-Specific Peptidase 10 Alleviates Persistent Corneal Epithelial Defect in Mice 沉默USP10可减轻小鼠持续性角膜上皮缺陷。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-11-06 DOI: 10.1016/j.ajpath.2025.10.006

Arpan Banerjee , Mohammad Anjum Shaik , Christine Tilstra-Smith , Nileyma Castro , Jelissa Reynoso-Garcia , Michael E. Zuber , Audrey M. Bernstein

Persistent corneal epithelial defect is a condition in which the corneal epithelium fails to heal properly after injury, resulting in vision loss. Previous studies demonstrate that the deubiquitinase, ubiquitin-specific peptidase 10 (USP10), is a key regulator of wound healing and scarring in the cornea. Here, a highly modified in vivo self-delivering siRNA (sdRNA) targeting USP10 in a mouse model of persistent corneal epithelial defect was used. In this model, the corneal epithelium is scraped from the basement membrane and, although the wound initially closes, the epithelium re-opens at day 28, thereby modeling a persistent corneal defect. These studies revealed that one dose of USP10-targeting sdRNA after wounding prevented re-opening of the wound at day 28. Optical coherence tomography images, hematoxylin and eosin staining, and immunohistochemistry demonstrated improved corneal morphology and normal epithelial stratification of the regrown epithelium, with re-establishment of hemidesmosomes and reduced scarring and inflammation (CD45⁺ cells). Correspondingly, RNA sequencing of the regenerated corneal epithelium revealed that USP10 knockdown altered gene expression and pathways controlling tissue repair. Specifically, cell proliferation pathways were enhanced, whereas extracellular matrix, integrin, and immune cell signatures that lead to scar formation were reduced. The results demonstrate that a one-time application of in vivo sdRNA targeting USP10 is a novel method to prevent epithelial wound re-opening and subsequent scarring and inflammation and may be useful to promote regenerative healing in other tissues.

持续性角膜上皮缺损（PCED）是一种角膜上皮在损伤后不能正常愈合而导致视力丧失的疾病。先前的研究表明，去泛素酶USP10是角膜创面愈合和瘢痕形成的关键调节因子。在PCED小鼠模型中，我们使用了一种高度修饰的靶向USP10的体内自传递siRNA （sdRNA）。在该模型中，从基底膜上刮取角膜上皮，虽然伤口最初闭合，但上皮在第28天重新打开，从而形成了持续性角膜缺损。我们的研究显示，在受伤后1剂量usp10靶向sdRNA可防止伤口在第28天重新开放。光学相干断层扫描（OCT）图像、H&E染色和免疫组织化学显示，角膜形态改善，再生上皮上皮分层正常，半脂粒重建，瘢痕和炎症（CD45+细胞）减少。相应地，再生角膜上皮的RNA-Seq显示，USP10敲低改变了控制组织修复的基因表达和途径。具体来说，细胞增殖途径增强，而导致疤痕形成的细胞外基质、整合素和免疫细胞特征减少。我们的研究结果表明，一次性应用体内靶向USP10的sdRNA是一种防止上皮伤口重新开放和随后的疤痕和炎症的新方法，可能有助于促进其他组织的再生愈合。

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引用次数: 0

Microglia Promote Neurodegeneration and Hyperkatifeia during Withdrawal and Abstinence from Binge Alcohol 小胶质细胞促进神经变性和酗酒戒断期间过度兴奋。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-11-01 DOI: 10.1016/j.ajpath.2025.10.005

Elizabeth M. McNair , Lamar W. Dawkins , Baylee Materia , Grace Ross , Alexandra Barnett , Puja Nakkala , Liya Qin , Jian Zou , Viktoriya Nikolova , Sheryl Moy , Leon G. Coleman Jr.

Proinflammatory microglial polarization, neuronal death, and hyperkatifeia/negative affect during withdrawal are key features of alcohol use disorder (AUD). However, the role microglia play in the development of AUD-related neuronal and behavioral pathology is unclear. Given the ability of microglia to impact neuronal function, it was hypothesized that proinflammatory microglia promote neuronal death and hyperkatifeia during prolonged abstinence from binge alcohol. Proinflammatory signaling and affective state were assessed in mice either during acute withdrawal (24 hours) or abstinence (>4 weeks) to binge alcohol exposure. Ten days of binge alcohol increased proinflammatory gene signaling 24 hours after ethanol, which lasted weeks into withdrawal. Alcohol reduced brain-derived neurotrophic factor in hyperkatifeia-associated regions (ie, the central amygdala and infralimbic cortex) during acute withdrawal and caused persistent microglial structural changes and loss of microglial brain-derived neurotrophic factor in the bed nucleus of the stria terminalis during abstinence. This was associated with increased anxiety-like behavior and hyperarousal, with persistent enhancement of conditioned fear memory during abstinence. Inhibition of proinflammatory microglia with Gi designer receptors exclusively activated by designer drugs blocked neuronal death and prevented persistent proinflammatory gene induction and hyperkatifeia in female mice. Thus, this identifies a direct role for microglia in the development of AUD-related neuropathology and behavioral dysfunction, implicating microglia as cellular targets for the prevention of AUD phenotypes.

促炎小胶质细胞极化、神经元死亡和戒断期间的过度兴奋/负面影响是酒精使用障碍（AUD）的主要特征。然而，小胶质细胞在aud相关神经元和行为病理发展中的作用尚不清楚。考虑到小胶质细胞影响神经元功能的能力，我们假设促炎小胶质细胞在长期戒酒期间促进神经元死亡和过度饮酒。在小鼠急性戒断（24小时）或戒断（4周）期间，对狂饮酒精暴露的促炎信号和情感状态进行评估。10天的狂饮会在EtOH后24小时增加促炎基因信号，持续数周直至停药。在急性戒断期间，酒精降低了高katifeia相关区域（即中央杏仁核和边缘下皮层）的脑源性神经营养因子（BDNF），并导致戒断期间BNST中持续的小胶质结构改变和小胶质BDNF的丧失。这与增加的焦虑样行为和过度觉醒有关，在禁欲期间持续增强条件性恐惧记忆。用设计药物（DREADDs）激活的Gi设计受体抑制雌性小鼠的促炎小胶质细胞，可阻断神经元死亡，防止持续的促炎基因诱导和过度兴奋。因此，这确定了小胶质细胞在AUD相关神经病理学和行为功能障碍发展中的直接作用，暗示小胶质细胞是预防AUD表型的细胞靶点。

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引用次数: 0

Liver Macrophage Changes during Early Adaptation to Alcohol Exposure 肝巨噬细胞在酒精暴露的早期适应过程中的变化。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-10-31 DOI: 10.1016/j.ajpath.2025.10.004

Kyle Yuquimpo , Janice Averilla , Zhuan Li , Priyanka Ghosh , Sheetalnath Rooge , Isabel A. Pulido Ruiz , Winston Dunn , Sumedha Gunewardena , Ann L. Wozniak , Irina Tikhanovich , Steven A. Weinman

Liver macrophages consist of both Kupffer cells (KCs) and infiltrating macrophages (IMs), and both populations change during alcohol-associated liver disease. It has been suggested that KCs undergo a proinflammatory change after alcohol exposure, but the extent to which a proinflammatory shift results from IM rather than KC activation is unclear. The purpose of this study was to examine the early effects of alcohol exposure on KCs and IMs in a murine model and compare these effects with observations in human liver. Mice were fed the Lieber-Decarli ethanol diet, and total liver macrophage and KC-specific phenotypes were examined by flow cytometry, ex vivo cell culture, and KC single-cell RNA sequencing. Liver tissues from autopsy and transplant patients with different alcohol phenotypes were assessed. Early alcohol exposure caused a shift in the properties of total liver macrophages, with an initial proinflammatory effect that partially resolved by 10 days. KCs became steadily less inflammatory over the first 10 days of alcohol exposure. Alcohol exposure in the absence of liver disease also shifted macrophage phenotypes in human livers. These results show that early alcohol exposure is sufficient to cause KC adaptation in a way that maintains liver homeostasis and limits inflammation. Understanding the mechanisms of these changes and how to sustain them may help prevent the development of long-term liver injury.

肝巨噬细胞包括库普弗细胞（KCs）和浸润性巨噬细胞（IM），两者在酒精相关性肝病期间发生变化。有人认为，酒精暴露后KCs会发生促炎变化，但促炎变化在多大程度上是由IMs而不是KC激活引起的尚不清楚。本研究的目的是在小鼠模型中检查酒精暴露对KCs和IMs的早期影响，并将这些影响与人类肝脏中的观察结果进行比较。小鼠分别饲喂Lieber-Decarli乙醇饲料和总肝巨噬细胞，通过流式细胞术、离体细胞培养和KC单细胞RNAseq检测KC特异性表型。对不同酒精表型的尸检和移植患者的肝组织进行了评估。早期酒精暴露导致总肝巨噬细胞性质的改变，具有最初的促炎作用，10天后部分消退。在酒精暴露的前10天，KCs的炎症性逐渐减弱。在没有肝脏疾病的情况下，酒精暴露也会改变人类肝脏中的巨噬细胞表型。这些结果表明，早期酒精暴露足以以维持肝脏稳态和限制炎症的方式引起KC适应。了解这些变化的机制以及如何维持它们可能有助于预防长期肝损伤的发展。

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引用次数: 0

A Century of Progress Toward Gut Barrier Targeting Therapies in Inflammatory Diseases 炎症性疾病肠道屏障靶向治疗的一个世纪进展

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-10-24 DOI: 10.1016/j.ajpath.2025.04.021

Manuel B. Braga-Neto , Andrei I. Ivanov

引用次数: 0

Advancing Breast Cancer Management Through an Enhanced Understanding of Disease Heterogeneity from Initiation to Metastasis 通过加深对从发病到转移的疾病异质性的了解来推进乳腺癌的管理

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-10-24 DOI: 10.1016/j.ajpath.2025.08.003

Dennis Jones

引用次数: 0

Novel Insights into Neurodegenerative Diseases 神经退行性疾病的新见解

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-10-24 DOI: 10.1016/j.ajpath.2025.09.002

Steven L. Carroll, Jody Fromm Longo

引用次数: 0

Prostaglandin E2 Signaling Triggers CD31-Independent Transendothelial Migration in Vitro and in Vivo PGE2信号在体外和体内触发cd31不依赖的跨内皮迁移。

IF 3.6 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-10-17 DOI: 10.1016/j.ajpath.2025.09.012

Vanessa Hayashi , Michael A. Seidman , William A. Muller

Genetic deletion or antibody blockade of platelet endothelial cell adhesion molecule-1 (PECAM; CD31) inhibits transendothelial migration (TEM) of leukocytes in all mouse strains studied except C57BL/6. A prior publication showed that this phenotype maps to a single 35.8-Mb locus on mouse chromosome 2, that contains the genes Ptgs1, Ptges, and Ptges2, which encode key enzymes involved in the prostaglandin E₂ (PGE₂) synthesis pathway. PGE₂ is a proinflammatory lipid mediator that binds four E prostanoid receptors (EPs 1 to 4). It was hypothesized that PGE₂ signaling supports TEM via a CD31-independent mechanism. In vitro TEM assays demonstrate that PGE₂ or 16,16-dimethyl PGE₂ can restore transmigration of polymorphonuclear leukocytes and peripheral blood mononuclear cells despite a TEM blockade with anti-CD31. This protransmigratory effect could be blocked with the EP1 antagonist, SC-51089, or with transient receptor potential canonical 6 antagonist, BI-749327. 17-Phenyl trinor PGE₂, an agonist of EP1 and EP3, also restored transmigration of polymorphonuclear leukocytes blocked with anti-CD31. In vivo, PGE₂ overcame an anti-CD31 blockade when administered to FVB/n mice in thioglycolate peritonitis or croton oil dermatitis models, whereas blocking EP1 with SC-51089 decreased TEM in C57BL/6 pecam1^−/− mice. The findings support earlier data that identified PGE₂ as a candidate inducer of CD31-independent TEM, and pinpoint EP1 as the receptor that relays that signal to activate transient receptor potential canonical 6.

基因缺失或抗体阻断血小板内皮细胞粘附分子-1 （CD31， PECAM）可抑制除C57BL/6外所有小鼠品系白细胞的跨内皮迁移（TEM）。先前的一项研究表明，这种表型映射到小鼠2号染色体上一个35.8 Mb的位点，该位点包含基因Ptgs1， Ptges和Ptges2，这些基因编码参与前列腺素E2 （PGE2）合成途径的关键酶。PGE2是一种促炎脂质介质，可结合四种E前列腺素受体（EP1-4）。假设PGE2信号通过不依赖cd31的机制支持TEM。体外透射电镜分析表明，PGE2或16,16-二甲基PGE2可以恢复多形核白细胞（PMNs）和外周血单核细胞（PBMCs）的转运，尽管有抗cd31的透射电镜阻断。EP1拮抗剂SC-51089或瞬时受体电位规范6 （TRPC6）拮抗剂BI-749327可阻断这种促迁移作用。17-苯基三甲基PGE2是EP1和EP3的激动剂，也能恢复被抗cd31阻断的PMNs的转运。体内实验结果显示，巯基乙酸腹膜炎或巴豆油皮炎模型的FVB/n小鼠中，PGE2克服了抗cd31阻滞，而用SC-51089阻断EP1可降低C57BL/6 pecam1-/-小鼠的TEM。这些发现支持了先前的数据，即PGE2是cd31非依赖性TEM的候选诱导剂，并确定EP1是传递该信号以激活TRPC6的受体。

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引用次数: 0