American Journal of Pathology最新文献_第10页

Blocking IL-17a Signaling Decreases Lung Inflammation and Improves Alveolarization in Experimental Bronchopulmonary Dysplasia 阻断 IL-17a 信号传导可减轻实验性支气管肺发育不良的肺部炎症并改善肺泡化。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-08-06 DOI: 10.1016/j.ajpath.2024.07.011

Meagan Goates , Amrit Shrestha , Shyam Thapa , Matthew Bettini , Roberto Barrios , Binoy Shivanna

{"title":"Blocking IL-17a Signaling Decreases Lung Inflammation and Improves Alveolarization in Experimental Bronchopulmonary Dysplasia","authors":"Meagan Goates , Amrit Shrestha , Shyam Thapa , Matthew Bettini , Roberto Barrios , Binoy Shivanna","doi":"10.1016/j.ajpath.2024.07.011","DOIUrl":"10.1016/j.ajpath.2024.07.011","url":null,"abstract":"<div><div>Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease of preterm infants that is associated with life-long morbidities. Inflammatory insults contribute to BPD pathogenesis. Although the proinflammatory cytokine, IL-17a, plays a role in various neonatal inflammatory disorders, its role in BPD pathogenesis is unclear. To test the hypothesis that blocking IL-17a signaling decreases lipopolysaccharide (LPS)–mediated experimental BPD in neonatal mice, wild-type mice were injected intraperitoneally with phosphate-buffered saline or LPS during the saccular lung developmental phase. Pulmonary IL-17a expression was determined by enzyme-linked immunosorbent assay and by flow cytometry. LPS-injected mice had higher pulmonary IL-17a protein levels and IL-17a<sup>+</sup> and IL-22<sup>+</sup> cells. γδ T cells, followed by non–T lymphoid cells, were the primary producers of IL-17a. Wild-type mice were then injected intraperitoneally with isotype antibody (Ab) or IL-17a Ab, while they were treated with phosphate-buffered saline or LPS, followed by quantification of lung inflammatory markers, alveolarization, vascularization, cell proliferation, and apoptosis. LPS-mediated alveolar simplification, apoptosis, and cell proliferation inhibition were significantly greater in mice treated with isotype Ab than in those treated with IL-17a Ab. Furthermore, STAT1 activation and IL-6 levels were significantly greater in LPS-exposed mice treated with isotype Ab than in those treated with IL-17a Ab. The study results indicate that blocking IL-17a signaling decreases LPS-mediated experimental BPD.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 11","pages":"Pages 2023-2035"},"PeriodicalIF":4.7,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141905602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cancer-Associated Fibroblasts in Intrahepatic Cholangiocarcinoma: Insights into Origins, Heterogeneity, Lymphangiogenesis, and Peritoneal Metastasis. 肝内胆管癌中的癌相关成纤维细胞：对起源、异质性、淋巴管生成和腹膜转移的见解

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-08-06 DOI: 10.1016/j.ajpath.2024.07.009

Silvia Affὸ, Laura Sererols-Viñas, Gemma Garcia-Vicién, Massimiliano Cadamuro, Sanjukta Chakraborty, Alphonse E Sirica

{"title":"Cancer-Associated Fibroblasts in Intrahepatic Cholangiocarcinoma: Insights into Origins, Heterogeneity, Lymphangiogenesis, and Peritoneal Metastasis.","authors":"Silvia Affὸ, Laura Sererols-Viñas, Gemma Garcia-Vicién, Massimiliano Cadamuro, Sanjukta Chakraborty, Alphonse E Sirica","doi":"10.1016/j.ajpath.2024.07.009","DOIUrl":"10.1016/j.ajpath.2024.07.009","url":null,"abstract":"<p><p>Intrahepatic cholangiocarcinoma (iCCA) denotes a rare, highly malignant, and heterogeneous class of primary liver adenocarcinomas exhibiting phenotypic characteristics of cholangiocyte differentiation. Among the distinctive pathological features of iCCA, one that differentiates the most common macroscopic subtype (eg, mass-forming type) of this hepatic tumor from conventional hepatocellular carcinoma, is a prominent desmoplastic reaction manifested as a dense fibro-collagenous-enriched tumor stroma. Cancer-associated fibroblasts (CAFs) represent the most abundant mesenchymal cell type in the desmoplastic reaction. Although the protumor effects of CAFs in iCCA have been increasingly recognized, more recent cell lineage tracing studies, advanced single-cell RNA sequencing, and expanded biomarker analyses have provided new awareness into their ontogeny, as well as underscored their biological complexity as reflected by the presence of multiple subtypes. In addition, evidence has been described to support CAFs' potential to display cancer-restrictive roles, including immunosuppression. However, CAFs also play important roles in facilitating metastasis, as exemplified by lymph node metastasis and peritoneal carcinomatosis, which are common in iCCA. Herein, the authors provide a timely appraisal of the origins and phenotypic and functional complexity of CAFs in iCCA, together with providing mechanistic insights into lymphangiogenesis and peritoneal metastasis relevant to this lethal human cancer.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141905604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

IL-2 Complexed With Anti–IL-2 Antibody Expands the Maternal T-Regulatory Cell Pool and Alleviates Fetal Loss in Abortion-Prone Mice IL-2/JES6-1抗体复合物能扩大母体T调节细胞库，减轻易流产小鼠的胎儿损失。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-08-06 DOI: 10.1016/j.ajpath.2024.07.012

Kerrie L. Foyle , Peck Y. Chin , Carsten Merkwirth , Jasmine Wilson , Shanna L. Hosking , Ella S. Green , Mei Y. Chong , Bihong Zhang , Lachlan M. Moldenhauer , Greg D. Ferguson , Gerald P. Morris , James G. Karras , Alison S. Care , Sarah A. Robertson

{"title":"IL-2 Complexed With Anti–IL-2 Antibody Expands the Maternal T-Regulatory Cell Pool and Alleviates Fetal Loss in Abortion-Prone Mice","authors":"Kerrie L. Foyle , Peck Y. Chin , Carsten Merkwirth , Jasmine Wilson , Shanna L. Hosking , Ella S. Green , Mei Y. Chong , Bihong Zhang , Lachlan M. Moldenhauer , Greg D. Ferguson , Gerald P. Morris , James G. Karras , Alison S. Care , Sarah A. Robertson","doi":"10.1016/j.ajpath.2024.07.012","DOIUrl":"10.1016/j.ajpath.2024.07.012","url":null,"abstract":"<div><div>Regulatory T (Treg) cells are essential for immune tolerance of embryo implantation, and insufficient Treg cells provokes early pregnancy loss. An abortion-prone mouse model was used to evaluate IL-2 complexed with JES6-1 anti–IL-2 antibody (IL-2/JES6-1) to boost uterine Treg cells and improve reproductive success. IL-2/JES6-1, but not IL-2/IgG, administered in periconception to CBA/J females mated with DBA/2 males elicited a greater than twofold increase in the proportion of CD4<sup>+</sup> T cells expressing forkhead box P3 (FOXP3), and an increased ratio of FOXP3<sup>+</sup> Treg cells/FOXP3<sup>–</sup> T conventional cells in the uterus and its draining lymph nodes at embryo implantation that was sustained into midgestation. An attenuated phenotype was evident in both thymic-derived and peripheral Treg cells with elevated cytotoxic T-lymphocyte antigen-4, CD25, and FOXP3 indicating improved suppressive function, as well as increased proliferative marker Ki-67. IL-2/JES6-1 treatment reduced fetal loss from 31% to 10%, accompanied by a 6% reduction in late gestation fetal weight, despite comparable placental size and architecture. Similar effects of IL-2/JES6-1 on Treg cells and fetal growth were seen in CBA/J females with healthy pregnancies sired by BALB/c males. These findings show that expanding the uterine Treg cell pool through targeting IL-2 signaling is a strategy worthy of further investigation for mitigating risk of immune-mediated fetal loss.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 11","pages":"Pages 2128-2149"},"PeriodicalIF":4.7,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141905605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cell Death and Survival Mechanisms in Cholangiocarcinogenesis. 胆管癌发生过程中的细胞死亡和存活机制

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-08-03 DOI: 10.1016/j.ajpath.2024.06.014

Luana D'Artista, Marco Seehawer

引用次数: 0

Small Nuclear Ribonucleoprotein Polypeptides B and B1 Promote Osteosarcoma Progression via Activating the Ataxia-Telangiectasia Mutated Signaling Pathway through Ribonucleotide Reductase Subunit M2 SNRPB 通过 RRM2 激活 ATM 信号通路，促进骨肉瘤的发展。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-08-03 DOI: 10.1016/j.ajpath.2024.06.015

Yongxiang Shi , Zhan Wang , Jiahao Zhang , Peiwen He , Minglei Yang , Chenglong Zhao , Bo Li , Ming Qian

{"title":"Small Nuclear Ribonucleoprotein Polypeptides B and B1 Promote Osteosarcoma Progression via Activating the Ataxia-Telangiectasia Mutated Signaling Pathway through Ribonucleotide Reductase Subunit M2","authors":"Yongxiang Shi , Zhan Wang , Jiahao Zhang , Peiwen He , Minglei Yang , Chenglong Zhao , Bo Li , Ming Qian","doi":"10.1016/j.ajpath.2024.06.015","DOIUrl":"10.1016/j.ajpath.2024.06.015","url":null,"abstract":"<div><div>Osteosarcoma is a malignant bone tumor characterized by high metastatic potential and recurrence rates after therapy. The small nuclear ribonucleoprotein polypeptides B and B1 (SNRPB), core components of a spliceosome, exhibit up-regulation across several cancer types. However, the precise role of SNRPB in osteosarcoma progression remains poorly elucidated. Herein, SNRPB expression was explored in human osteosarcoma tissues and normal bone tissues by immunohistochemical staining, revealing a notable up-regulation of SNRPB in osteosarcoma, correlating with diminished survival rates. The <em>in vitro</em> loss-of-function experiments showed that SNRPB knockdown significantly suppressed the osteosarcoma cell proliferation and migration, as well as tubule formation of human umbilical vascular endothelial cells, while enhancing osteosarcoma cell apoptosis. Mechanistically, SNRPB promoted the transcription of ribonucleotide reductase subunit M2 via E2F transcription factor 1. Further rescue experiments indicated that ribonucleotide reductase subunit M2 was required for SNRPB-induced malignant behaviors in osteosarcoma. Additionally, the function of SNRPB in osteosarcoma cell growth and apoptosis was confirmed to be associated with ataxia-telangiectasia mutated (ATM) signaling pathway activation. In conclusion, these findings provide initial insights into the underlying mechanisms governing SNRPB-induced osteosarcoma progression, and we propose SNRPB as a novel therapeutic target in osteosarcoma management.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 11","pages":"Pages 2163-2178"},"PeriodicalIF":4.7,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Search for Risk, Diagnostic, and Prognostic Biomarkers of Cholangiocarcinoma and Their Biological and Clinicopathologic Significance. 寻找胆管癌的风险、诊断和预后生物标志物及其生物学和临床病理学意义。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-08-03 DOI: 10.1016/j.ajpath.2024.06.013

Rocio I R Macias, Hiroaki Kanzaki, Carmen Berasain, Matias A Avila, Jose J G Marin, Yujin Hoshida

{"title":"The Search for Risk, Diagnostic, and Prognostic Biomarkers of Cholangiocarcinoma and Their Biological and Clinicopathologic Significance.","authors":"Rocio I R Macias, Hiroaki Kanzaki, Carmen Berasain, Matias A Avila, Jose J G Marin, Yujin Hoshida","doi":"10.1016/j.ajpath.2024.06.013","DOIUrl":"10.1016/j.ajpath.2024.06.013","url":null,"abstract":"<p><p>Cholangiocarcinomas (CCAs) are a heterogeneous group of malignant tumors that originate from the biliary tract. They are usually diagnosed in advanced stages, leading to a dismal prognosis for affected patients. As CCA often arises as a sporadic cancer in individuals lacking specific risk factors or with heterogeneous backgrounds, and there are no defined high-risk groups, the implementation of effective surveillance programs for CCA is problematic. The identification and validation of new biomarkers useful for risk stratification, diagnosis, prognosis, and prediction of treatment response remains an unmet need for patients with CCA, even though numerous studies have been conducted lately to try to discover and validate CCA biomarkers. In this review, we overview the available information about the different types of biomarkers that have been investigated in recent years using minimally invasive biospecimens (blood, serum/plasma, bile, and urine) and their potential usefulness in diagnosis, prognosis, and risk stratification. It is widely accepted that early detection of CCA will impact patients' outcomes, by improving survival rates, quality of life, and the possibility of less invasive and/or curative treatments; however, challenges to its translation and clinical application for patients with CCA need to be resolved.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Finding Your CAR 寻找你的 CAR：工程 T 细胞的未来之路。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-08-01 DOI: 10.1016/j.ajpath.2024.04.002

{"title":"Finding Your CAR","authors":"","doi":"10.1016/j.ajpath.2024.04.002","DOIUrl":"10.1016/j.ajpath.2024.04.002","url":null,"abstract":"<div><p>Adoptive cellular therapy using chimeric antigen receptors (CARs) has transformed immunotherapy by engineering T cells to target specific antigens on tumor cells. As the field continues to advance, pathology laboratories will play increasingly essential roles in the complicated multi-step process of CAR T-cell therapy. These include detection of targetable tumor antigens by flow cytometry or immunohistochemistry at the time of disease diagnosis and the isolation and infusion of CAR T cells. Additional roles include: i) detecting antigen loss or heterogeneity that renders resistance to CAR T cells as well as identifying alternative targetable antigens on tumor cells, ii) monitoring the phenotype, persistence, and tumor infiltration properties of CAR T cells and the tumor microenvironment for factors that predict CAR T-cell therapy success, and iii) evaluating side effects and biomarkers of CAR T-cell cytotoxicity such as cytokine release syndrome. This review highlights existing technologies that are applicable to monitoring CAR T-cell persistence, target antigen identification, and loss. Also discussed are emerging technologies that address new challenges such as how to put a brake on CAR T cells. Although pathology laboratories have already provided companion diagnostic tests important in immunotherapy (eg, programmed death-ligand 1, microsatellite instability, and human epidermal growth factor receptor 2 testing), it draws attention to the exciting new translational research opportunities in adoptive cellular therapy.</p></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 8","pages":"Pages 1409-1423"},"PeriodicalIF":4.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11284763/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140848923","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

Aging-Associated Metabolite Methylmalonic Acid Increases Susceptibility to Pulmonary Fibrosis 与衰老相关的代谢物甲基丙二酸增加肺纤维化的易感性

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-08-01 DOI: 10.1016/j.ajpath.2024.04.011

{"title":"Aging-Associated Metabolite Methylmalonic Acid Increases Susceptibility to Pulmonary Fibrosis","authors":"","doi":"10.1016/j.ajpath.2024.04.011","DOIUrl":"10.1016/j.ajpath.2024.04.011","url":null,"abstract":"<div><p>Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by pulmonary fibroblast overactivation, resulting in the accumulation of abnormal extracellular matrix and lung parenchymal damage. Although the pathogenesis of IPF remains unclear, aging was proposed as the most prominent nongenetic risk factor. Propionate metabolism undergoes reprogramming in the aging population, leading to the accumulation of the by-product methylmalonic acid (MMA). This study aimed to explore alterations in propionate metabolism in IPF and the impact of the by-product MMA on pulmonary fibrosis. It revealed alterations in the expression of enzymes involved in propionate metabolism within IPF lung tissues, characterized by an increase in propionyl-CoA carboxylase and methylmalonyl-CoA epimerase expression, and a decrease in methylmalonyl-CoA mutase expression. Knockdown of methylmalonyl-CoA mutase, the key enzyme in propionate metabolism, induced a profibrotic phenotype and activated co-cultured fibroblasts in A549 cells. MMA exacerbated bleomycin-induced mouse lung fibrosis and induced a profibrotic phenotype in both epithelial cells and fibroblasts through activation of the canonical transforming growth factor-β/Smad pathway. Overall, these findings unveil an alteration of propionate metabolism in IPF, leading to MMA accumulation, thus exacerbating lung fibrosis through promoting profibrotic phenotypic transitions via the canonical transforming growth factor-β/Smad signaling pathway.</p></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 8","pages":"Pages 1478-1493"},"PeriodicalIF":4.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141287604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dysregulation of the Long Noncoding RNA X-Inactive–Specific Transcript Expression in Male Patients with Pulmonary Arterial Hypertension 男性肺动脉高压患者体内长非编码 RNA Xist 的表达失调

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-08-01 DOI: 10.1016/j.ajpath.2024.04.005

{"title":"Dysregulation of the Long Noncoding RNA X-Inactive–Specific Transcript Expression in Male Patients with Pulmonary Arterial Hypertension","authors":"","doi":"10.1016/j.ajpath.2024.04.005","DOIUrl":"10.1016/j.ajpath.2024.04.005","url":null,"abstract":"<div><p>Pulmonary arterial hypertension (PAH) is a sex-biased disease with female sex as a significant risk factor. Increased expression of the long noncoding RNA X-inactive–specific transcript (Xist), as induced by an intersectin-1s protein fragment with proliferative potential (EH<sub>ITSN</sub>), may explain the sexual dimorphism of female pulmonary artery endothelial cells (ECs) and at least in part, the imbalance sex/ratio of PAH. Xist is essential for X-chromosome inactivation and dosage compensation of X-linked genes. Herein, increased Xist expression was detected in a subset of ECs and lung tissue samples of male patients with PAH. The role of different Xist expression levels in ECs of male patients with PAH (EC<sub>PAH</sub>) was studied in several lines of male EC<sub>PAH</sub> in conjunction with molecular, biochemical, morphologic, and functional approaches. Male EC<sub>PAH</sub> showed on average 10.3-fold increase in high Xist versus low Xist, a significant association between Xist levels and their proliferative potential, and a heterogeneous methylation of the Xist/XIST antisense RNA (Tsix) locus. Interestingly, Xist up-regulation in male EC<sub>PAH</sub> decreased the expression of Krueppel-like factor 2 (Klf2), via EH<sub>ITSN</sub> interaction with enhancer of zeste polycomb repressive complex 2 subunit (EZH2), the catalytic subunit of the polycomb repressive complex 2. Moreover, the studies demonstrate that EH<sub>ITSN</sub>-triggered p38/ETS domain-containing protein Elk1/AP-1 transcription factor subunit (c-Fos) signaling is a pathologic mechanism central to EC<sub>PAH</sub> proliferation and the dynamic crosstalk with cell cycle regulatory proteins cyclin A1/cyclin D2 and Xist-EZH2-Klf2 interaction participate directly and differentially in establishing the proliferative profile of male EC<sub>PAH</sub>.</p></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 8","pages":"Pages 1592-1606"},"PeriodicalIF":4.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11284765/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140846738","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

Collagen 17A1 in the Urothelium Regulates Epithelial Cell Integrity and Local Immunologic Responses in Obstructive Uropathy 尿路上皮细胞中的胶原蛋白 17A1 可调节梗阻性尿病上皮细胞的完整性和局部免疫反应。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-08-01 DOI: 10.1016/j.ajpath.2024.04.009

{"title":"Collagen 17A1 in the Urothelium Regulates Epithelial Cell Integrity and Local Immunologic Responses in Obstructive Uropathy","authors":"","doi":"10.1016/j.ajpath.2024.04.009","DOIUrl":"10.1016/j.ajpath.2024.04.009","url":null,"abstract":"<div><p>Collagen 17A1 (COL17A1), an epidermal hemidesmosome component, is ectopically induced in the urothelium of mouse and human renal pelvis (RP) in parallel with urinary tract–associated lymphoid structure development. Here, COL17A1 was induced in obstructive uropathy–prone ureter of humans and cats. To ascertain its function, murine urinary organs with unilateral ureteral obstruction (UUO) were analyzed during 1 week after surgery. One day after UUO, COL17A1 expression increased in urothelial cells of RP and ureter, and was positively correlated with renal tubulointerstitial lesions. A portion of RP where the smooth muscle layer from the ureter was interrupted was sensitive to urothelium deciduation and COL17A1 induction, showing urine leaked from the RP lumen into the parenchyma. After urine stimulation, cultured immune cells expressed <em>Cxcl2</em>, also up-regulated in CD11b<sup>+</sup> cells following COL17A1 stimulation. One day after UUO, CXCL2<sup>+</sup> CD11b<sup>+</sup> cells infiltrated the urothelium-disrupted area. However, these numbers were significantly lower in <em>Col17a1</em>-deficient mice. COL17A1<sup>+</sup> urothelial cells partially co-expressed cytokeratin-14, a progenitor cell marker for urothelium, whereas <em>Col17a1</em>-deficient mice had lower numbers of cytokeratin-14<sup>+</sup> cells. Gene Ontology analysis revealed that expression of epithelial- and immune-associated genes was up-regulated and down-regulated, respectively, in the ureter of <em>Col17a1</em>-deficient mice 4 days after UUO. Thus, COL17A1 maintains urothelium integrity by regulating urothelial cell adhesion, proliferation, and differentiation, and activates local immune responses during obstructive uropathy in mammals.</p></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"194 8","pages":"Pages 1550-1570"},"PeriodicalIF":4.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141070125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0