American Journal of Pathology最新文献

{"title":"Tmco1-Deficient Mice Exhibit a High Incidence of Otitis Media Associated with Impaired Bone Homeostasis in the Middle Ear","authors":"Yaning Dong ,&nbsp;Peng Ma ,&nbsp;Shuli Wang ,&nbsp;Lan Wang ,&nbsp;Yingying Chen ,&nbsp;Fangfang Zhao ,&nbsp;Keyan Yang ,&nbsp;Xiaolin Zhang ,&nbsp;Hongchun Zhao ,&nbsp;Bo Li ,&nbsp;Ruishuang Geng ,&nbsp;Tie-shan Tang ,&nbsp;Qingyin Zheng ,&nbsp;Tihua Zheng","doi":"10.1016/j.ajpath.2024.11.008","DOIUrl":"10.1016/j.ajpath.2024.11.008","url":null,"abstract":"<div><div>Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome (CFSMR1; Online Inheritance in Man number <span><span>213980</span><svg><path></path></svg></span>) is characterized by craniofacial dysmorphism, skeletal anomalies, and mental retardation. However, reports of hearing issues have been limited. To investigate hearing-related aspects of CFSMR1, <em>Tmco1</em> knockout mice (<em>Tmco1</em>^{<em>−/−</em>}) exhibiting similar symptoms to human patients were used in this study. Otitis media (OM) was discovered in approximately 80% of <em>Tmco1</em>^{<em>−/−</em>} mice, which led to moderate conductive hearing loss at 3 months old and further progressed to deafness 2 months later. Pathology studies of <em>Tmco1</em>^{<em>−/−</em>} mice revealed a thickened middle ear (ME) epithelium and pronounced inflammatory infiltrates in the ME cavity and Eustachian tube of <em>Tmco1</em>^{<em>−/−</em>} OM mice. Micro–computed tomography scan of 5-month–old <em>Tmco1</em>^{<em>−/−</em>} OM mice showed significantly reduced ME volume and ME malformation. Tartrate-resistant acid phosphatase and Runt-related transcription factor 2, receptor activator of NF-κB ligand expression in ME revealed increased osteoclast activity and significantly decreased bone formation, suggesting potential causes of ME malformation. This study represents the first report of the audiological characteristics and the elucidation of potential mechanisms in <em>Tmco1</em>^{<em>−/−</em>} mice. It enriches our understanding of the phenotypes associated with CFSMR1 in the field of otology and provides a promising model for chronic OM with conductive hearing loss.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 4","pages":"Pages 690-704"},"PeriodicalIF":4.7,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891640","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}

{"title":"IL-35 May Prevent the Exacerbation of Aspiration Pneumonia Involving Porphyromonas gingivalis by Suppressing IL-17 Production","authors":"Shotaro Kawamura ,&nbsp;Hisashi Goto ,&nbsp;Takeshi Kikuchi ,&nbsp;Teppei Okabe ,&nbsp;Yoshiaki Hasegawa ,&nbsp;Yoshihiko Sugita ,&nbsp;Hirotaka Fujitsuka ,&nbsp;Ryosuke Kataoka ,&nbsp;Koudai Katsumata ,&nbsp;Ryoma Goto ,&nbsp;Yuiko Suzuki ,&nbsp;Jun-ichiro Hayashi ,&nbsp;Masayuki Umemura ,&nbsp;Akio Mitani","doi":"10.1016/j.ajpath.2024.11.009","DOIUrl":"10.1016/j.ajpath.2024.11.009","url":null,"abstract":"<div><div>Periodontitis is associated with aspiration pneumonia. However, the relationship between periodontitis and aspiration pneumonia remains unclear. This study investigated the virulence factor of <em>Porphyromonas gingivalis</em>, which exacerbates aspiration pneumonia, and the role of IL-35, an inhibitory heterodimeric cytokine of Epstein-Barr virus-induced gene 3 (EBI3) and p35, in aspiration pneumonia using <em>Ebi3</em> knockout (KO) mice. Aspiration pneumonia was induced by the intratracheal injection of <em>Streptococcus pneumoniae</em> and <em>P. gingivalis</em> culture supernatant (mixed infection). Leupeptin was used to inhibit gingipain, a virulence factor of <em>P. gingivalis</em>. Four days after infection, lung tissues were collected for analyses. The percentage of interstitium in the group with mixed infection and leupeptin treatment was significantly reduced compared with the nonleupeptin administration group. Additionally, the percentage of interstitium in the field of <em>Ebi3</em> KO mice was significantly increased compared with wild-type (WT) mice in mixed infection. IL-35 production in WT mice with mixed infection was significantly increased compared with the control group. IL-17 production in <em>Ebi3</em> KO mice was significantly increased compared with WT mice with mixed infection. These findings suggest that gingipain exacerbates aspiration pneumonia and that IL-35 may contribute to suppressing the exacerbation of aspiration pneumonia.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 4","pages":"Pages 652-662"},"PeriodicalIF":4.7,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891616","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}

{"title":"P46Shc Inhibits Mitochondrial ACAA2 Thiolase, Exacerbating Mitochondrial Injury and Inflammation in Aging Livers","authors":"Yuan Li ,&nbsp;Weiguo Fan ,&nbsp;Tzu-Han Lo ,&nbsp;Joy X. Jiang ,&nbsp;Sarah R. Fish ,&nbsp;Alexey Tomilov ,&nbsp;Antonios Chronopoulos ,&nbsp;Vidushi Bansal ,&nbsp;Gergely Mozes ,&nbsp;Lorand Vancza ,&nbsp;Koshi Kunimoto ,&nbsp;Jiayu Ye ,&nbsp;Laren Becker ,&nbsp;Suvarthi Das ,&nbsp;Hyesuk Park ,&nbsp;Yi Wei ,&nbsp;Sara Ranjbarvaziri ,&nbsp;Daniel Bernstein ,&nbsp;Jon Ramsey ,&nbsp;Gino Cortopassi ,&nbsp;Natalie J. Török","doi":"10.1016/j.ajpath.2024.10.022","DOIUrl":"10.1016/j.ajpath.2024.10.022","url":null,"abstract":"<div><div>Mitochondrial maladaptation and dysfunction contribute to the progression of metabolic dysfunction-associated steatohepatitis (MASH). Induction of Shc is implicated in progressive MASH during aging and the cytoplasmic p52Shc isoform in the activation of redox enzyme NOX2. The mitochondrial Shc isoform p46Shc represses acetyl-coenzyme A acyltransferase 2 (ACAA2) <em>in vitro</em>. ACAA2 is a key enzyme for lipid β-oxidation; however, the metabolic consequences of <em>in vivo</em> p46Shc induction are unknown. In the current study, p46Shc-inducible mice were generated; these and littermate controls were aged and fed chow or fast-food (high-fat and high-fructose) diet. p46Shc induction increased liver injury, inflammation, and lipid peroxidation. p46Shc overexpression did not significantly change liver triglycerides. On electron microscopy studies, mitochondria were swollen with aberrant cristae. p46Shc induction reduced mitochondrial oxygen consumption as measured by Oroboros, as well as suppressed the production of β-hydroxybutyrate, the central metabolite of therapeutic ketosis. Mitochondria exhibited increased production of reactive oxidative species. By contrast, the expression of dominant negative p46Shc reduced ACAA2 thiolase activity, improved β-oxidation, and reduced lipid peroxidation and production of reactive oxidative species. In summary, these studies support the concept that p46Shc induction in aging represses ACAA2, resulting in decreased mitochondrial β-oxidation and increased lipid peroxidation. Maintaining β-oxidation and ketogenesis could prevent liver injury, and targeting Shc-related maladaptive responses could be a successful therapeutic strategy in aging/MASH.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 3","pages":"Pages 528-541"},"PeriodicalIF":4.7,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142902597","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}

{"title":"Ablation of Hepatic Asah1 Gene Disrupts Hepatic Lipid Homeostasis and Promotes Fibrotic Nonalcoholic Steatohepatitis in Mice","authors":"Rui Zuo ,&nbsp;Mi Wang ,&nbsp;Yun-Ting Wang ,&nbsp;YangPing ShenTu ,&nbsp;Alexandra K. Moura ,&nbsp;Ying Zhou ,&nbsp;Kiana Roudbari ,&nbsp;Jenny Z. Hu ,&nbsp;Pin-Lan Li ,&nbsp;JiuKuan Hao ,&nbsp;Xiang Li ,&nbsp;Yang Zhang","doi":"10.1016/j.ajpath.2024.11.003","DOIUrl":"10.1016/j.ajpath.2024.11.003","url":null,"abstract":"<div><div>Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of chronic liver conditions, ranging from simple steatosis to nonalcoholic steatohepatitis, which may progress to fibrosis/cirrhosis. Here, the GSE163211 data set was analyzed, and <em>Asah1</em> (encoding acid ceramidase) was identified as a crucial lysosomal gene that positively correlated with NAFLD stages in obese patients. To evaluate the role of <em>Asah1</em> in the progression of NAFLD, <em>Asah1</em>^fl/fl/<em>Alb</em>^cre mice (hepatocyte-specific deletion of <em>Asah1</em>) and <em>Asah1</em> floxed (<em>Asah1</em>^fl/fl/wild-type) mice were fed with either a normal diet or a high-fat, high-cholesterol paigen diet (PD) for 20 weeks. Hepatocyte-specific <em>Asah1</em> ablation markedly aggravated PD-induced hepatic steatosis, hepatitis, and apoptosis, and resulted in marked fibrotic changes. In addition, <em>Asah1</em> gene ablation exacerbated PD-induced portal venous hemodynamic abnormality. In cultured hepatocytes, <em>Asah1</em> gene knockdown resulted in increased ceramide and cholesterol levels but did not affect triglyceride level. Knocking down <em>Asah1</em> gene also exhibited broad impacts on lipid homeostasis pathways, including lipogenesis, fatty acid uptake, fatty acid oxidation, and lipid transport. Furthermore, <em>Asah1</em> knockdown resulted in increased endoplasmic reticulum stress and lipid droplet biogenesis. Finally, <em>Asah1</em> gene knockdown impaired chaperone-mediated autophagy. These results suggest that <em>Asah1</em> functions as an important regulator of hepatic lipid homeostasis, and its deficiency exacerbates hepatocyte lipotoxicity and injury, and promotes the development of fibrotic nonalcoholic steatohepatitis.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 3","pages":"Pages 542-560"},"PeriodicalIF":4.7,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884868","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}

{"title":"Cholangiocarcinoma Targeted Therapies","authors":"Haley Ellis ,&nbsp;Chiara Braconi ,&nbsp;Juan W. Valle ,&nbsp;Nabeel Bardeesy","doi":"10.1016/j.ajpath.2024.11.005","DOIUrl":"10.1016/j.ajpath.2024.11.005","url":null,"abstract":"<div><div>Cholangiocarcinoma is an aggressive bile duct malignancy with heterogeneous genomic features. Although most patients receive standard-of-care chemotherapy/immunotherapy, genomic changes that can be targeted with established or emerging therapeutics are common. Accordingly, precision medicine strategies are transforming the next-line treatment for patient subsets. Hotspot <em>IDH1</em> mutations and activating fibroblast growth factor receptor 2 fusions occur frequently, and small-molecule inhibitors against these alterations are US Food and Drug Administration approved. Translational and basic science studies have elucidated the mechanisms of response and resistance in cholangiocarcinoma, providing insights into these targets that extend to other cancers. Additional US Food and Drug Administration–approved and National Comprehensive Cancer Network guideline-recommended treatments for recurrent genomic changes include BRAF inhibition (<em>BRAF</em>-V600E) and trastumazab deruxtecan (human epidermal growth factor receptor 2 amplification). Furthermore, ongoing clinical trials show promising results with KRAS inhibition (<em>KRAS</em>-codon 12 mutations), PRTM5 inhibition, alone or with methylthioadenosine inhibition (5-methylthioadenosine phosphorylase deletion), and murine double minute 2 inhibition (murine double minute 2 amplification). Despite these advances, the rate, depth, and duration of response to each treatment need improvement. Moreover, many patients do not have currently targetable genotypes. This review examines the clinical efficacy and mechanisms of resistance associated with these treatments, as well as insights into the molecular and biological effects of pathway activation and inhibition, based on study of patient samples and preclinical models. It also explores strategies to overcome resistance and possible precision medicine approaches for additional patient subsets.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 3","pages":"Pages 437-452"},"PeriodicalIF":4.7,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891603","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}

{"title":"Gut Microbiome and Bile Acid Interactions","authors":"Nan Wu ,&nbsp;Sareh Bayatpour ,&nbsp;Phillip B. Hylemon ,&nbsp;Sayed O. Aseem ,&nbsp;Paul J. Brindley ,&nbsp;Huiping Zhou","doi":"10.1016/j.ajpath.2024.11.004","DOIUrl":"10.1016/j.ajpath.2024.11.004","url":null,"abstract":"<div><div>Cholangiocarcinoma (CCA) is a rare but highly malignant carcinoma of bile duct epithelial cells with a poor prognosis. The major risk factors of CCA carcinogenesis and progression are cholestatic liver diseases. The key feature of primary sclerosing cholangitis and primary biliary cholangitis is chronic cholestasis. It indicates a slowdown of hepatocyte secretion of biliary lipids and metabolites into bile as well as a slowdown of enterohepatic circulation (bile acid recirculation) of bile acids with dysbiosis of the gut microbiome. This leads to enterohepatic recirculation and an increase of toxic secondary bile acids. Alterations of serum and liver bile acid compositions via the disturbed enterohepatic circulation of bile acids and the disturbance of the gut microbiome then activate a series of hepatic and cancer cell signaling pathways that promote CCA carcinogenesis and progression. This review focuses on the mechanistic roles of bile acids and the gut microbiome in the pathogenesis and progression of CCA. It also evaluates the therapeutic potential of targeting the gut microbiome and bile acid–mediated signaling pathways for the therapy and prophylaxis of CCA.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 3","pages":"Pages 397-408"},"PeriodicalIF":4.7,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891613","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}

{"title":"Genetically Engineered Mouse Models for Alzheimer Disease and Frontotemporal Dementia: New Insights from Single-Cell and Spatial Transcriptomics.","authors":"Yuanpu Chiu, Shangzhou Xia, Haowen Qiao, Zhen Zhao","doi":"10.1016/j.ajpath.2024.11.006","DOIUrl":"https://doi.org/10.1016/j.ajpath.2024.11.006","url":null,"abstract":"<p><p>Neurodegenerative diseases, including Alzheimer disease, frontotemporal dementia, Parkinson disease, Huntington disease, and amyotrophic lateral sclerosis, are often casually linked to protein aggregation and inclusion. As the origins of those proteinopathies have been biochemically traced and genetically mapped, genetically engineered animal models carrying the specific mutations or variants are widely used for investigating the etiology of these diseases, as well as for testing potential therapeutics. This article focuses on the mouse models of Alzheimer disease and closely related frontotemporal dementia, particularly the ones that have provided most valuable knowledge, or are in a trajectory of doing so. More importantly, some of the major findings from these models are summarized, based on the recent single-cell transcriptomics, multiomics, and spatial transcriptomics studies. While no model is perfect, it is hoped that the new insights from these models and the practical use of these models will continue to help to establish a path forward.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913644","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}

{"title":"Development of CAR-T Therapies and Personalized Vaccines for the Treatment of Cholangiocarcinoma","authors":"Dan Li ,&nbsp;Lalitya Andaloori ,&nbsp;Matthew Crowe ,&nbsp;Shaoli Lin ,&nbsp;Jessica Hong ,&nbsp;Neeha Zaidi ,&nbsp;Mitchell Ho","doi":"10.1016/j.ajpath.2024.10.021","DOIUrl":"10.1016/j.ajpath.2024.10.021","url":null,"abstract":"<div><div>Cholangiocarcinoma (CCA) is a highly fatal malignancy with an increasing prevalence, a high mortality rate, poor overall survival, and limited responsiveness to conventional chemoradiotherapy. Targeted therapies addressing specific gene mutations have expanded treatment options for some patient populations. The introduction of chimeric antigen receptor–modified T-cell (CAR-T) immunotherapy and personalized vaccines have opened up a new avenue for managing various cancers. Considerable efforts have been dedicated to preclinical research and ongoing clinical trials of immunotherapeutic approaches including CAR-T therapy, vaccines, and antibody-based therapies such as antibody drug conjugates. However, the potential of CAR-T therapy and vaccines in treating advanced unresectable/metastatic cholangiocarcinoma remains largely unexplored. This article offers an overview of the current landscape of antibody-based immunotherapy, particularly CAR-T therapy and vaccines in the context of cholangiocarcinoma treatment. It outlines a framework for selecting CAR-T and vaccine targets and delves into the biology of promising targetable antigens, as well as potential future therapeutic targets.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 3","pages":"Pages 453-469"},"PeriodicalIF":4.7,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827015","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}

{"title":"Regulation of Adiponectin and Resistin in Liver Transplantation Protects Grafts from Extended-Criteria Donors","authors":"Araní Casillas-Ramírez ,&nbsp;Cristina Maroto-Serrat ,&nbsp;Francisco Sanus ,&nbsp;Marc Micó-Carnero ,&nbsp;Carlos Rojano-Alfonso ,&nbsp;Margalida Cabrer ,&nbsp;Carmen Peralta","doi":"10.1016/j.ajpath.2024.10.016","DOIUrl":"10.1016/j.ajpath.2024.10.016","url":null,"abstract":"<div><div>The donor shortage increases liver transplantation (LT) waiting lists, making it crucial to consider extended-criteria donors, such as steatotic donors after brain death (DBDs) or cardiocirculatory death (DCDs). Nevertheless, steatosis, brain death, and cardiocirculatory death are key risk factors for poor LT outcomes. Herein, the role and therapeutic usefulness of several adipocytokines was investigated to protect such grafts from extended-criteria donors. Sprague rats with nutritionally induced steatosis were used in an experimental LT model with grafts from DBDs or DCDs. Adiponectin, resistin, and visfatin were measured and pharmacologically modulated, and effects on liver injury were assessed. Visfatin played no role under conditions of either DBD or DCD LT. Brain death increased adiponectin and reduced resistin. Adiponectin harmed steatotic and nonsteatotic DBD grafts, via a resistin-dependent mechanism; restraining adiponectin increased resistin, reducing damage. Resistin treatment protected both types of DBD grafts, whereas suppressing it increased damage. This adiponectin-resistin pathway was dependent on protein kinase C. In DCD LT, adiponectin and resistin were not modified in nonsteatotic grafts, but reduced in steatotic ones. Adiponectin or resistin treatments protected steatotic grafts: hepatic adiponectin activated AMP-activated protein kinase ; hepatic resistin increased phosphatidylinositol 3-kinase–Akt. Concomitant administration of both adipocytokines increased both signaling pathways, intensifying protection. These data suggest that pharmacologic modulation of adiponectin and resistin as therapies might potentially be translated to clinical studies to improve surgical outcomes for LT from extended-criteria donors.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 3","pages":"Pages 494-527"},"PeriodicalIF":4.7,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680658","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}

{"title":"Genetic Loss of HIF-Prolyl-Hydroxylase 1, but Not Pharmacological Inhibition, Mitigates Hepatic Fibrosis","authors":"Christopher Tuffs ,&nbsp;Mareen Dupovac ,&nbsp;Katrin Richter ,&nbsp;Sophia Holten ,&nbsp;Thomas Schaschinger ,&nbsp;Oliver Marg ,&nbsp;Adisa Poljo ,&nbsp;Ayse nur Tasdemir ,&nbsp;Jonathan M. Harnoss ,&nbsp;Adrian Billeter ,&nbsp;Martin Schneider ,&nbsp;Moritz J. Strowitzki","doi":"10.1016/j.ajpath.2024.10.018","DOIUrl":"10.1016/j.ajpath.2024.10.018","url":null,"abstract":"<div><div>Liver fibrosis is characterized by excessive deposition of extracellular matrix due to chronic inflammation of the liver. Hepatic stellate cells (HSCs) become activated and produce increased amounts of extracellular matrix. Loss of HIF-prolyl-hydroxylase 1 (PHD1) attenuates HSC activation and fibrotic tissue remodeling in a murine model of biliary liver fibrosis. Herein, the protective effect of PHD1 deficiency (<em>PHD1</em>^{<em>−/−</em>}) in an additional (toxic) model of liver fibrosis was validated and the effect of dimethyloxalylglycine (DMOG), a pan-HIF-prolyl-hydroxylase inhibitor, on the development of liver fibrosis, was evaluated. Liver fibrosis was induced utilizing carbon tetrachloride in wild-type (WT) and <em>PHD1</em>^{<em>−/−</em>} mice treated with either vehicle or DMOG. To assess fibrosis development, expression of profibrotic genes in the livers was analyzed by Sirius red staining. When compared with WT mice, <em>PHD1</em>^{<em>−/−</em>} mice developed less-severe liver fibrosis. DMOG treatment did not prevent this liver fibrosis. <em>PHD1</em>^{<em>−/−</em>} mice had fewer α-SMA⁺ cells and less macrophage infiltration compared with WT mice. Expression of profibrogenic and proinflammatory genes was reduced in livers from carbon tetrachloride–exposed <em>PHD1</em>^{<em>−/−</em>} mice. <em>In vitro</em> analyses of PHD1-deficient human HSCs revealed attenuated mRNA levels of profibrotic genes, as well as impaired migration and invasion. Although PHD1 deficiency attenuated activation of HSCs, pharmacologic PHD inhibition did not ameliorate fibrosis development. These data indicate that selective PHD1 inhibitors could prove effective in preventing and treating liver fibrosis.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 3","pages":"Pages 480-493"},"PeriodicalIF":4.7,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680656","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}