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Liu L, Niu K, Yang Z, Song J, Wei D, Zhang R, Tao K. Osteopontin: an indispensable component in common liver, pancreatic, and biliary related disease. J Cancer Res Clin Oncol 2024; 150:508. [PMID: 39572438 PMCID: PMC11582231 DOI: 10.1007/s00432-024-06038-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 11/15/2024] [Indexed: 11/24/2024]
Abstract
BACKGROUND The liver, gallbladder, and pancreas constitute a critically important system of digestive and endocrine organs in the human body, performing essential and complex physiological functions. At present, diseases of this digestive system have a high incidence in the world and is a more common disease. However, osteopontin (OPN) plays a crucial role in common liver, pancreatic, and biliary diseases, and its mechanisms of action merit further exploration and study. METHODS We performed an analysis to assess the role of osteopontin in liver, pancreatic, and biliary diseases, focusing on its significance in these conditions. RESULTS Osteopontin, a profoundly phosphorylated glycoprotein, can be utilized as a diagnostic marker for hepatocellular carcinoma and cholangiopathies. Additionally it assists in the treatment of non-alcoholic fatty liver disease and promotes the proliferation, migration, and invasion of pancreatic cancer cells. Furthermore, osteopontin regulates inflammatory responses in chronic pancreatitis. CONCLUSIONS This review offers a thorough analysis of the genetic and protein architecture of OPN, and elucidates the relationship between osteopontin and liver, pancreatic, and biliary diseases. Furthermore, exclusive focus is lavished on the potential utility of OPN as a biomarker and an innovative therapeutic target in the management of these disorder.
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Affiliation(s)
- Lu Liu
- College of Life Sciences, Northwest University, Xi'an, 710069, China
- Department of Hepatobiliary Surgery, Xijing Hosptial, Fourth Military Medical University, Xi'an, 710032, China
| | - Kunwei Niu
- Department of Hepatobiliary Surgery, Xijing Hosptial, Fourth Military Medical University, Xi'an, 710032, China
| | - Zhipeng Yang
- College of Life Sciences, Northwest University, Xi'an, 710069, China
- Department of Hepatobiliary Surgery, Xijing Hosptial, Fourth Military Medical University, Xi'an, 710032, China
| | - Junbo Song
- Department of Hepatobiliary Surgery, Xijing Hosptial, Fourth Military Medical University, Xi'an, 710032, China
| | - Dan Wei
- Department of Hepatobiliary Surgery, Xijing Hosptial, Fourth Military Medical University, Xi'an, 710032, China.
| | - Ruohan Zhang
- Department of Hepatobiliary Surgery, Xijing Hosptial, Fourth Military Medical University, Xi'an, 710032, China.
| | - Kaishan Tao
- Department of Hepatobiliary Surgery, Xijing Hosptial, Fourth Military Medical University, Xi'an, 710032, China.
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Dos Santos AC, França TCS, Venzon L, Polli V, Polleti G, Trembulak E, Pilati SFM, da Silva LM. Are silymarin and N-acetylcysteine able to prevent liver damage mediated by multiple factors? Findings against ethanol plus LPS-induced liver injury in mice. J Biochem Mol Toxicol 2024; 38:e23560. [PMID: 37860953 DOI: 10.1002/jbt.23560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 09/11/2023] [Accepted: 10/05/2023] [Indexed: 10/21/2023]
Abstract
This study investigated the effect of N-acetylcysteine (NAC) and silymarin (SIL) in the liver of mice exposed to ethanol and lipopolysaccharides (LPS). Mice were divided into four groups (n = 6): naive, vehicle, NAC (200 mg/kg), and SIL (200 mg/kg). Treatments were given orally (po) once daily for 10 days. Liver injury was induced by administration of ethanol (30%, po) for 10 days, once daily, followed by a single administration of LPS (2 mg/kg, ip) 24 h before euthanasia. After the treatment period, animals were euthanized, and liver and blood samples were collected. NAC, but not SIL, prevented the increase in oxalacetic glutamic transaminase (OGT) and pyruvic glutamic transaminase (PGT) serum levels. NAC and SIL did not restore levels of reduced glutathione or hepatic malonaldehyde. The treatments with NAC or SIL showed no difference in the activity of glutathione S-transferase, superoxide dismutase, and catalase compared to vehicle group. Myeloperoxidase and N-acetylglucosaminidase activities are increased, as well as the IL-6 and IL-10 levels in the liver. The treatment with NAC, but not SIL, reduced the N-acetylglucosamines activity and the IL-6 and IL-10 amount in the liver. Histological findings revealed microsteatosis in the vehicle group, which was not prevented by SIL but was partially reduced in animals receiving NAC. Unlike other liver injury models, NAC (200 mg/kg) or SIL (200 mg/kg) did not positively affect antioxidant patterns in liver tissue of animals exposed to ethanol plus LPS, but NAC treatment displays anti-inflammatory properties in this model.
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Affiliation(s)
- Ana Caroline Dos Santos
- Postgraduate Program in Pharmaceutical Sciences, Universidade do Vale do Itajaí, Itajaí, Santa Catarina, Brazil
| | | | - Larissa Venzon
- Postgraduate Program in Pharmaceutical Sciences, Universidade do Vale do Itajaí, Itajaí, Santa Catarina, Brazil
| | - Vitor Polli
- Postgraduate Program in Pharmaceutical Sciences, Universidade do Vale do Itajaí, Itajaí, Santa Catarina, Brazil
| | - Gustavo Polleti
- Postgraduate Program in Pharmaceutical Sciences, Universidade do Vale do Itajaí, Itajaí, Santa Catarina, Brazil
| | - Erica Trembulak
- Postgraduate Program in Pharmaceutical Sciences, Universidade do Vale do Itajaí, Itajaí, Santa Catarina, Brazil
| | | | - Luísa Mota da Silva
- Postgraduate Program in Pharmaceutical Sciences, Universidade do Vale do Itajaí, Itajaí, Santa Catarina, Brazil
- LaFaTI-Laboratório de Farmacologia do Trato Gastrointestinal e suas Interações, Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil
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Salati NA, Sharma M, Rao NN, Shetty SS, Radhakrishnan RA. Role of osteopontin in oral epithelial dysplasia, oral submucous fibrosis and oral squamous cell carcinoma. J Oral Maxillofac Pathol 2023; 27:706-714. [PMID: 38304518 PMCID: PMC10829450 DOI: 10.4103/jomfp.jomfp_492_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 12/27/2022] [Accepted: 03/06/2023] [Indexed: 02/03/2024] Open
Abstract
Background Inflammatory cells and cytokines in the chronically injured mucosa promote fibrosis in the oral submucous fibrosis (OSF) fibrotic milieu. Osteopontin (OPN) is a wound-healing mediator that upregulates the inflammatory response and is involved in the malignancy and fibrosis of multiple organ systems. Objectives We investigated the expression of OPN in oral potentially malignant disorders (OPMDs) and oral squamous cell carcinomas (OSCCs) to determine its role in the malignant transformation and fibrosis of oral tissues. The expression of OPN in OPMDs and OSCCs was compared and correlated, and the role of OPN as a fibrotic mediator in OSF was explained. Study Design A total of 30 cases of normal mucosa and OPMDs (mild dysplasia, severe dysplasia, OSF and OSCCs) were studied by purposive sampling. In these groups, OPN immunoreactivity was examined and correlated with clinical findings. Results In mild dysplasia, OPN expression was restricted to the basal cell layer with moderate staining intensity. In severe dysplasia, it was extremely intense and extended throughout the epithelium. In the OSF, OPN expression was moderate in the perinuclear areas of the basal cell layer. The expression of OPN was very strong in OSCC. A flow diagram explaining the profibrotic role of OPN in OSF has been provided. Conclusion A positive role of OPN in both pathogenesis and malignant transformation of OPMDs and OSCC has been demonstrated.
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Affiliation(s)
- Nasir A. Salati
- Department of Oral and Maxillofacial Pathology, Dr. Ziauddin Ahmad Dental College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - Mohit Sharma
- Department of Oral Pathology, SGT Dental College Hospital and Research Institute, Gurugram, Haryana, India
| | - Nirmala N. Rao
- Former Dean, Manipal College of Dental Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Smitha S. Shetty
- Department of Oral Pathology, Manipal College of Dental Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Raghu A. Radhakrishnan
- Department of Oral Pathology, Manipal College of Dental Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
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Robinson JA, Toribio M, Quinaglia T, Awadalla M, Talathi R, Durbin CG, Alhallak I, Alagpulinsa DA, Fourman LT, Suero-Abreu GA, Nelson MD, Stanley TL, Longenecker CT, Szczepaniak LS, Jerosch-Herold M, Neilan TG, Zanni MV, Burdo TH. Plasma osteopontin relates to myocardial fibrosis and steatosis and to immune activation among women with HIV. AIDS 2023; 37:305-310. [PMID: 36541642 PMCID: PMC9782710 DOI: 10.1097/qad.0000000000003417] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
OBJECTIVE Women with HIV (WWH) have heightened heart failure risk. Plasma OPN (osteopontin) is a powerful predictor of heart failure outcomes in the general population. Limited data exist on relationships between plasma OPN and surrogates of HIV-associated heart failure risk. DESIGN Prospective, cross-sectional. METHODS We analyzed relationships between plasma OPN and cardiac structure/function (assessed using cardiovascular magnetic resonance imaging) and immune activation (biomarkers and flow cytometry) among 20 WWH and 14 women without HIV (WWOH). RESULTS Plasma OPN did not differ between groups. Among WWH, plasma OPN related directly to the markers of cardiac fibrosis, growth differentiation factor-15 (ρ = 0.51, P = 0.02) and soluble interleukin 1 receptor-like 1 (ρ = 0.45, P = 0.0459). Among WWH (but not among WWOH or the whole group), plasma OPN related directly to both myocardial fibrosis (ρ = 0.49, P = 0.03) and myocardial steatosis (ρ = 0.46, P = 0.0487). Among the whole group and WWH (and not among WWOH), plasma OPN related directly to the surface expression of C-X3-C motif chemokine receptor 1 (CX3CR1) on nonclassical (CD14-CD16+) monocytes (whole group: ρ = 0.36, P = 0.04; WWH: ρ = 0.46, P = 0.04). Further, among WWH and WWOH (and not among the whole group), plasma OPN related directly to the surface expression of CC motif chemokine receptor 2 (CCR2) on inflammatory (CD14+CD16+) monocytes (WWH: ρ = 0.54, P = 0.01; WWOH: ρ = 0.60, P = 0.03), and in WWH, this held even after controlling for HIV-specific parameters. CONCLUSION Among WWH, plasma OPN, a powerful predictor of heart failure outcomes, related to myocardial fibrosis and steatosis and the expression of CCR2 and CX3CR1 on select monocyte subpopulations. OPN may play a role in heart failure pathogenesis among WWH. CLINICALTRIALSGOV REGISTRATION NCT02874703.
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Affiliation(s)
- Jake A Robinson
- Department of Microbiology, Immunology, and Inflammation, Center for Neurovirology and Gene Editing, Lewis Katz School of Medicine at Temple University, Philadelphia, PA
| | | | - Thiago Quinaglia
- Cardiovascular Imaging Research Center (CIRC), Department of Radiology and Division of Cardiology
| | - Magid Awadalla
- Cardiovascular Imaging Research Center (CIRC), Department of Radiology and Division of Cardiology
| | | | | | | | - David A Alagpulinsa
- Vaccine and Immunotherapy Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | | | | | - Michael D Nelson
- Applied Physiology and Advanced Imaging Laboratory, Department of Kinesiology, University of Texas at Arlington, Arlington, TX
| | | | | | | | - Michael Jerosch-Herold
- Division of Radiology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Tomas G Neilan
- Cardiovascular Imaging Research Center (CIRC), Department of Radiology and Division of Cardiology
| | | | - Tricia H Burdo
- Department of Microbiology, Immunology, and Inflammation, Center for Neurovirology and Gene Editing, Lewis Katz School of Medicine at Temple University, Philadelphia, PA
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Wang Y, Liu Y. Neutrophil-Induced Liver Injury and Interactions Between Neutrophils and Liver Sinusoidal Endothelial Cells. Inflammation 2021; 44:1246-1262. [PMID: 33649876 DOI: 10.1007/s10753-021-01442-x] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Revised: 01/29/2021] [Accepted: 02/19/2021] [Indexed: 12/12/2022]
Abstract
Neutrophils are the most abundant type of leukocytes with diverse functions in immune defense including production of reactive oxygen species, bacteriocidal proteins, neutrophil extracellular traps, and pro-inflammatory mediators. However, aberrant accumulation of neutrophils in host tissues and excessive release of bacteriocidal compounds can lead to unexpected injury to host organs. Neutrophil-mediated liver injury has been reported in various types of liver diseases including liver ischemia/reperfusion injury, nonalcoholic fatty liver disease, endotoxin-induced liver injury, alcoholic liver disease, and drug-induced liver injury. Yet the mechanisms of neutrophil-induced hepatotoxicity in different liver diseases are complicated. Current knowledge of these mechanisms are summarized in this review. In addition, a substantial body of evidence has emerged showing that liver sinusoidal endothelial cells (LSECs) participate in several key steps of neutrophil-mediated liver injury including neutrophil recruitment, adhesion, transmigration, and activation. This review also highlights the current understanding of the interactions between LSECs and neutrophils in liver injury. The future challenge is to explore new targets for selectively interfering neutrophil-induced liver injury without impairing host defense function against microbial infection. Further understanding the role of LSECs in neutrophil-induced hepatotoxicity would aid in developing more selective therapeutic approaches for liver disease.
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Affiliation(s)
- Yang Wang
- Department of Gastroenterology, Peking University People's Hospital, No.11, Xizhimen South Street, Xicheng District, Beijing, 100044, China
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, No. 11, Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Yulan Liu
- Department of Gastroenterology, Peking University People's Hospital, No.11, Xizhimen South Street, Xicheng District, Beijing, 100044, China.
- Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, No. 11, Xizhimen South Street, Xicheng District, Beijing, 100044, China.
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Zhang Y, de Boer M, van der Wel EJ, Van Eck M, Hoekstra M. PRMT4 inhibitor TP-064 inhibits the pro-inflammatory macrophage lipopolysaccharide response in vitro and ex vivo and induces peritonitis-associated neutrophilia in vivo. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166212. [PMID: 34311083 DOI: 10.1016/j.bbadis.2021.166212] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 06/14/2021] [Accepted: 07/05/2021] [Indexed: 01/19/2023]
Abstract
Previous in vitro studies have shown that protein arginine N-methyltransferase 4 (PRMT4) is a co-activator for an array of cellular activities, including NF-κB-regulated pro-inflammatory responses. Here we investigated the effect of PRMT4 inhibitor TP-064 treatment on macrophage inflammation in vitro and in vivo. Exposure of RAW 264.7 monocyte/macrophages to TP-064 was associated with a significant decrease in the production of pro-inflammatory cytokines upon a lipopolysaccharide challenge. Similarly, thioglycollate-elicited peritoneal cells isolated from wildtype mice treated with TP-064 showed lowered mRNA expression levels and cytokine production of pro-inflammatory mediators interleukin (IL)-1β, IL-6, IL-12p40, and tumor necrosis factor-α in response to lipopolysaccharide exposure. However, TP-064-treated mice exhibited an ongoing pro-inflammatory peritonitis after 5 days of thioglycollate exposure, as evident from a shift in the peritoneal macrophage polarization state from an anti-inflammatory LY6ClowCD206hi to a pro-inflammatory LY6ChiCD206low phenotype. In addition, TP-064-treated mice accumulated (activated) neutrophils within the peritoneum as well as in the blood (7-fold higher; P < 0.001) and major organs such as kidney and liver, without apparent tissue toxicity. TP-064 treatment downregulated hepatic mRNA expression levels of the PRMT4 target genes glucose-6-phosphatase catalytic subunit (-50%, P < 0.05) and the cyclin-dependent kinases 2 (-50%, P < 0.05) and 4 (-30%, P < 0.05), suggesting a direct transcriptional effect of PRMT4 also in hepatocytes. In conclusion, we have shown that the PRMT4 inhibitor TP-064 induces peritonitis-associated neutrophilia in vivo and inhibits the pro-inflammatory macrophage lipopolysaccharide response in vitro and ex vivo. Our findings suggest that TP-064 can possibly be applied as therapy in NF-κB-based inflammatory diseases.
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Affiliation(s)
- Yiheng Zhang
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, the Netherlands.
| | - Miriam de Boer
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, the Netherlands
| | - Ezra J van der Wel
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, the Netherlands
| | - Miranda Van Eck
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, the Netherlands
| | - Menno Hoekstra
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, the Netherlands
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Tang J, Yan Z, Feng Q, Yu L, Wang H. The Roles of Neutrophils in the Pathogenesis of Liver Diseases. Front Immunol 2021; 12:625472. [PMID: 33763069 PMCID: PMC7982672 DOI: 10.3389/fimmu.2021.625472] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 01/25/2021] [Indexed: 01/30/2023] Open
Abstract
Neutrophils are the largest population of circulating leukocytes and the first responder against invading pathogens or other danger signals. Sophisticated machineries help them play critical roles in immunity and inflammation, including phagocytosis, superoxide production, cytokine and chemokine production, degranulation, and formation of neutrophil extracellular traps (NETs). After maturation and release from the bone marrow, neutrophils migrate to inflamed tissues in response to many stimuli. Increasing evidences indicate that neutrophils are critically involved in the pathogenesis of liver diseases, including liver cancer, thus making them promising target for the treatment of liver diseases. Here, we would like to provide the latest finding about the role of neutrophils in liver diseases and discuss the potentiality of neutrophils as target for liver diseases.
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Affiliation(s)
- Jiaojiao Tang
- Division of Life Sciences and Medicine, Cancer Research Center, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China
- International Cooperation Laboratory on Signal Transduction, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-Biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Zijun Yan
- International Cooperation Laboratory on Signal Transduction, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-Biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
- Graduate Management Unit, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Qiyu Feng
- Division of Life Sciences and Medicine, Cancer Research Center, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China
- International Cooperation Laboratory on Signal Transduction, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-Biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
- National Center for Liver Cancer, Shanghai, China
| | - Lexing Yu
- Division of Life Sciences and Medicine, Cancer Research Center, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China
- International Cooperation Laboratory on Signal Transduction, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-Biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
- National Center for Liver Cancer, Shanghai, China
| | - Hongyang Wang
- Division of Life Sciences and Medicine, Cancer Research Center, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China
- International Cooperation Laboratory on Signal Transduction, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-Biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
- National Center for Liver Cancer, Shanghai, China
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Bruellman R, Llorente C. A Perspective Of Intestinal Immune-Microbiome Interactions In Alcohol-Associated Liver Disease. Int J Biol Sci 2021; 17:307-327. [PMID: 33390852 PMCID: PMC7757023 DOI: 10.7150/ijbs.53589] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 11/13/2020] [Indexed: 02/07/2023] Open
Abstract
Uncovering the intricacies of the gut microbiome and how it interacts with the host immune system has opened up pathways in the search for the treatment of disease conditions. Alcohol-associated liver disease is a major cause of death worldwide. Research has shed light on the breakdown of the protective gut barriers, translocation of gut microbes to the liver and inflammatory immune response to microbes all contributing to alcohol-associated liver disease. This knowledge has opened up avenues for alternative therapies to alleviate alcohol-associated liver disease based on the interaction of the commensal gut microbiome as a key player in the regulation of the immune response. This review describes the relevance of the intestinal immune system, the gut microbiota, and specialized and non-specialized intestinal cells in the regulation of intestinal homeostasis. It also reflects how these components are altered during alcohol-associated liver disease and discusses new approaches for potential future therapies in alcohol-associated liver disease.
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Affiliation(s)
- Ryan Bruellman
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Cristina Llorente
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
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Napoli S, Scuderi C, Gattuso G, Di Bella V, Candido S, Basile MS, Libra M, Falzone L. Functional Roles of Matrix Metalloproteinases and Their Inhibitors in Melanoma. Cells 2020; 9:cells9051151. [PMID: 32392801 PMCID: PMC7291303 DOI: 10.3390/cells9051151] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 05/01/2020] [Accepted: 05/06/2020] [Indexed: 12/12/2022] Open
Abstract
The extracellular matrix (ECM) plays an important role in the regulation of the tissue microenvironment and in the maintenance of cellular homeostasis. Several proteins with a proteolytic activity toward several ECM components are involved in the regulation and remodeling of the ECM. Among these, Matrix Metalloproteinases (MMPs) are a class of peptidase able to remodel the ECM by favoring the tumor invasive processes. Of these peptidases, MMP-9 is the most involved in the development of cancer, including that of melanoma. Dysregulations of the MAPKs and PI3K/Akt signaling pathways can lead to an aberrant overexpression of MMP-9. Even ncRNAs are implicated in the aberrant production of MMP-9 protein, as well as other proteins responsible for the activation or inhibition of MMP-9, such as Osteopontin and Tissue Inhibitors of Metalloproteinases. Currently, there are different therapeutic approaches for melanoma, including targeted therapies and immunotherapies. However, no biomarkers are available for the prediction of the therapeutic response. In this context, several studies have tried to understand the diagnostic, prognostic and therapeutic potential of MMP-9 in melanoma patients by performing clinical trials with synthetic MMPs inhibitors. Therefore, MMP-9 may be considered a promising molecule for the management of melanoma patients due to its role as a biomarker and therapeutic target.
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Affiliation(s)
- Salvatore Napoli
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (S.N.); (C.S.); (G.G.); (V.D.B.); (S.C.); (M.S.B.)
| | - Chiara Scuderi
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (S.N.); (C.S.); (G.G.); (V.D.B.); (S.C.); (M.S.B.)
| | - Giuseppe Gattuso
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (S.N.); (C.S.); (G.G.); (V.D.B.); (S.C.); (M.S.B.)
| | - Virginia Di Bella
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (S.N.); (C.S.); (G.G.); (V.D.B.); (S.C.); (M.S.B.)
| | - Saverio Candido
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (S.N.); (C.S.); (G.G.); (V.D.B.); (S.C.); (M.S.B.)
- Research Center for Prevention, Diagnosis and Treatment of Cancer, University of Catania, 95123 Catania, Italy
| | - Maria Sofia Basile
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (S.N.); (C.S.); (G.G.); (V.D.B.); (S.C.); (M.S.B.)
| | - Massimo Libra
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (S.N.); (C.S.); (G.G.); (V.D.B.); (S.C.); (M.S.B.)
- Research Center for Prevention, Diagnosis and Treatment of Cancer, University of Catania, 95123 Catania, Italy
- Correspondence: (M.L.); or (L.F.); Tel.: +39-095-478-1271 (M.L.); +39-094-478-1278 (L.F.)
| | - Luca Falzone
- Epidemiology Unit, IRCCS Istituto Nazionale Tumori “Fondazione G. Pascale”, 80131 Naples, Italy
- Correspondence: (M.L.); or (L.F.); Tel.: +39-095-478-1271 (M.L.); +39-094-478-1278 (L.F.)
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Wang C, He M, Peng J, Li S, Long M, Chen W, Liu D, Yang G, Zhang L. Increased plasma osteopontin levels are associated with nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus. Cytokine 2020; 125:154837. [PMID: 31514105 DOI: 10.1016/j.cyto.2019.154837] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 08/27/2019] [Accepted: 09/03/2019] [Indexed: 12/29/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) commonly occurs in patients with type 2 diabetes mellitus (T2DM). Osteopontin (OPN) is a multifunctional protein with pleiotropic physiological functions. This study aimed to investigate the interrelation between circulating OPN and NAFLD in T2DM patients. Overall, 249 subjects were classified into 4 groups: 53 patients with NAFLD and T2DM; 57 with newly diagnosed T2DM; 59 with NAFLD; and 80 healthy age- and sex-matched controls. Serum OPN was measured by ELISA. The OPN distribution in the pooled data was divided into quartiles; significant trends across increasing quartiles were estimated by the Cochran-Armitage trend test. Compared with the controls, circulating OPN concentrations were significantly elevated in NAFLD patients and T2DM patients with or without NAFLD. Serum OPN levels were higher in the overweight/obese group than that in the lean group. Circulating OPN levels were positively correlated with CRP, age, BMI, SBP, DBP, HbA1c, UA, TGs, WBCs, neutrophils, FBG, and HOMA-IR and negatively correlated with ADP, albumin and HDL. Age, albumin, HbA1c, HDL and hsCRP were independently related to circulating OPN. The relative risks for NAFLD, T2DM and T2DM with NAFLD increased significantly along with increasing OPN quartiles based on the Cochran-Armitage trend test. OPN is an optimal predictor in the diagnosis of T2DM with NAFLD and T2DM and may contribute to the aggravation of the metabolic state.
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Affiliation(s)
- Cong Wang
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, 400010 Chongqing, China
| | - Miao He
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, 400010 Chongqing, China
| | - Jiajia Peng
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, 400010 Chongqing, China
| | - Shengbing Li
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, 400010 Chongqing, China
| | - Min Long
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, 400010 Chongqing, China
| | - Wenwen Chen
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, 400010 Chongqing, China
| | - Dongfang Liu
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, 400010 Chongqing, China
| | - Gangyi Yang
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, 400010 Chongqing, China
| | - Lili Zhang
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, 400010 Chongqing, China.
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Li S, Tan HY, Wang N, Feng Y, Wang X, Feng Y. Recent Insights Into the Role of Immune Cells in Alcoholic Liver Disease. Front Immunol 2019; 10:1328. [PMID: 31244862 PMCID: PMC6581703 DOI: 10.3389/fimmu.2019.01328] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 05/24/2019] [Indexed: 12/12/2022] Open
Abstract
Accumulating clinical and experimental evidences have demonstrated that both innate and adaptive immunity are involved in the pathogenesis of alcoholic liver disease (ALD), in which the role of immunity is to fuel the inflammation and to drive the progression of ALD. Various immune cells are implicated in the pathogenesis of ALD. The activation of innate immune cells induced by alcohol and adaptive immune response triggered by oxidative modification of hepatic constituents facilitate the persistent hepatic inflammation. Meanwhile, the suppressed antigen-presenting capability of various innate immune cells and impaired function of T cells may consequently lead to an increased risk of infection in the patients with advanced ALD. In this review, we summarized the significant recent findings of immune cells participating in ALD. The pathways and molecules involved in the regulation of specific immune cells, and novel mediators protecting the liver from alcoholic injury via affecting these cells are particularly highlighted. This review aims to update the knowledge about immunity in the pathogenesis of ALD, which may facilitate to enhancement of currently available interventions for ALD treatment.
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Affiliation(s)
- Sha Li
- Li Ka Shing Faculty of Medicine, School of Chinese Medicine, The University of Hong Kong, Hong Kong, China
| | - Hor-Yue Tan
- Li Ka Shing Faculty of Medicine, School of Chinese Medicine, The University of Hong Kong, Hong Kong, China
| | - Ning Wang
- Li Ka Shing Faculty of Medicine, School of Chinese Medicine, The University of Hong Kong, Hong Kong, China
| | - Yigang Feng
- Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Xuanbin Wang
- Laboratory of Chinese Herbal Pharmacology, Laboratory of Wudang Local Chinese Medicine Research, Oncology Center, Renmin Hospital, Hubei University of Medicine, Shiyan, China
| | - Yibin Feng
- Li Ka Shing Faculty of Medicine, School of Chinese Medicine, The University of Hong Kong, Hong Kong, China
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12
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Ma C, Sun Z, Zeng B, Huang S, Zhao J, Zhang Y, Su X, Xu J, Wei H, Zhang H. Cow-to-mouse fecal transplantations suggest intestinal microbiome as one cause of mastitis. MICROBIOME 2018; 6:200. [PMID: 30409169 PMCID: PMC6225715 DOI: 10.1186/s40168-018-0578-1] [Citation(s) in RCA: 99] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 10/17/2018] [Indexed: 05/09/2023]
Abstract
BACKGROUND Mastitis, which affects nearly all lactating mammals including human, is generally thought to be caused by local infection of the mammary glands. For treatment, antibiotics are commonly prescribed, which however are of concern in both treatment efficacy and neonate safety. Here, using bovine mastitis which is the most costly disease in the dairy industry as a model, we showed that intestinal microbiota alone can lead to mastitis. RESULTS Fecal microbiota transplantation (FMT) from mastitis, but not healthy cows, to germ-free (GF) mice resulted in mastitis symptoms in mammary gland and inflammations in serum, spleen, and colon. Probiotic intake in parallel with FMT from diseased cows led to relieved mastitis symptoms in mice, by shifting the murine intestinal microbiota to a state that is functionally distinct from either healthy or diseased microbiota yet structurally similar to the latter. Despite conservation in mastitis symptoms, diseased cows and mice shared few mastitis-associated bacterial organismal or functional markers, suggesting striking divergence in mastitis-associated intestinal microbiota among lactating mammals. Moreover, an "amplification effect" of disease-health distinction in both microbiota structure and function was apparent during the cow-to-mouse FMT. CONCLUSIONS Hence, dysbiosis of intestinal microbiota may be one cause of mastitis, and probiotics that restore intestinal microbiota function are an effective and safe strategy to treat mastitis.
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Affiliation(s)
- Chen Ma
- Key Laboratory of Dairy Biotechnology and Engineering, Inner Mongolia Agricultural University, Hohhot, 010018, China
| | - Zheng Sun
- Single-Cell Center, CAS Key Laboratory of Biofuels and Shandong Key Laboratory of Energy Genetics, Qingdao Institute of BioEnergy and Bioprocess Technology, Chinese Academy of Sciences, Qingdao, 266101, Shandong, China
| | - Benhua Zeng
- Department of Laboratory Animal Science, College of Basic Medical Sciences, Third Military Medical University, Chongqing, 400038, China
| | - Shi Huang
- Single-Cell Center, CAS Key Laboratory of Biofuels and Shandong Key Laboratory of Energy Genetics, Qingdao Institute of BioEnergy and Bioprocess Technology, Chinese Academy of Sciences, Qingdao, 266101, Shandong, China
| | - Jie Zhao
- Key Laboratory of Dairy Biotechnology and Engineering, Inner Mongolia Agricultural University, Hohhot, 010018, China
| | - Yong Zhang
- Key Laboratory of Dairy Biotechnology and Engineering, Inner Mongolia Agricultural University, Hohhot, 010018, China
| | - Xiaoquan Su
- Single-Cell Center, CAS Key Laboratory of Biofuels and Shandong Key Laboratory of Energy Genetics, Qingdao Institute of BioEnergy and Bioprocess Technology, Chinese Academy of Sciences, Qingdao, 266101, Shandong, China
| | - Jian Xu
- Single-Cell Center, CAS Key Laboratory of Biofuels and Shandong Key Laboratory of Energy Genetics, Qingdao Institute of BioEnergy and Bioprocess Technology, Chinese Academy of Sciences, Qingdao, 266101, Shandong, China.
| | - Hong Wei
- The Engineering Technology Research Center for Germ-free and Genome-editing Animal, Huazhong Agricultural University, Wuhan, 430070, People's Republic of China.
| | - Heping Zhang
- Key Laboratory of Dairy Biotechnology and Engineering, Inner Mongolia Agricultural University, Hohhot, 010018, China.
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Shah R, Reyes-Gordillo K, Cheng Y, Varatharajalu R, Ibrahim J, Lakshman MR. Thymosin β4 Prevents Oxidative Stress, Inflammation, and Fibrosis in Ethanol- and LPS-Induced Liver Injury in Mice. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:9630175. [PMID: 30116499 PMCID: PMC6079392 DOI: 10.1155/2018/9630175] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Revised: 03/25/2018] [Accepted: 04/18/2018] [Indexed: 12/14/2022]
Abstract
Thymosin beta 4 (Tβ4), an actin-sequestering protein, is involved in tissue development and regeneration. It prevents inflammation and fibrosis in several tissues. We investigated the role of Tβ4 in chronic ethanol- and acute lipopolysaccharide- (LPS-) induced mouse liver injury. C57BL/6 mice were fed 5% ethanol in liquid diet for 4 weeks plus binge ethanol (5 g/kg, gavage) with or without LPS (2 mg/kg, intraperitoneal) for 6 hours. Tβ4 (1 mg/kg, intraperitoneal) was administered for 1 week. We demonstrated that Tβ4 prevented ethanol- and LPS-mediated increase in liver injury markers as well as changes in liver pathology. It also prevented ethanol- and LPS-mediated increase in oxidative stress by decreasing ROS and lipid peroxidation and increasing the antioxidants, reduced glutathione and manganese-dependent superoxide dismutase. It also prevented the activation of nuclear factor kappa B by blocking the phosphorylation of the inhibitory protein, IκB, thereby prevented proinflammatory cytokine production. Moreover, Tβ4 prevented fibrogenesis by suppressing the epigenetic repressor, methyl-CpG-binding protein 2, that coordinately reversed the expression of peroxisome proliferator-activated receptor-γ and downregulated fibrogenic genes, platelet-derived growth factor-β receptor, α-smooth muscle actin, collagen 1, and fibronectin, resulting in reduced fibrosis. Our data suggest that Tβ4 has antioxidant, anti-inflammatory, and antifibrotic potential during alcoholic liver injury.
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Affiliation(s)
- Ruchi Shah
- Lipid Research Laboratory, VA Medical Center, 50 Irving Street NW, Washington, DC, USA
- Department of Biochemistry and Molecular Medicine, The George Washington University Medical Center, 2300 I Street NW, Washington, DC, USA
- Institute of Biomedical Sciences, The George Washington University, 2300 I Street NW, Washington, DC, USA
| | - Karina Reyes-Gordillo
- Lipid Research Laboratory, VA Medical Center, 50 Irving Street NW, Washington, DC, USA
- Department of Biochemistry and Molecular Medicine, The George Washington University Medical Center, 2300 I Street NW, Washington, DC, USA
| | - Ying Cheng
- Lipid Research Laboratory, VA Medical Center, 50 Irving Street NW, Washington, DC, USA
- Department of Biochemistry and Molecular Medicine, The George Washington University Medical Center, 2300 I Street NW, Washington, DC, USA
| | - Ravi Varatharajalu
- Lipid Research Laboratory, VA Medical Center, 50 Irving Street NW, Washington, DC, USA
- Department of Biochemistry and Molecular Medicine, The George Washington University Medical Center, 2300 I Street NW, Washington, DC, USA
| | - Joseph Ibrahim
- Lipid Research Laboratory, VA Medical Center, 50 Irving Street NW, Washington, DC, USA
- Department of Biochemistry and Molecular Medicine, The George Washington University Medical Center, 2300 I Street NW, Washington, DC, USA
| | - M. Raj Lakshman
- Lipid Research Laboratory, VA Medical Center, 50 Irving Street NW, Washington, DC, USA
- Department of Biochemistry and Molecular Medicine, The George Washington University Medical Center, 2300 I Street NW, Washington, DC, USA
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14
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Choi Y, Abdelmegeed MA, Song BJ. Preventive effects of indole-3-carbinol against alcohol-induced liver injury in mice via antioxidant, anti-inflammatory, and anti-apoptotic mechanisms: Role of gut-liver-adipose tissue axis. J Nutr Biochem 2017; 55:12-25. [PMID: 29331880 DOI: 10.1016/j.jnutbio.2017.11.011] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Revised: 10/01/2017] [Accepted: 11/14/2017] [Indexed: 12/12/2022]
Abstract
Indole-3-carbinol (I3C), found in Brassica family vegetables, exhibits antioxidant, anti-inflammatory, and anti-cancerous properties. Here, we aimed to evaluate the preventive effects of I3C against ethanol (EtOH)-induced liver injury and study the protective mechanism(s) by using the well-established chronic-plus-binge alcohol exposure model. The preventive effects of I3C were evaluated by conducting various histological, biochemical, and real-time PCR analyses in mouse liver, adipose tissue, and colon, since functional alterations of adipose tissue and intestine can also participate in promoting EtOH-induced liver damage. Daily treatment with I3C alleviated EtOH-induced liver injury and hepatocyte apoptosis, but not steatosis, by attenuating elevated oxidative stress, as evidenced by the decreased levels of hepatic lipid peroxidation, hydrogen peroxide, CYP2E1, NADPH-oxidase, and protein acetylation with maintenance of mitochondrial complex I, II, and III protein levels and activities. I3C also restored the hepatic antioxidant capacity by preventing EtOH-induced suppression of glutathione contents and mitochondrial aldehyde dehydrogenase-2 activity. I3C preventive effects were also achieved by attenuating the increased levels of hepatic proinflammatory cytokines, including IL1β, and neutrophil infiltration. I3C also attenuated EtOH-induced gut leakiness with decreased serum endotoxin levels through preventing EtOH-induced oxidative stress, apoptosis of enterocytes, and alteration of tight junction protein claudin-1. Furthermore, I3C alleviated adipose tissue inflammation and decreased free fatty acid release. Collectively, I3C prevented EtOH-induced liver injury via attenuating the damaging effect of ethanol on the gut-liver-adipose tissue axis. Therefore, I3C may also have a high potential for translational research in treating or preventing other types of hepatic injury associated with oxidative stress and inflammation.
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Affiliation(s)
- Youngshim Choi
- Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.
| | - Mohamed A Abdelmegeed
- Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA
| | - Byoung-Joon Song
- Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.
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15
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Wang W, Li P, Li W, Jiang J, Cui Y, Li S, Wang Z. Osteopontin activates mesenchymal stem cells to repair skin wound. PLoS One 2017; 12:e0185346. [PMID: 28957406 PMCID: PMC5619734 DOI: 10.1371/journal.pone.0185346] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Accepted: 09/11/2017] [Indexed: 01/11/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are promising candidates for skin wound repair due to their capabilities of accumulating at wounds and differentiating into multiple types of skin cells. However, the underlying mechanisms responsible for these processes remain unclear. In this study, we found that osteopontin (OPN) stimulated the migration of MSCs in vitro, and observed the recruitment of endogenous MSCs to a skin wound and their differentiation into keratinocytes and endothelial cells. In OPN knock-out mice, the recruitment of MSCs to the skin wound was significantly inhibited, and wound closure was hampered after an intradermal injection of exogenous MSCs compared to wild-type mice. Consistent with these observations, the expressions of adhesion molecule CD44 and its receptor E-selectin were significantly decreased in the lesions of OPN knock-out mice compared with wild-type mice suggesting that OPN may regulate the migration of MSCs through its interactions with CD44 during skin wound recovery. In summary, our data demonstrated that OPN played a critical role in activating the migration of MSCs to injured sites and their differentiation into specific skin cell types during skin wound healing.
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Affiliation(s)
- Wenping Wang
- Department of Plastic and Aesthetic Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Pei Li
- Department of Orthopedics, No.89 Hospital of People’s Liberation Army, Weifang, Shandong, China
| | - Wei Li
- Department of Plastic and Burn Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Junzi Jiang
- Department of Plastic and Aesthetic Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Yanyan Cui
- Department of Genetics and Cell Biology, Chongqing Medical University, Chongqing, China
| | - Shirong Li
- Department of Plastic and Aesthetic Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
- * E-mail: (ZW); (SL)
| | - Zhenxiang Wang
- Department of Plastic and Aesthetic Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
- * E-mail: (ZW); (SL)
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16
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Abstract
Alcoholic liver disease (ALD) is a leading cause of chronic liver disease with a wide spectrum of manifestations including simple steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma. Liver injury in ALD is caused by chronic inflammation, which has been actively investigated as a therapeutic target for the treatment of ALD for over the last four decades. In this review, we summarize a wide variety of inflammatory mediators that have been shown to contribute to the pathogenesis of ALD, and discuss the therapeutic potential of these mediators for the treatment of ALD.
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17
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Singh R, Hui T, Matsui A, Allahem Z, Johnston CD, Ruiz-Torruella M, Rittling SR. Modulation of infection-mediated migration of neutrophils and CXCR2 trafficking by osteopontin. Immunology 2016; 150:74-86. [PMID: 27599164 DOI: 10.1111/imm.12668] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Revised: 08/23/2016] [Accepted: 08/31/2016] [Indexed: 12/16/2022] Open
Abstract
Osteopontin (OPN) is a pro-inflammatory protein that paradoxically protects against inflammation and bone destruction in a mouse model of endodontic infection. Here we have tested the hypothesis that this effect of OPN is mediated by effects on migration of innate immune cells to the site of infection. Using the air pouch as a model of endodontic infection in mice, we showed that neutrophil accumulation at the site of infection with a mixture of endodontic pathogens is significantly reduced in OPN-deficient mice. Reduced neutrophil accumulation in the absence of OPN was accompanied by an increase in bacterial load. OPN-deficiency did not affect neutrophil survival, CXCR2 ligand expression, or the production of inflammatory cytokines in the air pouch. In vitro, OPN enhanced neutrophil migration to CXCL1, whereas in vivo, inhibition of CXCR2 suppressed cellular infiltration in air pouches of infected wild-type mice by > 50%, but had no effect in OPN-deficient mice. OPN increased cell surface expression of CXCR2 on bone marrow neutrophils in an integrin-αv -dependent manner, and suppressed the internalization of CXCR2 in the absence of ligand. Together, these results support a model where the protective effect of OPN results from enhanced initial neutrophil accumulation at sites of infection resulting in optimal bacterial killing. We describe a novel mechanism for this effect of OPN: integrin-αv -dependent suppression of CXCR2 internalization in neutrophils, which increases the ability of these cells to migrate to sites of infection in response to CXCR2 ligands.
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Affiliation(s)
- Rani Singh
- Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA.,Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA
| | - Tommy Hui
- Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA
| | - Aritsune Matsui
- Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA
| | - Ziyad Allahem
- Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA
| | - Christopher D Johnston
- Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA.,Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA
| | | | - Susan R Rittling
- Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA.,Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA
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18
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Vatsalya V, Song M, Schwandt ML, Cave MC, Barve SS, George DT, Ramchandani VA, McClain CJ. Effects of Sex, Drinking History, and Omega-3 and Omega-6 Fatty Acids Dysregulation on the Onset of Liver Injury in Very Heavy Drinking Alcohol-Dependent Patients. Alcohol Clin Exp Res 2016; 40:2085-2093. [PMID: 27589090 PMCID: PMC5367046 DOI: 10.1111/acer.13197] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 07/24/2016] [Indexed: 12/19/2022]
Abstract
BACKGROUND Heavy alcohol consumption frequently causes liver inflammation/injury, and certain fatty acids (FAs) may be involved in this liver pathology. In this study, we evaluated the association of heavy drinking and the changes in the FA levels involved in the ω-6 (pro-inflammatory) and ω-3 (anti-inflammatory) state in alcohol-dependent (AD) patients who had no clinical manifestations of liver injury. We aimed to identify sex-based differences in patients with mild or no biochemical evidence of liver injury induced by heavy drinking. METHODS A total of 114 heavy drinking AD female and male patients aged 21 to 65 years without clinical manifestations of liver injury, who were admitted to an alcohol dependence treatment program, were grouped by the alanine aminotransferase (ALT) levels: ≤40 IU/l, as no liver injury (GR.1), and >40 IU/l, as mild liver injury (GR.2). Patients were actively drinking until the day of admission. Comprehensive metabolic panel, comprehensive FA panel, and drinking history data were evaluated. RESULTS Elevated ALT and aspartate aminotransferase (AST) showed close association with markers of heavy alcohol intake. In the patients with mild biochemical liver injury (GR.2), females showed significantly higher AST level than males. Significant association of AST and total drinks in past 90 days (TD90) in females, and AST and heavy drinking days in past 90 days (HDD90) in males was observed. The ω-6:ω-3 ratio showed a significant pro-inflammatory response only in females with mild liver injury (GR.2) when adjusted by drinking history marker, TD90. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were increased in males with liver injury, while females did not show any comparable rise in EPA; and DHA levels were lower. CONCLUSIONS Measures of heavy drinking, TD90 and HDD90, predicted changes in liver injury. Changes in the ω-3 and ω-6 FA levels and the ω-6:ω-3 ratio showed a pro-inflammatory shift in patients with biochemical liver injury with a significant effect in females. Changes in FAs involved in the inflammatory state may represent one mechanism for liver inflammation/injury in response to heavy alcohol drinking.
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Affiliation(s)
- Vatsalya Vatsalya
- Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky.
- Robley Rex Veterans Affairs Medical Center, Louisville, Kentucky.
- Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland.
| | - Ming Song
- Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky
| | - Melanie L Schwandt
- Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland
| | - Matthew C Cave
- Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky
- Robley Rex Veterans Affairs Medical Center, Louisville, Kentucky
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky
| | - Shirish S Barve
- Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky
| | - David T George
- Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland
| | - Vijay A Ramchandani
- Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland
| | - Craig J McClain
- Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky
- Robley Rex Veterans Affairs Medical Center, Louisville, Kentucky
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky
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19
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Wen Y, Jeong S, Xia Q, Kong X. Role of Osteopontin in Liver Diseases. Int J Biol Sci 2016; 12:1121-8. [PMID: 27570486 PMCID: PMC4997056 DOI: 10.7150/ijbs.16445] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2016] [Accepted: 07/08/2016] [Indexed: 12/12/2022] Open
Abstract
Osteopontin (OPN), a multifunctional protein, is involved in numerous pathological conditions including inflammation, immunity, angiogenesis, fibrogenesis and carcinogenesis in various tissues. Extensive studies have elucidated the critical role of OPN in cell signaling such as regulation of cell proliferation, migration, inflammation, fibrosis and tumor progression. In the liver, OPN interacts with integrins, CD44, vimentin and MyD88 signaling, thereby induces infiltration, migration, invasion and metastasis of cells. OPN is highlighted as a chemoattractant for macrophages and neutrophils during injury in inflammatory liver diseases. OPN activates hepatic stellate cells (HSCs) to exert an enhancer in fibrogenesis. The role of OPN in hepatocellular carcinoma (HCC) has also generated significant interests, especially with regards to its role as a diagnostic and prognostic factor. Interestingly, OPN acts an opposing role in liver repair under different pathological conditions. This review summarizes the current understanding of OPN in liver diseases. Further understanding of the pathophysiological role of OPN in cellular interactions and molecular mechanisms associated with hepatic inflammation, fibrosis and cancer may contribute to the development of novel strategies for clinical diagnosis, monitoring and therapy of liver diseases.
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Affiliation(s)
- Yankai Wen
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China;; School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Seogsong Jeong
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qiang Xia
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaoni Kong
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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20
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Kalaz EB, Aydın AF, Doğan-Ekici I, Çoban J, Doğru-Abbasoğlu S, Uysal M. Protective effects of carnosine alone and together with alpha-tocopherol on lipopolysaccharide (LPS) plus ethanol-induced liver injury. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2016; 42:23-29. [PMID: 26773358 DOI: 10.1016/j.etap.2015.12.018] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/10/2015] [Revised: 12/22/2015] [Accepted: 12/26/2015] [Indexed: 06/05/2023]
Abstract
The aim of this study was to investigate the effect of carnosine (CAR) alone and together with vitamin E (Vit E) on alcoholic steatohepatitis (ASH) in rats. ASH was induced by ethanol (3 times; 5 g/kg; 12 h intervals, via gavage), followed by a single dose of lipopolysaccharide (LPS; 10 mg/kg; i.p.). CAR (250 mg/kg; i.p.) and Vit E (200 mg D-α-tocopherol/kg; via gavage) were administered 30 min before and 90 min after the LPS injection. CAR treatment lowered high serum transaminase activities together with hepatic histopathologic improvements in rats with ASH. Reactive oxygen species formation, malondialdehyde levels, myeloperoxidase activities and transforming growth factor β1 (TGF-β1) and collagen 1α1 (COL1A1) expressions were observed to decrease. These improvements were more remarkable in CAR plus Vit E-treated rats. Our results indicate that CAR may be effective in suppressing proinflammatory, prooxidant, and profibrotic factors in the liver of rats with ASH.
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Affiliation(s)
- Esra Betül Kalaz
- Department of Biochemistry, Istanbul Medical Faculty, Istanbul University, Çapa, Istanbul, Turkey
| | - A Fatih Aydın
- Department of Biochemistry, Istanbul Medical Faculty, Istanbul University, Çapa, Istanbul, Turkey
| | - Işın Doğan-Ekici
- Department of Pathology, Yeditepe University Medical Faculty, Kayışdağı, Istanbul, Turkey
| | - Jale Çoban
- Department of Biochemistry, Yeditepe University Medical Faculty, Kayışdağı, Istanbul, Turkey
| | - Semra Doğru-Abbasoğlu
- Department of Biochemistry, Istanbul Medical Faculty, Istanbul University, Çapa, Istanbul, Turkey.
| | - Müjdat Uysal
- Department of Biochemistry, Istanbul Medical Faculty, Istanbul University, Çapa, Istanbul, Turkey
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21
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The Response of Macrophages and Neutrophils to Hypoxia in the Context of Cancer and Other Inflammatory Diseases. Mediators Inflamm 2016; 2016:2053646. [PMID: 27034586 PMCID: PMC4789443 DOI: 10.1155/2016/2053646] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2015] [Accepted: 02/08/2016] [Indexed: 12/21/2022] Open
Abstract
Lack of oxygen (hypoxia) is a hallmark of a multitude of acute and chronic diseases and can be either beneficial or detrimental for organ restitution and recovery. In the context of inflammation, hypoxia is particularly important and can significantly influence the course of inflammatory diseases. Macrophages and neutrophils, the chief cellular components of innate immunity, display distinct properties when exposed to hypoxic conditions. Virtually every aspect of macrophage and neutrophil function is affected by hypoxia, amongst others, morphology, migration, chemotaxis, adherence to endothelial cells, bacterial killing, differentiation/polarization, and protumorigenic activity. Prominent arenas of macrophage and neutrophil function, for example, acute/chronic inflammation and the microenvironment of solid tumors, are characterized by low oxygen levels, demonstrating the paramount importance of the hypoxic response for proper function of these cells. Members of the hypoxia-inducible transcription factor (HIF) family emerged as pivotal molecular regulators of macrophages and neutrophils. In this review, we will summarize the molecular responses of macrophages and neutrophils to hypoxia in the context of cancer and other chronic inflammatory diseases and discuss the potential avenues for therapeutic intervention that arise from this knowledge.
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22
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Jovic S, Shikhagaie M, Mörgelin M, Erjefält JS, Kjellström S, Egesten A. Osteopontin is increased in cystic fibrosis and can skew the functional balance between ELR-positive and ELR-negative CXC-chemokines. J Cyst Fibros 2015; 14:453-63. [DOI: 10.1016/j.jcf.2014.11.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Revised: 11/24/2014] [Accepted: 11/25/2014] [Indexed: 12/13/2022]
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23
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Simão A, Madaleno J, Silva N, Rodrigues F, Caseiro P, Costa JN, Carvalho A. Plasma osteopontin is a biomarker for the severity of alcoholic liver cirrhosis, not for hepatocellular carcinoma screening. BMC Gastroenterol 2015; 15:73. [PMID: 26122937 PMCID: PMC4487194 DOI: 10.1186/s12876-015-0307-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Accepted: 06/24/2015] [Indexed: 12/11/2022] Open
Abstract
Background Implementation of surveillance programs for at-risk populations and identification of biomarkers for early hepatocellular carcinoma (HCC) detection are a major public health goal. Recently, osteopontin (OPN) has attracted attention as a promising biomarker, with some potential advantages compared to alpha-fetoprotein (AFP), but its role in the context of alcoholic cirrhosis has never been assessed. The aims of this study are to assess the utility of plasma OPN in the diagnosis of HCC in alcoholic cirrhotic patients and to investigate whether increased values are due to the tumor or underlying liver disease severity. Methods A total of 90 consecutively alcoholic cirrhosis patients, observed between Jun 2013 and May 2014 at a Liver Disease Unit, were included and divided into two groups: 45 without (group I) and 45 with HCC (group II). Plasma levels of OPN (ELISA, Immuno-Biological Laboratories, Gunma, Japan) and AFP (IMMULITE® 2000 AFP, Siemens Healthcare Diagnostics, Tarrytown, New York) were assessed. The diagnostic accuracy of each marker was evaluated using Receiver-Operating Characteristic (ROC) curve analysis (AUC) and its 95 % Confidence Interval (CI). Results Plasma OPN levels in group I patients (1176.28 +/–744.59 ng/mL) weren’t significantly different from those of group II (1210.75 +/–800.60 ng/mL) (p = 0.826). OPN levels significantly increased with advancing BCLC tumor stage and with advancing Child-Pugh class, in both groups. Comparing the two groups, AUC for OPN and AFP were 0.51 (95 % CI: 0.39–0.63) and 0.79 (95 % CI: 0.70–0.89), respectively. Based on the ROC analysis, there were no satisfactory cut-off values for OPN that would distinguish patients with from those without tumour. Conclusions Despite having a correlation with BCLC stage, the same was observed with progressive deterioration of underlying liver function in terms of Child-Pugh class and MELD score, and isn’t a useful diagnostic biomarker for HCC in alcoholic cirrhotic patients, particularly in the early stages. AFP confirms the performance evidenced in other studies, being superior to OPN. Searching more specific biomarkers for early diagnosis of HCC in alcoholic cirrhosis is still warranted.
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Affiliation(s)
- Adélia Simão
- Internal Medicine A-Centro Hospitalar e Universitário de Coimbra, Portugal, and University of Coimbra, Faculty of Medicine, Coimbra, Portugal, Av. Bissaya Barreto e Praceta Mota Pinto, 3000-075, Coimbra, Portugal.
| | - João Madaleno
- Internal Medicine A-Centro Hospitalar e Universitário de Coimbra, Portugal, and University of Coimbra, Faculty of Medicine, Coimbra, Portugal, Av. Bissaya Barreto e Praceta Mota Pinto, 3000-075, Coimbra, Portugal.
| | - Nuno Silva
- Internal Medicine A-Centro Hospitalar e Universitário de Coimbra, Portugal, and University of Coimbra, Faculty of Medicine, Coimbra, Portugal, Av. Bissaya Barreto e Praceta Mota Pinto, 3000-075, Coimbra, Portugal.
| | - Fernando Rodrigues
- Clinical Pathology-Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
| | - Paula Caseiro
- Clinical Pathology-Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
| | - José Nascimento Costa
- Internal Medicine A-Centro Hospitalar e Universitário de Coimbra, Portugal, and University of Coimbra, Faculty of Medicine, Coimbra, Portugal, Av. Bissaya Barreto e Praceta Mota Pinto, 3000-075, Coimbra, Portugal.
| | - Armando Carvalho
- Internal Medicine A-Centro Hospitalar e Universitário de Coimbra, Portugal, and University of Coimbra, Faculty of Medicine, Coimbra, Portugal, Av. Bissaya Barreto e Praceta Mota Pinto, 3000-075, Coimbra, Portugal.
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Lazaro R, Wu R, Lee S, Zhu NL, Chen CL, French SW, Xu J, Machida K, Tsukamoto H. Osteopontin deficiency does not prevent but promotes alcoholic neutrophilic hepatitis in mice. Hepatology 2015; 61:129-40. [PMID: 25132354 PMCID: PMC4280361 DOI: 10.1002/hep.27383] [Citation(s) in RCA: 97] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2013] [Accepted: 08/14/2014] [Indexed: 12/13/2022]
Abstract
UNLABELLED Alcoholic hepatitis (AH) is a distinct spectrum of alcoholic liver disease (ALD) with intense neutrophilic (polymorphonuclear; PMN) inflammation and high mortality. Although a recent study implicates osteopontin (SPP1) in AH, SPP1 is also shown to have protective effects on experimental ALD. To address this unsettled question, we examined the effects of SPP1 deficiency in male mice given 40% calories derived from ad libitum consumption of the Western diet high in cholesterol and saturated fat and the rest from intragastric feeding of alcohol diet without or with weekly alcohol binge. Weekly binge in this new hybrid feeding model shifts chronic ASH with macrophage inflammation and perisinusoidal and pericellular fibrosis to AH in 57% (15 of 26) of mice, accompanied by inductions of chemokines (Spp1, Cxcl1, and interleukin [Il]-17a), progenitor genes (Cd133, Cd24, Nanog, and epithelial cell adhesion molecule), PMN infiltration, and clinical features of AH, such as hypoalbuminemia, bilirubinemia, and splenomegaly. SPP1 deficiency does not reduce AH incidence and inductions of progenitor and fibrogenic genes, but rather enhances the Il-17a induction and PMN infiltration in some mice. Furthermore, in the absence of SPP1, chronic ASH mice without weekly binge begin to develop AH. CONCLUSION These results suggest that SPP1 has a protective, rather than causal, role for experimental AH reproduced in our model.
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Affiliation(s)
- Raul Lazaro
- Southern California Research Center for ALPD and Cirrhosis,Department of Pathology, Keck School of Medicine of the University of Southern California
| | - Raymond Wu
- Southern California Research Center for ALPD and Cirrhosis,Department of Pathology, Keck School of Medicine of the University of Southern California
| | - Sunyoung Lee
- Southern California Research Center for ALPD and Cirrhosis,Department of Pathology, Keck School of Medicine of the University of Southern California
| | - Nian-Ling Zhu
- Southern California Research Center for ALPD and Cirrhosis,Department of Pathology, Keck School of Medicine of the University of Southern California
| | - Chia-Lin Chen
- Southern California Research Center for ALPD and Cirrhosis,Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California
| | - Samuel W. French
- Southern California Research Center for ALPD and Cirrhosis,Harbor-UCLA Medical Center, Los Angeles, California, USA
| | - Jun Xu
- Southern California Research Center for ALPD and Cirrhosis,Department of Pathology, Keck School of Medicine of the University of Southern California
| | - Keigo Machida
- Southern California Research Center for ALPD and Cirrhosis,Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California
| | - Hidekazu Tsukamoto
- Southern California Research Center for ALPD and Cirrhosis,Department of Pathology, Keck School of Medicine of the University of Southern California,Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, USA
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25
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Seth D, Duly A, Kuo PC, McCaughan GW, Haber PS. Osteopontin is an important mediator of alcoholic liver disease via hepatic stellate cell activation. World J Gastroenterol 2014; 20:13088-13104. [PMID: 25278703 PMCID: PMC4177488 DOI: 10.3748/wjg.v20.i36.13088] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Accepted: 05/05/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate over-expression of Osteopontin (OPN) pathway expression and mechanisms of action in human alcoholic liver disease (ALD), in vivo and in vitro acute alcohol models.
METHODS: OPN pathway was evaluated in livers from patients with progressive stages of human ALD and serum from drinkers with and without liver cirrhosis. In vitro stellate LX2 cells exposed to acute alcohol and in vivo in acute alcoholic steatosis mouse models were also investigated for OPN pathway expression and function. WT and OPN-/- mice were administered an acute dose of alcohol and extent of liver injury was examined by histopathology and liver biochemistry after 16-24 h. The causative role of OPN was studied in OPN knockout animals and in vitro in stellate LX2 cells, utilizing siRNA, aptamer and neutralizing antibodies to block OPN and OPN pathway. OPN pathway expression and downstream functional consequences were measured for signaling by Western blotting, plasmin activation by spectrophotometric assays and cell migration by confocal imaging and quantitation.
RESULTS: OPN expression positively correlated with disease severity in patients with progressive stages of ALD. In vivo, associated with alcoholic steatosis, a single dose of acute alcohol significantly increased hepatic OPN mRNA and protein, and a cleaved OPN form in a dose dependent manner. OPN mRNA and secreted OPN also increased in parallel with activation of LX2 stellate cells within 4 h of a single dose of alcohol. Expression of OPN receptors, αvβ3-integrin and CD44, increased in human ALD, and in vivo and in vitro with alcohol administration. This was accompanied by downstream phosphorylation of Akt and Erk, increased mRNA expression of several fibrogenesis, fibrinolysis and extracellular matrix pathway genes, plasmin activation and hepatic stellate cell (HSC) migration. Inhibition of OPN and OPN-receptor mediated signaling partially inhibited alcohol-induced HSC activation, plasmin activity and cell migration.
CONCLUSION: OPN is a key mediator of the alcohol-induced effects on hepatic stellate cell functions and liver fibrogenesis.
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MESH Headings
- Animals
- Case-Control Studies
- Cell Movement
- Cells, Cultured
- Disease Models, Animal
- Extracellular Matrix/metabolism
- Extracellular Signal-Regulated MAP Kinases/metabolism
- Fatty Liver, Alcoholic/genetics
- Fatty Liver, Alcoholic/metabolism
- Fatty Liver, Alcoholic/pathology
- Female
- Fibrinolysin/metabolism
- Fibrinolysis
- Hepatic Stellate Cells/metabolism
- Hepatic Stellate Cells/pathology
- Humans
- Hyaluronan Receptors/metabolism
- Integrin alphaVbeta3/metabolism
- Liver Cirrhosis, Alcoholic/genetics
- Liver Cirrhosis, Alcoholic/metabolism
- Liver Cirrhosis, Alcoholic/pathology
- Mice, Inbred C57BL
- Mice, Knockout
- Osteopontin/deficiency
- Osteopontin/genetics
- Osteopontin/metabolism
- Phosphorylation
- Proto-Oncogene Proteins c-akt/metabolism
- RNA Interference
- RNA, Messenger/metabolism
- Severity of Illness Index
- Signal Transduction
- Time Factors
- Transfection
- Up-Regulation
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26
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Williams JA, Manley S, Ding WX. New advances in molecular mechanisms and emerging therapeutic targets in alcoholic liver diseases. World J Gastroenterol 2014; 20:12908-12933. [PMID: 25278688 PMCID: PMC4177473 DOI: 10.3748/wjg.v20.i36.12908] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Revised: 03/07/2014] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease is a major health problem in the United States and worldwide. Chronic alcohol consumption can cause steatosis, inflammation, fibrosis, cirrhosis and even liver cancer. Significant progress has been made to understand key events and molecular players for the onset and progression of alcoholic liver disease from both experimental and clinical alcohol studies. No successful treatments are currently available for treating alcoholic liver disease; therefore, development of novel pathophysiological-targeted therapies is urgently needed. This review summarizes the recent progress on animal models used to study alcoholic liver disease and the detrimental factors that contribute to alcoholic liver disease pathogenesis including miRNAs, S-adenosylmethionine, Zinc deficiency, cytosolic lipin-1β, IRF3-mediated apoptosis, RIP3-mediated necrosis and hepcidin. In addition, we summarize emerging adaptive protective effects induced by alcohol to attenuate alcohol-induced liver pathogenesis including FoxO3, IL-22, autophagy and nuclear lipin-1α.
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27
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Chang PL, Hsieh YH, Wang CC, Juliana MM, Tsuruta Y, Timares L, Elmets C, Ho KJ. Osteopontin facilitates ultraviolet B-induced squamous cell carcinoma development. J Dermatol Sci 2014; 75:121-32. [PMID: 24888687 PMCID: PMC4128184 DOI: 10.1016/j.jdermsci.2014.05.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2013] [Revised: 05/06/2014] [Accepted: 05/10/2014] [Indexed: 12/29/2022]
Abstract
BACKGROUND Osteopontin (OPN) is a matricellular glycoprotein that is markedly expressed in cutaneous squamous cell carcinomas (cSCCs) and in actinic keratoses implicating its role in photocarcinogenesis. OBJECTIVE To determine whether OPN facilitates the development of cSCC and its function. METHODS cSCCs development was compared between wild-type (WT) and OPN-null mice subjected to UVB irradiation for 43 weeks. UVB-induced OPN expression was determined by Western blot, immunoprecipitation, ELISA, and semi-quantitative RT-PCR. Epidermal layer and TUNEL analyses assessed if OPN mediates UVB-induced epidermal hyperplasia or suppresses UVB-induced apoptosis of basal keratinocytes, respectively. In vitro experiments determined whether OPN enhances cell survival of UVB-induced apoptosis and its potential mechanisms. Immunohistochemical analyses of epidermis assessed the expression of CD44 and focal adhesion kinase (FAK), molecules that mediate OPN survival function. RESULTS Compared to female WT mice, OPN-null mice did not develop cSCCs. UVB irradiation stimulated OPN protein expression in the dorsal skin by 11h and remains high at 24-48h. OPN did not mediate UVB-induced epidermal hyperplasia; instead, it protected basal keratinocytes from undergoing apoptosis upon UVB exposure. Likewise, the addition of OPN suppressed UVB-induced OPN-null cSCC cell apoptosis, the activation of caspase-9 activity, and increased phosphorylation of FAK at Y397. Furthermore, the expression of CD44 and FAK in WT mice epidermis was greater than that of OPN-null mice prior to and during early acute UVB exposure. CONCLUSION These data support the hypothesis that chronic UVB-induced OPN expression protects the survival of initiated basal keratinocytes and, consequently, facilitates cSCC develop.
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MESH Headings
- Animals
- Apoptosis/radiation effects
- Carcinoma, Squamous Cell/genetics
- Carcinoma, Squamous Cell/metabolism
- Carcinoma, Squamous Cell/pathology
- Carcinoma, Squamous Cell/prevention & control
- Cell Line
- Cell Survival/radiation effects
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Disease Models, Animal
- Epidermis/metabolism
- Epidermis/pathology
- Epidermis/radiation effects
- Female
- Focal Adhesion Kinase 1/metabolism
- Gene Expression Regulation
- Hyaluronan Receptors/metabolism
- Hyperplasia
- Keratinocytes/metabolism
- Keratinocytes/pathology
- Keratinocytes/radiation effects
- Mice, 129 Strain
- Mice, Knockout
- Neoplasms, Radiation-Induced/genetics
- Neoplasms, Radiation-Induced/metabolism
- Neoplasms, Radiation-Induced/pathology
- Neoplasms, Radiation-Induced/prevention & control
- Osteopontin/deficiency
- Osteopontin/genetics
- Osteopontin/metabolism
- Skin Neoplasms/genetics
- Skin Neoplasms/metabolism
- Skin Neoplasms/pathology
- Skin Neoplasms/prevention & control
- Time Factors
- Ultraviolet Rays/adverse effects
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Affiliation(s)
- Pi-Ling Chang
- Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
| | - Yu-Hua Hsieh
- Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Chao-Cheng Wang
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - M Margaret Juliana
- Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Yuko Tsuruta
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Laura Timares
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Craig Elmets
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Kang-Jey Ho
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
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28
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Ge X, Leung TM, Arriazu E, Lu Y, Urtasun R, Christensen B, Fiel MI, Mochida S, Sørensen ES, Nieto N. Osteopontin binding to lipopolysaccharide lowers tumor necrosis factor-α and prevents early alcohol-induced liver injury in mice. Hepatology 2014; 59:1600-16. [PMID: 24214181 PMCID: PMC3966944 DOI: 10.1002/hep.26931] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2013] [Accepted: 11/06/2013] [Indexed: 12/16/2022]
Abstract
UNLABELLED Although osteopontin (OPN) is induced in alcoholic patients, its role in the pathophysiology of alcoholic liver disease (ALD) remains unclear. Increased translocation of lipopolysaccharide (LPS) from the gut is key for the onset of ALD because it promotes macrophage infiltration and activation, tumor necrosis factor-α (TNFα) production, and liver injury. Since OPN is protective for the intestinal mucosa, we postulated that enhancing OPN expression in the liver and consequently in the blood and/or in the gut could protect from early alcohol-induced liver injury. Wild-type (WT), OPN knockout (Opn(-/-)), and transgenic mice overexpressing OPN in hepatocytes (Opn(HEP) Tg) were fed either the control or the ethanol Lieber-DeCarli diet. Ethanol increased hepatic, plasma, biliary, and fecal OPN more in Opn(HEP) Tg than in WT mice. Steatosis was less in ethanol-treated Opn(HEP) Tg mice as shown by decreased liver-to-body weight ratio, hepatic triglycerides, the steatosis score, oil red-O staining, and lipid peroxidation. There was also less inflammation and liver injury as demonstrated by lower alanine aminotransferase (ALT) activity, hepatocyte ballooning degeneration, LPS levels, the inflammation score, and the number of macrophages and TNFα(+) cells. To establish if OPN could limit LPS availability and its noxious effects in the liver, binding studies were performed. OPN showed binding affinity for LPS which prevented macrophage activation, reactive oxygen, and nitrogen species generation and TNFα production. Treatment with milk OPN (m-OPN) blocked LPS translocation in vivo and protected from early alcohol-induced liver injury. CONCLUSION Natural induction plus forced overexpression of OPN in the liver or treatment with m-OPN protect from early alcohol-induced liver injury by blocking the gut-derived LPS and TNFα effects in the liver.
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Affiliation(s)
- Xiaodong Ge
- Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, Box 1123, 1425 Madison Avenue, Room 11-76, New York, NY 10029, USA
| | - Tung-Ming Leung
- Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, Box 1123, 1425 Madison Avenue, Room 11-76, New York, NY 10029, USA
| | - Elena Arriazu
- Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, Box 1123, 1425 Madison Avenue, Room 11-76, New York, NY 10029, USA
| | - Yongke Lu
- Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, Box 1123, 1425 Madison Avenue, Room 11-76, New York, NY 10029, USA
| | - Raquel Urtasun
- Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, Box 1123, 1425 Madison Avenue, Room 11-76, New York, NY 10029, USA
| | - Brian Christensen
- Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10, Aarhus Science Park, DK-8000 Denmark
| | - Maria Isabel Fiel
- Department of Pathology, Mount Sinai School of Medicine, 1468 Madison Avenue, Room 15-28A, New York, NY 10029, USA
| | - Satoshi Mochida
- Gastroenterology and Hepatology, Internal Medicine, Saitama Medical School, 38 Morohongo, Moroyama-cho, Iruma-gun, Saitama 350-0495, Japan
| | - Esben S. Sørensen
- Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10, Aarhus Science Park, DK-8000 Denmark
| | - Natalia Nieto
- Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, Box 1123, 1425 Madison Avenue, Room 11-76, New York, NY 10029, USA
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29
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Wang Y, Kou Y, Wang X, Cederbaum A, Wang R. Multifactorial comparative proteomic study of cytochrome P450 2E1 function in chronic alcohol administration. PLoS One 2014; 9:e92504. [PMID: 24658151 PMCID: PMC3962406 DOI: 10.1371/journal.pone.0092504] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2014] [Accepted: 02/17/2014] [Indexed: 12/16/2022] Open
Abstract
With the use of iTRAQ technique, a multifactorial comparative proteomic study can be performed. In this study, to obtain an overview of ethanol, CYP2E1 and gender effects on liver injury and gain more insight into the underlying molecular mechanism, mouse liver proteomes were quantitatively analyzed using iTRAQ under eight conditions including mice of different genders, wild type versus CYP2E1 knockout, and normal versus alcohol diet. A series of statistical and bioinformatic analyses were explored to simplify and clarify multifactorial comparative proteomic data. First, with the Principle Component analysis, six proteins, CYP2E1, FAM25, CA3, BHMT, HIBADH and ECHS1, involved in oxidation reduction, energy and lipid metabolism and amino acid metabolism, were identified as the most differentially expressed gene products across all of the experimental conditions of our chronic alcoholism model. Second, hierarchical clustering analysis showed CYP2E1 knockout played a primary role in the overall differential protein expression compared with ethanol and gender factors. Furthermore, pair-wise multiple comparisons have revealed that the only significant expression difference lied in wild-type and CYP2E1 knockout mice both treated with ethanol. Third, K-mean clustering analysis indicated that the CYP2E1 knockout had the reverse effect on ethanol induced oxidative stress and lipid oxidation. More importantly, IPA analysis of proteomic data inferred that the gene expressions of two upstream regulators, NRF2 and PPARα, regulated by chronic alcohol feeding and CYP2E1 knockout, are involved in ethanol induced oxidative stress and lipid oxidation. The present study provides an effectively comprehensive data analysis strategy to compare multiple biological factors, contributing to biochemical effects of alcohol on the liver. The mass spectrometry proteomics data have been deposited to the ProteomeXchange with data set identifier of PXD000635.
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Affiliation(s)
- Yuan Wang
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Yan Kou
- Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Xiaodong Wang
- Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Arthur Cederbaum
- Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Rong Wang
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
- * E-mail:
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30
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Hoffman EP, Gordish-Dressman H, McLane VD, Devaney JM, Thompson PD, Visich P, Gordon PM, Pescatello LS, Zoeller RF, Moyna NM, Angelopoulos TJ, Pegoraro E, Cox GA, Clarkson PM. Alterations in osteopontin modify muscle size in females in both humans and mice. Med Sci Sports Exerc 2014; 45:1060-8. [PMID: 23274598 DOI: 10.1249/mss.0b013e31828093c1] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
PURPOSE An osteopontin (OPN; SPP1) gene promoter polymorphism modifies disease severity in Duchenne muscular dystrophy, and we hypothesized that it might also modify muscle phenotypes in healthy volunteers. METHODS Gene association studies were carried out for OPN (rs28357094) in the FAMuSS cohort (n = 752; mean ± SD age = 23.7 ± 5.7 yr). The phenotypes studied included muscle size (MRI), strength, and response to supervised resistance training. We also studied 147 young adults that had carried out a bout of eccentric elbow exercise (age = 24.0 ± 5.2 yr). Phenotypes analyzed included strength, soreness, and serum muscle enzymes. RESULTS In the FAMuSS cohort, the G allele was associated with 17% increase in baseline upper arm muscle volume only in women (F = 26.32; P = 5.32 × 10), explaining 5% of population variance. In the eccentric damage cohort, weak associations of the G allele were seen in women with both baseline myoglobin and elevated creatine kinase. The sexually dimorphic effects of OPN on muscle were also seen in OPN-null mice. Five of seven muscle groups examined showed smaller size in OPN-null female mice, whereas two were smaller in male mice. The query of OPN gene transcription after experimental muscle damage in mice showed rapid induction within 12 h (100-fold increase from baseline), followed by sustained high-level expression through 16 d of regeneration before falling to back to baseline. CONCLUSION OPN is a sexually dimorphic modifier of muscle size in normal humans and mice and responds to muscle damage. The OPN gene is known to be estrogen responsive, and this may explain the female-specific genotype effects in adult volunteers.
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Affiliation(s)
- Eric P Hoffman
- Department of Integrative Systems Biology, Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC 20010, USA.
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31
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Nagoshi S. Osteopontin: Versatile modulator of liver diseases. Hepatol Res 2014; 44:22-30. [PMID: 23701387 DOI: 10.1111/hepr.12166] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2013] [Revised: 05/12/2013] [Accepted: 05/16/2013] [Indexed: 12/16/2022]
Abstract
Osteopontin (OPN) is a multifunctional protein, involved in pathological conditions including inflammation, immunity, angiogenesis, fibrosis and cancer progression in various tissues. Hepatic inflammation and fibrosis induced by feeding with a diet deficient in methionine and choline (MCD diet) were markedly attenuated in OPN knockout mice when compared with wild-type mice in the model of non-alcoholic steatohepatitis (NASH). Hepatic cholangiocytes, myofibroblastic stellate cells and natural killer T cells were suggested to secret OPN in mice fed an MCD diet. Plasma and hepatic OPN levels were significantly higher in patients with NASH with advanced fibrosis than in those with early fibrosis. Hepatic OPN mRNA level was correlated with hepatic neutrophil infiltration and fibrosis in patients with alcoholic liver diseases. In those with hepatocellular carcinoma (HCC), OPN levels in plasma and HCC were prognostic factors after liver resection or transplantation. Downregulation of OPN inhibited tumor growth and lung metastasis in nude mice implanted with HCC cells. The single nucleotide polymorphism in the promoter region of the OPN gene was shown to be associated with activity of hepatitis in chronic hepatitis C patients, prognosis in patients with HCC, and growth and lung metastasis of HCC xenografts in nude mice. OPN was reported to be a downstream effecter of Hedgehog pathway, which modulates hepatic fibrosis and carcinogenesis. This review focuses on the roles of OPN in hepatic inflammation, fibrosis and cancer progression. Further elucidation of cellular interactions and molecular mechanisms associated with OPN actions may contribute to development of novel strategies for treatment of the liver diseases.
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Affiliation(s)
- Sumiko Nagoshi
- Department of Gastroenterology and Hepatology, Saitama Medical Center, Saitama Medical University, Saitama, Japan
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Pagel CN, Wasgewatte Wijesinghe DK, Taghavi Esfandouni N, Mackie EJ. Osteopontin, inflammation and myogenesis: influencing regeneration, fibrosis and size of skeletal muscle. J Cell Commun Signal 2013; 8:95-103. [PMID: 24318932 DOI: 10.1007/s12079-013-0217-3] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Accepted: 11/25/2013] [Indexed: 12/20/2022] Open
Abstract
Osteopontin is a multifunctional matricellular protein that is expressed by many cell types. Through cell-matrix and cell-cell interactions the molecule elicits a number of responses from a broad range of target cells via its interaction with integrins and the hyaluronan receptor CD44. In many tissues osteopontin has been found to be involved in important physiological and pathological processes, including tissue repair, inflammation and fibrosis. Post-natal skeletal muscle is a highly differentiated and specialised tissue that retains a remarkable capacity for regeneration following injury. Regeneration of skeletal muscle requires the co-ordinated activity of inflammatory cells that infiltrate injured muscle and are responsible for initiating muscle fibre degeneration and phagocytosis of necrotic tissue, and muscle precursor cells that regenerate the injured muscle fibres. This review focuses on the current evidence that osteopontin plays multiple roles in skeletal muscle, with particular emphasis on its role in regeneration and fibrosis following injury, and in determining the severity of myopathic diseases such as Duchenne muscular dystrophy.
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Affiliation(s)
- Charles N Pagel
- Faculty of Veterinary Science, University of Melbourne, Parkville, Victoria, 3010, Australia,
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Yang M, Ramachandran A, Yan HM, Woolbright BL, Copple BL, Fickert P, Trauner M, Jaeschke H. Osteopontin is an initial mediator of inflammation and liver injury during obstructive cholestasis after bile duct ligation in mice. Toxicol Lett 2013; 224:186-95. [PMID: 24188933 DOI: 10.1016/j.toxlet.2013.10.030] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2013] [Revised: 10/24/2013] [Accepted: 10/25/2013] [Indexed: 12/13/2022]
Abstract
Osteopontin (OPN) is a chemotactic factor which can be cleaved to the pro-inflammatory form by matrix metalloproteinases (MMPs). To test the hypothesis that OPN can modulate inflammatory liver injury during cholestasis, wild-type (WT) C57BL/6 and OPN knockout (OPN-KO) mice underwent bile duct ligation (BDL). OPN-KO mice showed significant reduction in liver injury (plasma ALT and necrosis) and neutrophil recruitment compared with WT animals at 24h but not 72h after BDL. In WT mice, a 4-fold increase in hepatic MMP-3 mRNA and elevated MMP activities and cleaved OPN levels were observed in bile. WT mice subjected to BDL in the presence of the MMP inhibitor BB-94 showed reduced liver injury, less neutrophil extravasation and diminished levels of cleaved OPN in bile. Thus, during obstructive cholestasis, OPN released from biliary epithelial cells could be cleaved by MMPs in bile. When the biliary system leaks, cleaved OPN enters the parenchyma and attracts neutrophils. In the absence of OPN, other chemoattractants, e.g. chemokines, mediate a delayed inflammatory response and injury. Taken together, our data suggest that OPN is the pro-inflammatory mediator that initiates the early neutrophil-mediated injury phase during obstructive cholestasis in mice.
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Affiliation(s)
- Min Yang
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
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Barreno RX, Richards JB, Schneider DJ, Cromar KR, Nadas AJ, Hernandez CB, Hallberg LM, Price RE, Hashmi SS, Blackburn MR, Haque IU, Johnston RA. Endogenous osteopontin promotes ozone-induced neutrophil recruitment to the lungs and airway hyperresponsiveness to methacholine. Am J Physiol Lung Cell Mol Physiol 2013; 305:L118-29. [PMID: 23666750 DOI: 10.1152/ajplung.00080.2013] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Inhalation of ozone (O₃), a common environmental pollutant, causes pulmonary injury, pulmonary inflammation, and airway hyperresponsiveness (AHR) in healthy individuals and exacerbates many of these same sequelae in individuals with preexisting lung disease. However, the mechanisms underlying these phenomena are poorly understood. Consequently, we sought to determine the contribution of osteopontin (OPN), a hormone and a pleiotropic cytokine, to the development of O₃-induced pulmonary injury, pulmonary inflammation, and AHR. To that end, we examined indices of these aforementioned sequelae in mice genetically deficient in OPN and in wild-type, C57BL/6 mice 24 h following the cessation of an acute (3 h) exposure to filtered room air (air) or O₃ (2 parts/million). In wild-type mice, O₃ exposure increased bronchoalveolar lavage fluid (BALF) OPN, whereas immunohistochemical analysis demonstrated that there were no differences in the number of OPN-positive alveolar macrophages between air- and O₃-exposed wild-type mice. O₃ exposure also increased BALF epithelial cells, protein, and neutrophils in wild-type and OPN-deficient mice compared with genotype-matched, air-exposed controls. However, following O₃ exposure, BALF neutrophils were significantly reduced in OPN-deficient compared with wild-type mice. When airway responsiveness to inhaled acetyl-β-methylcholine chloride (methacholine) was assessed using the forced oscillation technique, O₃ exposure caused hyperresponsiveness to methacholine in the airways and lung parenchyma of wild-type mice, but not OPN-deficient mice. These results demonstrate that OPN is increased in the air spaces following acute exposure to O₃ and functionally contributes to the development of O₃-induced pulmonary inflammation and airway and lung parenchymal hyperresponsiveness to methacholine.
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Affiliation(s)
- Ramon X Barreno
- Division of Pediatric Critical Care Medicine, Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX 77030, USA
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Abstract
Hepatic fibrosis is a known consequence of long-term use of alcohol and is regarded as a turning point in alcohol-induced liver disease because it can lead to cirrhosis. The mechanisms of injury are not well understood, but recent studies have helped advance the understanding of the earliest events in the process that eventually leads to hepatic injury and, in some cases, fibrosis. It is hoped that increasing understanding of the role played by the immune system in the process will lead to the development of new therapies for these patients.
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Affiliation(s)
- Anupama T Duddempudi
- Division of Gastroenterology, Hepatology and Nutrition North Shore University Hospital, 300 Community Drive, Manhasset, NY 11030, USA.
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Uaesoontrachoon K, Wasgewatte Wijesinghe DK, Mackie EJ, Pagel CN. Osteopontin deficiency delays inflammatory infiltration and the onset of muscle regeneration in a mouse model of muscle injury. Dis Model Mech 2012; 6:197-205. [PMID: 22917925 PMCID: PMC3529351 DOI: 10.1242/dmm.009993] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Osteopontin is secreted by skeletal muscle myoblasts and stimulates their proliferation. Expression of osteopontin in skeletal muscle is upregulated in pathological conditions including Duchenne muscular dystrophy, and recent evidence suggests that osteopontin might influence the course of this disease. The current study was undertaken to determine whether osteopontin regulates skeletal muscle regeneration. A whole muscle autografting model of regeneration in osteopontin-null and wild-type mice was used. Osteopontin expression was found to be strongly upregulated in wild-type grafts during the initial degeneration and subsequent early regeneration phases that are observed in this model. Grafted muscle from osteopontin-null mice degenerated more slowly than that of wild-type mice, as determined by histological assessment, fibre diameter and fibre number. The delayed degeneration in osteopontin-null grafts was associated with a delay in neutrophil and macrophage infiltration. Centrally nucleated (regenerating) muscle fibres also appeared more slowly in osteopontin-null grafts than in wild-type grafts. These results demonstrate that osteopontin plays a non-redundant role in muscle remodelling following injury.
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The osteopontin level in liver, adipose tissue and serum is correlated with fibrosis in patients with alcoholic liver disease. PLoS One 2012; 7:e35612. [PMID: 22530059 PMCID: PMC3329460 DOI: 10.1371/journal.pone.0035612] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2011] [Accepted: 03/18/2012] [Indexed: 12/11/2022] Open
Abstract
Background Osteopontin (OPN) plays an important role in the progression of chronic liver diseases. We aimed to quantify the liver, adipose tissue and serum levels of OPN in heavy alcohol drinkers and to compare them with the histological severity of hepatic inflammation and fibrosis. Methodology/Principal Findings OPN was evaluated in the serum of a retrospective and prospective group of 109 and 95 heavy alcohol drinkers, respectively, in the liver of 34 patients from the retrospective group, and in the liver and adipose tissue from an additional group of 38 heavy alcohol drinkers. Serum levels of OPN increased slightly with hepatic inflammation and progressively with the severity of hepatic fibrosis. Hepatic OPN expression correlated with hepatic inflammation, fibrosis, TGFβ expression, neutrophils accumulation and with the serum OPN level. Interestingly, adipose tissue OPN expression also correlated with hepatic fibrosis even after 7 days of alcohol abstinence. The elevated serum OPN level was an independent risk factor in estimating significant (F≥2) fibrosis in a model combining alkaline phosphatase, albumin, hemoglobin, OPN and FibroMeter® levels. OPN had an area under the receiving operator curve that estimated significant fibrosis of 0.89 and 0.88 in the retrospective and prospective groups, respectively. OPN, Hyaluronate (AUROC: 0.88), total Cytokeratin 18 (AUROC: 0.83) and FibroMeter® (AUROC: 0.90) estimated significance to the same extent in the retrospective group. Finally, the serum OPN levels also correlated with hepatic fibrosis and estimated significant (F≥2) fibrosis in 86 patients with chronic hepatitis C, which suggested that its elevated level could be a general response to chronic liver injury. Conclusion/Significance OPN increased in the liver, adipose tissue and serum with liver fibrosis in alcoholic patients. Further, OPN is a new relevant biomarker for significant liver fibrosis. OPN could thus be an important actor in the pathogenesis of this chronic liver disease.
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Urtasun R, Lopategi A, George J, Leung TM, Lu Y, Wang X, Ge X, Fiel MI, Nieto N. Osteopontin, an oxidant stress sensitive cytokine, up-regulates collagen-I via integrin α(V)β(3) engagement and PI3K/pAkt/NFκB signaling. Hepatology 2012; 55:594-608. [PMID: 21953216 PMCID: PMC3561739 DOI: 10.1002/hep.24701] [Citation(s) in RCA: 201] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
UNLABELLED A key feature in the pathogenesis of liver fibrosis is fibrillar Collagen-I deposition; yet, mediators that could be key therapeutic targets remain elusive. We hypothesized that osteopontin (OPN), an extracellular matrix (ECM) cytokine expressed in hepatic stellate cells (HSCs), could drive fibrogenesis by modulating the HSC pro-fibrogenic phenotype and Collagen-I expression. Recombinant OPN (rOPN) up-regulated Collagen-I protein in primary HSCs in a transforming growth factor beta (TGFβ)-independent fashion, whereas it down-regulated matrix metalloprotease-13 (MMP13), thus favoring scarring. rOPN activated primary HSCs, confirmed by increased α-smooth muscle actin (αSMA) expression and enhanced their invasive and wound-healing potential. HSCs isolated from wild-type (WT) mice were more profibrogenic than those from OPN knockout (Opn(-/-)) mice and infection of primary HSCs with an Ad-OPN increased Collagen-I, indicating correlation between both proteins. OPN induction of Collagen-I occurred via integrin α(v)β(3) engagement and activation of the phosphoinositide 3-kinase/phosphorylated Akt/nuclear factor kappa B (PI3K/pAkt/NFκB)-signaling pathway, whereas cluster of differentiation 44 (CD44) binding and mammalian target of rapamycin/70-kDa ribosomal protein S6 kinase (mTOR/p70S6K) were not involved. Neutralization of integrin α(v) β(3) prevented the OPN-mediated activation of the PI3K/pAkt/NFκB-signaling cascade and Collagen-I up-regulation. Likewise, inhibition of PI3K and NFκB blocked the OPN-mediated Collagen-I increase. Hepatitis C Virus (HCV) cirrhotic patients showed coinduction of Collagen-I and cleaved OPN compared to healthy individuals. Acute and chronic liver injury by CCl(4) injection or thioacetamide (TAA) treatment elevated OPN expression. Reactive oxygen species up-regulated OPN in vitro and in vivo and antioxidants prevented this effect. Transgenic mice overexpressing OPN in hepatocytes (Opn(HEP) Tg) mice developed spontaneous liver fibrosis compared to WT mice. Last, chronic CCl(4) injection and TAA treatment caused more liver fibrosis to WT than to Opn(-/-) mice and the reverse occurred in Opn(HEP) Tg mice. CONCLUSION OPN emerges as a key cytokine within the ECM protein network driving the increase in Collagen-I protein contributing to scarring and liver fibrosis.
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Affiliation(s)
| | | | | | | | | | | | | | - Maria Isabel Fiel
- Division of Liver Diseases, Departments of Medicine and Pathology, Mount Sinai School of Medicine, Box 1123, 1425 Madison Avenue, Room 11-76, New York, NY 10029, USA
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Kong L, Ren W, Li W, Zhao S, Mi H, Wang R, Zhang Y, Wu W, Nan Y, Yu J. Activation of peroxisome proliferator activated receptor alpha ameliorates ethanol induced steatohepatitis in mice. Lipids Health Dis 2011. [PMID: 22208561 DOI: 10.1016/j.jnutbio.2012.02.246] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Peroxisome proliferator activated receptor alpha (PPARα) regulates lipids metabolism and inhibits inflammatory response. However, the role of PPARα in alcoholic liver disease is largely unknown. We aim to elucidate the effect and the molecular basis of PPARα in ethanol induced hepatic injury in mice. RESULTS C57BL/6J mice fed with 4% ethanol-containing Lieber-DeCarli liquid diet for 12 weeks exhibited hepatocyte steatosis, necrosis and inflammatory infiltration, accompanied with elevated serum alanine aminotransferase (ALT) and aspartic transaminase (AST) levels, decreased hepatic expression of PPARα, lipids oxidation promoting genes and anti-inflammatory factors, as well as enhanced hepatic expression of fatty acids synthesis promoting genes and pro-inflammatory cytokines. Induction of PPARα by PPARα agonist WY14643 treatment for 2 weeks ameliorated the severity of liver injury and restored expression of genes altered by ethanol treatment. However, administration of PPARα antagonist GW6471 for 2 weeks promoted the inflammatory response. CONCLUSIONS The present study provided the evidence for the protective role of PPARα in ameliorating ethanol induced liver injury through modulation of the genes related to lipid metabolism and inflammatory response.
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Affiliation(s)
- Lingbo Kong
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, China
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Kong L, Ren W, Li W, Zhao S, Mi H, Wang R, Zhang Y, Wu W, Nan Y, Yu J. Activation of peroxisome proliferator activated receptor alpha ameliorates ethanol induced steatohepatitis in mice. Lipids Health Dis 2011; 10:246. [PMID: 22208561 PMCID: PMC3278384 DOI: 10.1186/1476-511x-10-246] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2011] [Accepted: 12/30/2011] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Peroxisome proliferator activated receptor alpha (PPARα) regulates lipids metabolism and inhibits inflammatory response. However, the role of PPARα in alcoholic liver disease is largely unknown. We aim to elucidate the effect and the molecular basis of PPARα in ethanol induced hepatic injury in mice. RESULTS C57BL/6J mice fed with 4% ethanol-containing Lieber-DeCarli liquid diet for 12 weeks exhibited hepatocyte steatosis, necrosis and inflammatory infiltration, accompanied with elevated serum alanine aminotransferase (ALT) and aspartic transaminase (AST) levels, decreased hepatic expression of PPARα, lipids oxidation promoting genes and anti-inflammatory factors, as well as enhanced hepatic expression of fatty acids synthesis promoting genes and pro-inflammatory cytokines. Induction of PPARα by PPARα agonist WY14643 treatment for 2 weeks ameliorated the severity of liver injury and restored expression of genes altered by ethanol treatment. However, administration of PPARα antagonist GW6471 for 2 weeks promoted the inflammatory response. CONCLUSIONS The present study provided the evidence for the protective role of PPARα in ameliorating ethanol induced liver injury through modulation of the genes related to lipid metabolism and inflammatory response.
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Affiliation(s)
- Lingbo Kong
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, China
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Arjomandi M, Frelinger J, Donde A, Wong H, Yellamilli A, Raymond W. Secreted osteopontin is highly polymerized in human airways and fragmented in asthmatic airway secretions. PLoS One 2011; 6:e25678. [PMID: 22031818 PMCID: PMC3198733 DOI: 10.1371/journal.pone.0025678] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2011] [Accepted: 09/09/2011] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Osteopontin (OPN) is a member of the small integrin-binding ligand N-linked glycoprotein (SIBLING) family and a cytokine with diverse biologic roles. OPN undergoes extensive post-translational modifications, including polymerization and proteolytic fragmentation, which alters its biologic activity. Recent studies suggest that OPN may contribute to the pathogenesis of asthma. METHODOLOGY To determine whether secreted OPN (sOPN) is polymerized in human airways and whether it is qualitatively different in asthma, we used immunoblotting to examine sOPN in bronchoalveolar lavage (BAL) fluid samples from 12 healthy and 21 asthmatic subjects (and in sputum samples from 27 healthy and 21 asthmatic subjects). All asthmatic subjects had mild to moderate asthma and abstained from corticosteroids during the study. Furthermore, we examined the relationship between airway sOPN and cellular inflammation. PRINCIPAL FINDINGS We found that sOPN in BAL fluid and sputum exists in polymeric, monomeric, and cleaved forms, with most of it in polymeric form. Compared to healthy subjects, asthmatic subjects had proportionately less polymeric sOPN and more monomeric and cleaved sOPN. Polymeric sOPN in BAL fluid was associated with increased alveolar macrophage counts in airways in all subjects. CONCLUSIONS These results suggest that sOPN in human airways (1) undergoes extensive post-translational modification by polymerization and proteolytic fragmentation, (2) is more fragmented and less polymerized in subjects with mild to moderate asthma, and (3) may contribute to recruitment or survival of alveolar macrophages.
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Affiliation(s)
- Mehrdad Arjomandi
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
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Hsieh YH, Margaret Juliana M, Ho KJ, Kuo HC, van der Heyde H, Elmets C, Chang PL. Host-derived osteopontin maintains an acute inflammatory response to suppress early progression of extrinsic cancer cells. Int J Cancer 2011; 131:322-33. [PMID: 21826648 DOI: 10.1002/ijc.26359] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2010] [Accepted: 07/27/2011] [Indexed: 01/13/2023]
Abstract
The matricellular protein osteopontin (OPN), expressed in various cancer types and elevated in the blood of cancer patients, is thought to have different functions when derived from host versus cancer cells. To assess the effect of host-derived OPN on growth of cancers of epithelial origin, we established a line of cutaneous squamous cell carcinoma (SCC) cells, named ONSC, which lacks the OPN gene and develops SCC in syngeneic wild-type (WT) and OPN-null mice. At 8 and/or 10 week after subcutaneous injection of ONSC cells in mice, however, there was a lower tumor incidence in WT mice, suggesting that host-derived OPN is associated with suppression of early growth of extrinsic cancer cells. Histological, immunohistochemical, biochemical and hematological analyses were performed on the tumor microenvironment and blood from tumor-bearing mice during the first week after implantation. Host-derived OPN suppression of extrinsic ONSC cell progression is likely mediated through elicitation of an early innate inflammatory response, through its function as a chemoattractant and/or by enhancing survival of inflammatory cells. Further, consistent with a previous report, the serum levels of host-derived OPN, which are elevated during the early phase of tumor growth in mice implanted with ONSC, appear to reflect an anti-tumor progression effect.
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Affiliation(s)
- Yu-Hua Hsieh
- Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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van der Windt GJW, Hoogendijk AJ, Schouten M, Hommes TJ, de Vos AF, Florquin S, van der Poll T. Osteopontin Impairs Host Defense During Pneumococcal Pneumonia. J Infect Dis 2011; 203:1850-8. [DOI: 10.1093/infdis/jir185] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
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Voican CS, Perlemuter G, Naveau S. Mechanisms of the inflammatory reaction implicated in alcoholic hepatitis: 2011 update. Clin Res Hepatol Gastroenterol 2011; 35:465-74. [PMID: 21571602 DOI: 10.1016/j.clinre.2011.01.017] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2011] [Revised: 01/26/2011] [Accepted: 01/31/2011] [Indexed: 02/07/2023]
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Yuan YS, Xie MQ, Qian ZH, Zhang XY, Yan DJ, Yu Y. Osteopontin: an important molecule in liver diseases. Shijie Huaren Xiaohua Zazhi 2011; 19:814-819. [DOI: 10.11569/wcjd.v19.i8.814] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Osteopontin (OPN) is a multi-functional glycoprotein that has been implicated in a number of physiological and pathological events in vivo. Recent studies have shown that abnormal changes in OPN expression occur in many liver diseases and animal models of liver diseases and may play an important role in the pathogenesis of these diseases. Elucidation of mechanisms underlying the role of OPN in the pathogenesis of different liver diseases will help identify new therapeutic targets and develop new drugs for these diseases.
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Nishimichi N, Hayashita-Kinoh H, Chen C, Matsuda H, Sheppard D, Yokosaki Y. Osteopontin undergoes polymerization in vivo and gains chemotactic activity for neutrophils mediated by integrin alpha9beta1. J Biol Chem 2011; 286:11170-8. [PMID: 21321126 DOI: 10.1074/jbc.m110.189258] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Osteopontin (OPN) is an integrin-binding inflammatory cytokine that undergoes polymerization catalyzed by transglutaminase 2. We have previously reported that polymeric OPN (polyOPN), but not unpolymerized OPN (OPN*), attracts neutrophils in vitro by presenting an acquired binding site for integrin α9β1. Among many in vitro substrates for transglutaminase 2, only a few have evidence for in vivo polymerization and concomitant function. Although polyOPN has been identified in bone and aorta, the in vivo functional significance of polyOPN is unknown. To determine whether OPN polymerization contributes to neutrophil recruitment in vivo, we injected OPN* into the peritoneal space of mice. Polymeric OPN was detected by immunoblotting in the peritoneal wash of mice injected with OPN*, and both intraperitoneal and plasma OPN* levels were higher in mice injected with a polymerization-incompetent mutant, confirming that OPN* polymerizes in vivo. OPN* injection induced neutrophil accumulation, which was significantly less following injection of a mutant OPN that was incapable of polymerization. The importance of in vivo polymerization was further confirmed with cystamine, a transglutaminase inhibitor, which blocked the polymerization and attenuated OPN*-mediated neutrophil recruitment. The thrombin-cleaved N-terminal fragment of OPN, another ligand for α9β1, was not responsible for neutrophil accumulation because a thrombin cleavage-incompetent mutant recruited similar numbers of neutrophils as wild type OPN*. Neutrophil accumulation in response to both wild type and thrombin cleavage-incompetent OPN* was reduced in mice lacking the integrin α9 subunit in leukocytes, indicating that α9β1 is required for polymerization-induced recruitment. We have illustrated a physiological role of molecular polymerization by demonstrating acquired chemotactic properties for OPN.
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Affiliation(s)
- Norihisa Nishimichi
- Cell-Matrix Frontier Laboratory, Biomedical Research Unit, Hiroshima University, Minamiku, Hiroshima, Japan
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Asai S, Kimbara N, Tada T, Imai M, Campbell W, Okada H, Okada N. Procarboxypeptidase R deficiency causes increased lethality in concanavalin A-induced hepatitis in female mice. Biol Pharm Bull 2010; 33:1256-9. [PMID: 20606325 DOI: 10.1248/bpb.33.1256] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Carboxypeptidase R (CPR), also known as thrombin-activatable fibrinolysis inhibitor (TAFI), is an enzyme generated by proteolytic cleavage of its zymogen (proCPR). CPR removes the C-terminal arginine from inflammatory peptides such as C3a and C5a, bradykinin, enkephalin, and the thrombin-cleaved N-terminal fragment osteopontin (cleaved N-OPN). In the mouse model of concanavalin A (Con A)-induced immune-mediated fulminating hepatitis, cleaved N-OPN is one of the important peptides that induce the production of chemokines or cytokines. In the current study using proCPR deficient mice, we showed that injection of Con A into the mouse tail vein can induce a significantly higher lethality in proCPR-deficient female but not in male mice. Furthermore, a lack of CPR activity increased serum macrophage inflammatory protein-2 (MIP-2) and high-mobility group box 1 (HMGB1) levels after Con A injection. These in vivo findings suggest that CPR helps to protect against Con A-induced hepatitis.
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Affiliation(s)
- Suzuka Asai
- Department of Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
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Stickel F, Seitz HK. Alcoholic steatohepatitis. Best Pract Res Clin Gastroenterol 2010; 24:683-93. [PMID: 20955970 DOI: 10.1016/j.bpg.2010.07.003] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2010] [Revised: 07/14/2010] [Accepted: 07/16/2010] [Indexed: 01/31/2023]
Abstract
Severe alcoholic steatohepatitis has a poor prognosis and is characterized by jaundice and signs of liver failure. Its incidence is unknown, but prevalence is around 20% in cohorts of alcoholics undergoing liver biopsy. Diagnosis is established with elevated liver transaminases, neutrophil counts, serum bilirubin, and impaired coagulation and a history of excessive alcohol consumption, and exclusion of other etiologies. Histology is helpful but not mandatory. Prognostic scores include the Maddrey's discriminant function, the model of end-stage liver disease, and the Glasgow Alcoholic Hepatitis Score. Pathophysiology involves hepatic fat storage, increased hepatic uptake of gut-derived endotoxins triggering Kupffer cell activation and release of proinflammatory triggers, induction of cytochrome P4502E1 producing toxic acetaldehyde and reactive oxygen species, and ethanol-mediated hyperhomocysteinemia causing endoplasmic reticulum stress. Treatment includes abstinence, enteral nutrition, corticosteroids, and possibly pentoxifylline. A debate is ongoing whether certain patients with severe alcoholic steatohepatitis could be eligible for liver transplantation.
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Affiliation(s)
- Felix Stickel
- Department of Visceral Surgery and Medicine, Inselspital, University of Bern, Murtenstrasse 35, CH-3010 Bern, Switzerland.
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van der Windt GJW, Wiersinga WJ, Wieland CW, Tjia ICSI, Day NP, Peacock SJ, Florquin S, van der Poll T. Osteopontin impairs host defense during established gram-negative sepsis caused by Burkholderia pseudomallei (melioidosis). PLoS Negl Trop Dis 2010; 4. [PMID: 20824216 PMCID: PMC2930856 DOI: 10.1371/journal.pntd.0000806] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2010] [Accepted: 07/30/2010] [Indexed: 11/18/2022] Open
Abstract
Background Melioidosis, caused by infection with Burkholderia (B.) pseudomallei, is a severe illness that is endemic in Southeast Asia. Osteopontin (OPN) is a phosphorylated glycoprotein that is involved in several immune responses including induction of T-helper 1 cytokines and recruitment of inflammatory cells. Methodology and Principal Findings OPN levels were determined in plasma from 33 melioidosis patients and 31 healthy controls, and in wild-type (WT) mice intranasally infected with B. pseudomallei. OPN function was studied in experimental murine melioidosis using WT and OPN knockout (KO) mice. Plasma OPN levels were elevated in patients with severe melioidosis, even more so in patients who went on to die. In patients who recovered plasma OPN concentrations had decreased after treatment. In experimental melioidosis in mice plasma and pulmonary OPN levels were also increased. Whereas WT and OPN KO mice were indistinguishable during the first 24 hours after infection, after 72 hours OPN KO mice demonstrated reduced bacterial numbers in their lungs, diminished pulmonary tissue injury, especially due to less necrosis, and decreased neutrophil infiltration. Moreover, OPN KO mice displayed a delayed mortality as compared to WT mice. OPN deficiency did not influence the induction of proinflammatory cytokines. Conclusions These data suggest that sustained production of OPN impairs host defense during established septic melioidosis. Melioidosis is a severe tropical disease caused by infection with the bacterium Burkholderia (B.) pseudomallei. In northeast Thailand infection with this bacterium is the major cause of community-acquired septicemia with a mortality rate up to 40%. Extending the knowledge on the mechanisms of host defense against B. pseudomallei infection would be helpful to improve treatment of this severe illness. Osteopontin (OPN) is a cytokine that is involved in several immune responses that occur during bacterial infection. In this study, we investigated levels of OPN in patients with melioidosis, and studied the function of OPN during experimental melioidosis in mice. We found that OPN concentrations were elevated in patients with severe melioidosis, and that high OPN concentrations are associated with poor outcome in patients with melioidosis. In experimental melioidosis in mice plasma and lung OPN levels were also increased. Moreover, mice with melioidosis that were deficient for OPN demonstrated reduced bacterial numbers in their lungs, diminished pulmonary tissue injury, and decreased neutrophil infiltration into the lungs during established melioidosis. Moreover, these mice displayed a delayed mortality as compared to control mice. In conclusion, sustained production of OPN impairs host defense during melioidosis.
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Affiliation(s)
- Gerritje J. W. van der Windt
- Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, The Netherlands
- Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands
| | - W. Joost Wiersinga
- Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, The Netherlands
- Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands
| | - Catharina W. Wieland
- Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, The Netherlands
- Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands
| | - Ivo C. S. I. Tjia
- Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, The Netherlands
- Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands
| | - Nicholas P. Day
- Mahidol University, Bangkok, Thailand
- Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Oxford, United Kingdom
| | - Sharon J. Peacock
- Mahidol University, Bangkok, Thailand
- Department of Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Sandrine Florquin
- Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands
| | - Tom van der Poll
- Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, The Netherlands
- Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands
- * E-mail:
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Zhang ZX, Shek K, Wang S, Huang X, Lau A, Yin Z, Sun H, Liu W, Garcia B, Rittling S, Jevnikar AM. Osteopontin expressed in tubular epithelial cells regulates NK cell-mediated kidney ischemia reperfusion injury. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2010; 185:967-973. [PMID: 20548025 DOI: 10.4049/jimmunol.0903245] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/29/2023]
Abstract
Renal ischemia reperfusion injury (IRI) occurs after reduced renal blood flow and is a major cause of acute injury in both native and transplanted kidneys. Studies have shown diverse cell types in both the innate and the adaptive immune systems participate in kidney IRI as dendritic cells, macrophages, neutrophils, B cells, CD4(+) NK(+) cells, and CD4(+) T cells all contribute to this form of injury. Recently, we have found that NK cells induce apoptosis in tubular epithelial cells (TECs) and also contribute to renal IRI. However, the mechanism of NK cell migration and activation during kidney IRI remains unknown. In this study, we have identified that kidney TECs express a high level of osteopontin (OPN) in vitro and in vivo. C57BL/6 OPN-deficient mice have reduced NK cell infiltration with less tissue damage compared with wild-type C57BL/6 mice after ischemia. OPN can directly activate NK cells to mediate TEC apoptotic death and can also regulate chemotaxis of NK cells to TECs. Taken together, our study's results indicate that OPN expression by TECs is an important factor in initial inflammatory responses that involves NK cells activity in kidney IRI. Inhibiting OPN expression at an early stage of IRI may be protective and preserve kidney function after transplantation.
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Affiliation(s)
- Zhu-Xu Zhang
- The Multi-Organ Transplant Program, London Health Sciences Centre, London, Ontario, Canada.
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