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Kumar K, Moon BH, Kumar S, Angdisen J, Kallakury BV, Fornace AJ, Suman S. Senolytic agent ABT-263 mitigates low- and high-LET radiation-induced gastrointestinal cancer development in Apc1638N/+ mice. Aging (Albany NY) 2025; 17:97-115. [PMID: 39792466 PMCID: PMC11810060 DOI: 10.18632/aging.206183] [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: 01/10/2024] [Accepted: 12/12/2024] [Indexed: 01/12/2025]
Abstract
Exposure to ionizing radiation (IR), both low-LET (e.g., X-rays, γ rays) and high-LET (e.g., heavy ions), increases the risk of gastrointestinal (GI) cancer. Previous studies have linked IR-induced GI cancer to cellular senescence associated secretory phenotype (SASP) signaling. This study explores the potential of senolytic therapy to mitigate IR-induced GI carcinogenesis. Male Apc1638N/+ mice were exposed to γ and 28Si-ions (69 keV/μm) IR. Two months later, they were treated with the senolytic agent ABT-263 orally for 5 days/week until euthanasia, followed by tumor counting and biospecimen collection at five months post-exposure. Tumors were classified as adenoma or carcinoma by a pathologist. Serum cytokine levels were measured, and the markers of senescence (p16), SASP (IL6), and oncogenic β-catenin signaling were assessed using in-situ immunostaining of intestinal tissue. Both low- and high-LET radiation exposure led to an increased frequency of adenoma and carcinoma in Apc1638N/+ mice, accompanied by increased cellular senescence, acquisition of SASP, and overexpression of BCL-XL protein in a subset of these cells. Furthermore, administration of ABT-263 resulted in the elimination of senescent/SASP cells, a decrease in pro-inflammatory cytokines (TNFRSF1B, CCL20, CXCL4, P-selectin, CCL27, and CXCL16) at the systemic level, and downregulation of β-catenin signaling that coincided with decreased GI cancer development. This study suggests a link between IR-induced senescent/SASP cell accumulation and GI cancer development. It also shows that the senolytic agent ABT-263 can regulate IR-induced inflammatory cytokines and carcinogenic mediators both systemically and in intestinal tissue. These findings support the potential of senolytic intervention to reduce IR-induced GI cancer risk.
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Affiliation(s)
- Kamendra Kumar
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Bo-Hyun Moon
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Santosh Kumar
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Jerry Angdisen
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Bhaskar V.S. Kallakury
- Department of Pathology, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Albert J. Fornace
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Shubhankar Suman
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
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Sano Y, Tomiyama T, Yagi N, Ito Y, Honzawa Y, Tahara T, Ikeura T, Fukui T, Shimoda S, Naganuma M. Platelet activation through CD62P and the formation of platelet-monocyte complexes are associated with the exacerbation of mucosal inflammation in patients with ulcerative colitis. Sci Rep 2024; 14:28055. [PMID: 39543171 PMCID: PMC11564891 DOI: 10.1038/s41598-024-78462-8] [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: 05/21/2024] [Accepted: 10/30/2024] [Indexed: 11/17/2024] Open
Abstract
Ulcerative colitis (UC) is a refractory, chronic inflammatory bowel disease of unknown etiology. Although platelets are activated in UC, their relevance in pathophysiology remains unclear. We analyzed the correlation of platelet activation and platelet-monocyte complexes (PMCs) with severity of mucosal inflammation using the Mayo endoscopic subscore (MES). Platelet activation marker, CD62P was upregulated in patients with UC compared with that in healthy controls (P < 0.05). CD62P expression was significantly higher in patients with MES3 (severe inflammation) than in those with MES ≤ 2 (endoscopic remission to moderate inflammation) (P < 0.001). The concentration of sCD62P in patients with MES0 (endoscopic remission) was significantly higher than in those with MES ≥ 1 (P < 0.01). The expression of CD40L, CD63, PAC-1, annexin V, and CD36, and the concentrations of sCD40L, PF4, and RANTES did not correlate with MES. The proportion of PMCs in patients with MES3 was higher than in those with MES ≤ 2 (P < 0.05). CD16 expression on monocytes with platelets was significantly higher than in monocytes without platelets (P < 0.001). Patients with complete remission after treatment showed significant reduction in PMCs 3 months after treatment (P < 0.05) but had no change in CD62P and sCD62P. Our data suggest that platelet activation via the CD62P-PMC axis is involved in UC pathophysiology.
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Affiliation(s)
- Yasuki Sano
- Third Department of Internal Medicine, Division of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan
| | - Takashi Tomiyama
- Third Department of Internal Medicine, Division of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan.
| | - Naoto Yagi
- Third Department of Internal Medicine, Division of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan
| | - Yuka Ito
- Third Department of Internal Medicine, Division of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan
| | - Yusuke Honzawa
- Third Department of Internal Medicine, Division of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan
| | - Tomomitsu Tahara
- Third Department of Internal Medicine, Division of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan
| | - Tsukasa Ikeura
- Third Department of Internal Medicine, Division of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan
| | - Toshiro Fukui
- Third Department of Internal Medicine, Division of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan
| | - Shinji Shimoda
- Third Department of Internal Medicine, Division of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan
| | - Makoto Naganuma
- Third Department of Internal Medicine, Division of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010, Japan
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3
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Xu M, Feng G, Fang J. Microcapsules based on biological macromolecules for intestinal health: A review. Int J Biol Macromol 2024; 276:133956. [PMID: 39029830 DOI: 10.1016/j.ijbiomac.2024.133956] [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: 04/03/2024] [Revised: 07/04/2024] [Accepted: 07/16/2024] [Indexed: 07/21/2024]
Abstract
Intestinal dysfunction is becoming increasingly associated with neurological and endocrine issues, raising concerns about its impact on world health. With the introduction of several breakthrough technologies for detecting and treating intestinal illnesses, significant progress has been made in the previous few years. On the other hand, traditional intrusive diagnostic techniques are expensive and time-consuming. Furthermore, the efficacy of conventional drugs (not capsules) is reduced since they are more likely to degrade before reaching their target. In this context, microcapsules based on different types of biological macromolecules have been used to encapsulate active drugs and sensors to track intestinal ailments and address these issues. Several biomacromolecules/biomaterials (natural protein, alginate, chitosan, cellulose and RNA etc.) are widely used for make microcapsules for intestinal diseases, and can significantly improve the therapeutic effect and reduce adverse reactions. This article systematically summarizes microencapsulated based on biomacromolecules material for intestinal health control and efficacy enhancement. It also discusses the application and mechanism research of microencapsulated biomacromolecules drugs in reducing intestinal inflammation, in addition to covering the preparation techniques of microencapsulated drug delivery systems used for intestinal health. Microcapsule delivery systems' limits and potential applications for intestinal disease diagnosis, treatment, and surveillance were highlighted.
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Affiliation(s)
- Minhui Xu
- College of Bioscience and Biotechnology, Hunan Agricultural University, Hunan Provincial Engineering Research Center of Applied Microbial Resources Development for Livestock and Poultry, Changsha 410128, Hunan, China
| | - Guangfu Feng
- College of Bioscience and Biotechnology, Hunan Agricultural University, Hunan Provincial Engineering Research Center of Applied Microbial Resources Development for Livestock and Poultry, Changsha 410128, Hunan, China.
| | - Jun Fang
- College of Bioscience and Biotechnology, Hunan Agricultural University, Hunan Provincial Engineering Research Center of Applied Microbial Resources Development for Livestock and Poultry, Changsha 410128, Hunan, China
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4
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Chen T, Meng W, Li Y, Li X, Yu X, Qi J, Ding D, Li W. Probiotics Armed with In Situ Mineralized Nanocatalysts and Targeted Biocoatings for Multipronged Treatment of Inflammatory Bowel Disease. NANO LETTERS 2024. [PMID: 38787330 DOI: 10.1021/acs.nanolett.4c01143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2024]
Abstract
While oral probiotics show promise in treating inflammatory bowel disease, the primary challenge lies in sustaining their activity and retention within the inflamed gastrointestinal environment. In this work, we develop an engineered probiotic platform that is armed with biocatalytic and inflamed colon-targeting nanocoatings for multipronged management of IBD. Notably, we achieve the in situ growth of artificial nanocatalysts on probiotics through a bioinspired mineralization strategy. The resulting ferrihydrite nanostructures anchored on bacteria exhibit robust catalase-like activity across a broad pH range, effectively scavenging ROS to alleviate inflammation. The further envelopment with fucoidan-based shields confers probiotics with additional inflamed colon-targeting functions. Upon oral administration, the engineered probiotics display markedly improved viability and colonization within the inflamed intestine, and they further elicit boosted prophylactic and therapeutic efficacy against colitis through the synergistic interplay of nanocatalysis-based immunomodulation and probiotics-mediated microbiota reshaping. The robust and multifunctional probiotic platforms offer great potential for the comprehensive management of gastrointestinal disorders.
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Affiliation(s)
- Ting Chen
- Tianjin Key Laboratory of Biomedical Materials and Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China
| | - Wen Meng
- Tianjin Key Laboratory of Biomedical Materials and Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China
| | - Yi Li
- Tianjin Key Laboratory of Biomedical Materials and Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China
| | - Xueping Li
- Tianjin Key Laboratory of Biomedical Materials and Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China
| | - Xuya Yu
- Tianjin Key Laboratory of Biomedical Materials and Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China
| | - Ji Qi
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, Frontiers Science Center for Cell Responses, and College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Dan Ding
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, Frontiers Science Center for Cell Responses, and College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Wen Li
- Tianjin Key Laboratory of Biomedical Materials and Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China
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5
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D'Antongiovanni V, Segnani C, Ippolito C, Antonioli L, Colucci R, Fornai M, Bernardini N, Pellegrini C. Pathological Remodeling of the Gut Barrier as a Prodromal Event of High-Fat Diet-Induced Obesity. J Transl Med 2023; 103:100194. [PMID: 37290605 DOI: 10.1016/j.labinv.2023.100194] [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: 02/17/2023] [Revised: 05/29/2023] [Accepted: 05/31/2023] [Indexed: 06/10/2023] Open
Abstract
Intestinal barrier alterations represent a primum movens in obesity and related intestinal dysfunctions. However, whether gut barrier remodeling represents prodromal events in obesity before weight gain, metabolic alterations, and systemic inflammation remains unclear. Herein, we examined morphologic changes in the gut barrier in a mouse model of high-fat diet (HFD) since the earliest phases of diet assumption. C57BL/6J mice were fed with standard diet (SD) or HFD for 1, 2, 4, or 8 weeks. Remodeling of intestinal epithelial barrier, inflammatory infiltrate, and collagen deposition in the colonic wall was assessed by histochemistry and immunofluorescence analysis. Obese mice displayed increased body and epididymal fat weight along with increased plasma resistin, IL-1β, and IL-6 levels after 8 weeks of HFD. Starting from 1 week of HFD, mice displayed (1) a decreased claudin-1 expression in lining epithelial cells, (2) an altered mucus in goblet cells, (3) an increase in proliferating epithelial cells in colonic crypts, (4) eosinophil infiltration along with an increase in vascular P-selectin, and (5) deposition of collagen fibers. HFD intake is associated with morphologic changes in the large bowel at mucosal and submucosal levels. In particular, the main changes include alterations in the mucous layer and intestinal epithelial barrier integrity and activation of mucosal defense-enhanced fibrotic deposition. These changes represent early events occurring before the development of obesity condition that could contribute to compromising the intestinal mucosal barrier and functions, opening the way for systemic dissemination.
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Affiliation(s)
- Vanessa D'Antongiovanni
- Unit of Histology and Medical Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Cristina Segnani
- Unit of Histology and Medical Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Chiara Ippolito
- Unit of Histology and Medical Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Luca Antonioli
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Rocchina Colucci
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | - Matteo Fornai
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Nunzia Bernardini
- Unit of Histology and Medical Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; Interdepartmental Research Centre "Nutraceuticals and Food for Health," University of Pisa, Pisa, Italy.
| | - Carolina Pellegrini
- Unit of Histology and Medical Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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Gala D, Newsome T, Roberson N, Lee SM, Thekkanal M, Shah M, Kumar V, Bandaru P, Gayam V. Thromboembolic Events in Patients with Inflammatory Bowel Disease: A Comprehensive Overview. Diseases 2022; 10:diseases10040073. [PMID: 36278572 PMCID: PMC9589934 DOI: 10.3390/diseases10040073] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 09/22/2022] [Accepted: 09/27/2022] [Indexed: 11/24/2022] Open
Abstract
Inflammatory bowel disease (IBD), Crohn’s disease and ulcerative colitis are chronic inflammatory disorders of the intestines. The underlying inflammation activates the coagulation cascade leading to an increased risk of developing arterial and venous thromboembolic events such as deep vein thrombosis and pulmonary embolism. Patients with IBD are at a 2–3-fold increased risk of developing thromboembolism. This risk increases in patients with active IBD disease, flare-ups, surgery, steroid treatment, and hospitalization. These complications are associated with significant morbidity and mortality making them important in clinical practice. Clinicians should consider the increased risk of thromboembolic events in patients with IBD and manage them with appropriate prophylaxis based on the risk. In this review, we discuss the literature associated with the pathophysiology of thromboembolism in patients with IBD, summarize the studies describing the various thromboembolic events, and the management of thromboembolism in patients with IBD.
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Affiliation(s)
- Dhir Gala
- American University of the Caribbean School of Medicine, 1 University Drive at Jordan Dr, Cupecoy, Sint Maarten, The Netherlands
- Correspondence:
| | - Taylor Newsome
- American University of the Caribbean School of Medicine, 1 University Drive at Jordan Dr, Cupecoy, Sint Maarten, The Netherlands
| | - Nicole Roberson
- American University of the Caribbean School of Medicine, 1 University Drive at Jordan Dr, Cupecoy, Sint Maarten, The Netherlands
| | - Soo Min Lee
- American University of the Caribbean School of Medicine, 1 University Drive at Jordan Dr, Cupecoy, Sint Maarten, The Netherlands
| | - Marvel Thekkanal
- American University of the Caribbean School of Medicine, 1 University Drive at Jordan Dr, Cupecoy, Sint Maarten, The Netherlands
| | - Mili Shah
- American University of the Caribbean School of Medicine, 1 University Drive at Jordan Dr, Cupecoy, Sint Maarten, The Netherlands
| | - Vikash Kumar
- Department of Internal Medicine, The Brooklyn Hospital Center, 121 DeKalb Ave, Brooklyn, NY 11201, USA
| | - Praneeth Bandaru
- Department of Gastroenterology, The Brooklyn Hospital Center, 121 DeKalb Ave, Brooklyn, NY 11201, USA
| | - Vijay Gayam
- Department of Gastroenterology, The Brooklyn Hospital Center, 121 DeKalb Ave, Brooklyn, NY 11201, USA
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Wang H, Vilches-Moure JG, Bettinger T, Cherkaoui S, Lutz A, Paulmurugan R. Contrast Enhanced Ultrasound Molecular Imaging of Spontaneous Chronic Inflammatory Bowel Disease in an Interleukin-2 Receptor α−/− Transgenic Mouse Model Using Targeted Microbubbles. NANOMATERIALS 2022; 12:nano12020280. [PMID: 35055297 PMCID: PMC8779209 DOI: 10.3390/nano12020280] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 01/09/2022] [Accepted: 01/14/2022] [Indexed: 12/15/2022]
Abstract
Inflammatory bowel disease (IBD) is a lifelong inflammatory disorder with relapsing–remission cycles, which is currently diagnosed by clinical symptoms and signs, along with laboratory and imaging findings. However, such clinical findings are not parallel to the disease activity of IBD and are difficult to use in treatment monitoring. Therefore, non-invasive quantitative imaging tools are required for the multiple follow-up exams of IBD patients in order to monitor the disease activity and determine treatment regimens. In this study, we evaluated a dual P- and E-selectin-targeted microbubble (MBSelectin) in an interleukin-2 receptor α deficient (IL-2Rα−/−) spontaneous chronic IBD mouse model for assessing long-term anti-inflammatory effects with ultrasound molecular imaging (USMI). We used IL-2Rα−/− (male and female on a C57BL/6 genetic background; n = 39) and C57BL/6 wild-type (negative control; n = 6) mice for the study. USMI of the proximal, middle, and distal colon was performed with MBSelectin using a small animal scanner (Vevo 2100) up to six times in each IL-2Rα−/− mouse between 6–30 weeks of age. USMI signals were compared between IL-2Rα−/− vs. wild-type mice, and sexes in three colonic locations. Imaged colon segments were analyzed ex vivo for inflammatory changes on H&E-stained sections and for selectin expression by immunofluorescence staining. We successfully detected spontaneous chronic colitis in IL-2Rα−/− mice between 6–30 weeks (onset at 6–14 weeks) compared to wild-type mice. Both male and female IL-2Rα−/− mice were equally (p = 0.996) affected with the disease, and there was no significant (p > 0.05) difference in USMI signals of colitis between the proximal, middle, and distal colon. We observed the fluctuating USMI signals in IL-2Rα−/− mice between 6–30 weeks, which might suggest a resemblance of the remission-flare pattern of human IBD. The ex vivo H&E and immunostaining further confirmed the inflammatory changes, and the high expression of P- and E-selectin in the colon. The results of this study highlight the IL-2Rα−/− mice as a chronic colitis model and are suitable for the long-term assessment of treatment response using a dual P- and E-selectin-targeted USMI.
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Affiliation(s)
- Huaijun Wang
- Department of Radiology, School of Medicine, Stanford University, Palo Alto, CA 94304, USA; (H.W.); (A.L.)
| | | | | | | | - Amelie Lutz
- Department of Radiology, School of Medicine, Stanford University, Palo Alto, CA 94304, USA; (H.W.); (A.L.)
| | - Ramasamy Paulmurugan
- Department of Radiology, School of Medicine, Stanford University, Palo Alto, CA 94304, USA; (H.W.); (A.L.)
- Correspondence: ; Tel.: +1-650-725-6097; Fax: +1-650-721-6921
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8
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Wéra O, Lecut C, Servais L, Hego A, Delierneux C, Jiang Z, Keutgens A, Evans RJ, Delvenne P, Lancellotti P, Oury C. P2X1 ion channel deficiency causes massive bleeding in inflamed intestine and increases thrombosis. J Thromb Haemost 2020; 18:44-56. [PMID: 31448510 DOI: 10.1111/jth.14620] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 08/09/2019] [Accepted: 08/21/2019] [Indexed: 01/15/2023]
Abstract
BACKGROUND Intestinal inflammation is associated with bleeding and thrombosis, two processes that may involve both platelets and neutrophils. However, the mechanisms and the respective contribution of these cells to intestinal bleeding and extra-intestinal thrombosis remain largely unknown. OBJECTIVE Our study aimed at investigating the mechanisms underlying the maintenance of vascular integrity and thrombosis in intestinal inflammation. METHODS We used a mouse model of acute colitis induced by oral administration of dextran sodium sulfate (DSS) for 7 days. Bleeding was assessed after depletion of platelets, neutrophils, or glycoprotein VI (GPVI); treatment with aspirin or clopidogrel; or in P2X1-deficient mice. Extra-intestinal thrombosis was analyzed using a laser-induced injury model of thrombosis in cremaster muscle arterioles. RESULTS Platelet depletion or P2X1 deficiency led to macrocytic regenerative anemia due to intestinal hemorrhage. In contrast, GPVI, P2Y12, and thromboxane A2 were dispensable. Platelet P-selectin expression and regulated on activation, normal T-cell expressed and secreted (RANTES) plasma levels were lower in DSS-treated P2X1-deficient mice as compared to wild-type mice, indicative of a platelet secretion defect. Circulating neutrophils had a more activated phenotype, and neutrophil infiltration in the colon was increased. P2X1-deficient mice also had elevated plasma granulocyte-colony stimulating factor (G-CSF) levels. Neutrophil depletion limited blood loss in these mice, whereas exogenous administration of G-CSF in colitic wild-type mice caused macrocytic anemia. Anemic colitic P2X1-deficient mice formed atypical neutrophil- and fibrin-rich, and platelet-poor thrombi upon arteriolar endothelial injury. CONCLUSIONS Platelets and P2X1 ion channels are mandatory to preserve vascular integrity in inflamed intestine. Upon P2X1 deficiency, neutrophils contribute to bleeding and they may also be responsible for enhanced thrombosis.
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Affiliation(s)
- Odile Wéra
- GIGA Cardiovascular Sciences, Laboratory of Thrombosis and Hemostasis and Valvular Heart Diseases, University of Liège, Liège, Belgium
- Department of Cardiology, University Hospital of Liège, Liège, Belgium
| | - Christelle Lecut
- Department of Laboratory of Hematology, University Hospital of Liège, Liège, Belgium
| | - Laurence Servais
- GIGA Cardiovascular Sciences, Laboratory of Thrombosis and Hemostasis and Valvular Heart Diseases, University of Liège, Liège, Belgium
- Department of Cardiology, University Hospital of Liège, Liège, Belgium
| | - Alexandre Hego
- GIGA Cardiovascular Sciences, Laboratory of Thrombosis and Hemostasis and Valvular Heart Diseases, University of Liège, Liège, Belgium
- Department of Cardiology, University Hospital of Liège, Liège, Belgium
| | - Céline Delierneux
- GIGA Cardiovascular Sciences, Laboratory of Thrombosis and Hemostasis and Valvular Heart Diseases, University of Liège, Liège, Belgium
- Department of Cardiology, University Hospital of Liège, Liège, Belgium
| | - Zheshen Jiang
- GIGA Cardiovascular Sciences, Laboratory of Thrombosis and Hemostasis and Valvular Heart Diseases, University of Liège, Liège, Belgium
- Department of Cardiology, University Hospital of Liège, Liège, Belgium
| | - Aurore Keutgens
- Department of Laboratory of Hematology, University Hospital of Liège, Liège, Belgium
| | - Richard J Evans
- Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, UK
| | - Philippe Delvenne
- Department of Pathology, University Hospital of Liège, Liège, Belgium
| | - Patrizio Lancellotti
- GIGA Cardiovascular Sciences, Laboratory of Thrombosis and Hemostasis and Valvular Heart Diseases, University of Liège, Liège, Belgium
- Gruppo Villa Maria Care and Research, Anthea Hospital, Bari, Italy
| | - Cécile Oury
- GIGA Cardiovascular Sciences, Laboratory of Thrombosis and Hemostasis and Valvular Heart Diseases, University of Liège, Liège, Belgium
- Department of Cardiology, University Hospital of Liège, Liège, Belgium
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9
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Patten DA, Shetty S. More Than Just a Removal Service: Scavenger Receptors in Leukocyte Trafficking. Front Immunol 2018; 9:2904. [PMID: 30631321 PMCID: PMC6315190 DOI: 10.3389/fimmu.2018.02904] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Accepted: 11/27/2018] [Indexed: 12/15/2022] Open
Abstract
Scavenger receptors are a highly diverse superfamily of proteins which are grouped by their inherent ability to bind and internalize a wide array of structurally diverse ligands which can be either endogenous or exogenous in nature. Consequently, scavenger receptors are known to play important roles in host homeostasis, with common endogenous ligands including apoptotic cells, and modified low density lipoproteins (LDLs); additionally, scavenger receptors are key regulators of inflammatory diseases, such as atherosclerosis. Also, as a consequence of their affinity for a wide range of microbial products, their role in innate immunity is also being increasingly studied. However, in this review, a secondary function of a number of endothelial-expressed scavenger receptors is discussed. There is increasing evidence that some endothelial-expressed scavenger receptors are able to directly bind leukocyte-expressed ligands and subsequently act as adhesion molecules in the trafficking of leukocytes in lymphatic and vascular tissues. Here, we cover the current literature on this alternative role for endothelial-expressed scavenger receptors and also speculate on their therapeutic potential.
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Affiliation(s)
- Daniel A Patten
- National Institute for Health Research Birmingham Liver Biomedical Research Unit and Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Shishir Shetty
- National Institute for Health Research Birmingham Liver Biomedical Research Unit and Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
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10
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Wang H, Felt SA, Guracar I, Taviani V, Zhou J, Sigrist RMS, Zhang H, Liau J, Vilches-Moure JG, Tian L, Saenz Y, Bettinger T, Hargreaves BA, Lutz AM, Willmann JK. Anatomical Road Mapping Using CT and MR Enterography for Ultrasound Molecular Imaging of Small Bowel Inflammation in Swine. Eur Radiol 2017; 28:2068-2076. [PMID: 29170798 DOI: 10.1007/s00330-017-5148-6] [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: 07/24/2017] [Revised: 09/27/2017] [Accepted: 10/18/2017] [Indexed: 10/18/2022]
Abstract
OBJECTIVES To evaluate the feasibility and time saving of fusing CT and MR enterography with ultrasound for ultrasound molecular imaging (USMI) of inflammation in an acute small bowel inflammation of swine. METHODS Nine swine with ileitis were scanned with either CT (n = 3) or MR (n = 6) enterography. Imaging times to load CT/MR images onto a clinical ultrasound machine, fuse them to ultrasound with an anatomical landmark-based approach, and identify ileitis were compared to the imaging times without anatomical road mapping. Inflammation was then assessed by USMI using dual selectin-targeted (MBSelectin) and control (MBControl) contrast agents in diseased and healthy control bowel segments, followed by ex vivo histology. RESULTS Cross-sectional image fusion with ultrasound was feasible with an alignment error of 13.9 ± 9.7 mm. Anatomical road mapping significantly reduced (P < 0.001) scanning times by 40%. Localising ileitis was achieved within 1.0 min. Subsequently performed USMI demonstrated significantly (P < 0.001) higher imaging signal using MBSelectin compared to MBControl and histology confirmed a significantly higher inflammation score (P = 0.006) and P- and E-selectin expression (P ≤ 0.02) in inflamed vs. healthy bowel. CONCLUSIONS Fusion of CT and MR enterography data sets with ultrasound in real time is feasible and allows rapid anatomical localisation of ileitis for subsequent quantification of inflammation using USMI. KEY POINTS • Real-time fusion of CT/MRI with ultrasound to localise ileitis is feasible. • Anatomical road mapping using CT/MRI significantly decreases the scanning time for USMI. • USMI allows quantification of inflammation in swine, verified with ex vivo histology.
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Affiliation(s)
- Huaijun Wang
- Department of Radiology, Stanford University, School of Medicine, 300 Pasteur Drive, Room H1307, Stanford, CA, 94305-5621, USA
| | - Stephen A Felt
- Department of Comparative Medicine, Stanford University, Stanford, CA, USA
| | - Ismayil Guracar
- Siemens Healthcare, Ultrasound Business Unit, Mountain View, CA, USA
| | - Valentina Taviani
- Department of Radiology, Stanford University, School of Medicine, 300 Pasteur Drive, Room H1307, Stanford, CA, 94305-5621, USA
| | - Jianhua Zhou
- Department of Radiology, Stanford University, School of Medicine, 300 Pasteur Drive, Room H1307, Stanford, CA, 94305-5621, USA
| | - Rosa Maria Silveira Sigrist
- Department of Radiology, Stanford University, School of Medicine, 300 Pasteur Drive, Room H1307, Stanford, CA, 94305-5621, USA
| | - Huiping Zhang
- Department of Radiology, Stanford University, School of Medicine, 300 Pasteur Drive, Room H1307, Stanford, CA, 94305-5621, USA
| | - Joy Liau
- Department of Radiology, Stanford University, School of Medicine, 300 Pasteur Drive, Room H1307, Stanford, CA, 94305-5621, USA
| | | | - Lu Tian
- Department of Health, Research & Policy, Stanford University, Stanford, CA, USA
| | - Yamil Saenz
- Department of Comparative Medicine, Stanford University, Stanford, CA, USA
| | | | - Brian A Hargreaves
- Department of Radiology, Stanford University, School of Medicine, 300 Pasteur Drive, Room H1307, Stanford, CA, 94305-5621, USA
| | - Amelie M Lutz
- Department of Radiology, Stanford University, School of Medicine, 300 Pasteur Drive, Room H1307, Stanford, CA, 94305-5621, USA
| | - Jürgen K Willmann
- Department of Radiology, Stanford University, School of Medicine, 300 Pasteur Drive, Room H1307, Stanford, CA, 94305-5621, USA.
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Increased Cell Adhesion Molecules, PECAM-1, ICAM-3, or VCAM-1, Predict Increased Risk for Flare in Patients With Quiescent Inflammatory Bowel Disease. J Clin Gastroenterol 2017; 51:522-527. [PMID: 27552332 PMCID: PMC5322248 DOI: 10.1097/mcg.0000000000000618] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
GOALS AND BACKGROUND Predicting the risk of flare-ups for patients with inflammatory bowel disease (IBD) is difficult. Alterations in gut endothelial regulation of mucosal immune homeostasis might be early events leading to flares in IBD. Cell adhesion molecules (CAMs), in particular, are important in maintaining endothelial integrity and regulating the migration of leukocytes into the gut. STUDY We evaluated the mRNA expression of various tight junction proteins, with an emphasis on CAMs, in 40 patients with IBD in clinical remission. Patients were retrospectively assessed at 6, 12, and 24 months after baseline colonoscopy, and at the end of all available follow-up (maximum 65 mo), for flare events to determine whether baseline mRNA expression was associated with subsequent flares. RESULTS At all follow-up points, the baseline expression of platelet endothelial cell adhesion molecule-1 (PECAM-1), ICAM-3, and VCAM-1 was significantly higher in patients who flared than in those who did not (2.4-fold elevation, P=0.012 for PECAM-1; 1.9-fold increased, P=0.03 for ICAM-3; and 1.4-fold increased, P=0.02 for VCAM-1). PECAM-1 and ICAM-3 expression was significantly increased in patients who flared as early as 6 months after baseline colonoscopy. In contrast, there were no significant differences between patients with and without flares in baseline expression of other CAMs (ESAM, ICAM-1, ICAM-2, E-selectin, P-selectin, and MadCAM1). CONCLUSIONS Increased expression of PECAM-1, ICAM-3, and VCAM-1 in colonic biopsies from patients with IBD in clinical remission is associated with subsequent flares. This suggests that increases in the expression of these proteins may be early events that lead to flares in patients with IBD.
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Almon E, Khoury T, Drori A, Gingis-Velitski S, Alon S, Chertkoff R, Mushkat M, Shaaltiel Y, Ilan Y. An oral administration of a recombinant anti-TNF fusion protein is biologically active in the gut promoting regulatory T cells: Results of a phase I clinical trial using a novel oral anti-TNF alpha-based therapy. J Immunol Methods 2017; 446:21-29. [PMID: 28392436 DOI: 10.1016/j.jim.2017.03.023] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Revised: 03/30/2017] [Accepted: 03/30/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND An orally administered BY-2 plant cell-expressed recombinant anti-TNF fusion protein (PRX-106) consists of the soluble form of the human TNF receptor (TNFR) fused to the Fc component of a human IgG1 domain. Aim This study aim at determining the safety and the immune modulatory effect of an oral administration of PRX-106 in humans. METHODS Three different doses (2, 8 or 16mg/day) of PRX-106 were orally administered for five consecutive days in 14 healthy volunteered participants. Subjects were followed for safety parameters and for an effect on T lymphocytes subsets and cytokine levels. RESULTS An oral administration of PRX-106 was safe and well tolerated. The PK study showed that PRX106 is not absorbed. No effect on white blood cells and lymphocytes counts were noted. A dose dependent effect was noted on systemic lymphocytes. The oral administration of all three dosages was associated with an increase in CD4+CD25+ and CD8+CD25+ subset of suppressor lymphocytes. A marked increase in CD4+CD25+FoxP3 regulatory T cells was noted in the 8mg treated group. In addition, NKT regulatory cells, CD3+CD69+ and CD4+CD62 lymphocyte subsets increased with treatment. No changes in serum TNF alpha were observed. CONCLUSION An oral administration of the non-absorbable recombinant anti-TNF fusion protein, PRX-106, is safe, not associated with immune suppression, while inducing a favorable anti-inflammatory immune modulation. The PRX-106 may provide a safe orally administered effective anti-TNF alpha-based immune therapy for inflammatory bowel diseases and non-alcoholic steatohepatitis, as well as other autoimmune, TNF-mediated diseases.
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Affiliation(s)
| | - Tawfik Khoury
- Gastroenterology and Liver Units, Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | - Ariel Drori
- Gastroenterology and Liver Units, Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | | | | | | | - Mordechai Mushkat
- Gastroenterology and Liver Units, Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | | | - Yaron Ilan
- Gastroenterology and Liver Units, Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
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Oommen AM, Somaiya N, Vijayan J, Kumar S, Venkatachalam S, Joshi L. GlycoGAIT: A web database to browse glycogenes and lectins under gastric inflammatory diseases. J Theor Biol 2016; 406:93-8. [PMID: 27436239 DOI: 10.1016/j.jtbi.2016.07.020] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Revised: 07/13/2016] [Accepted: 07/16/2016] [Indexed: 01/12/2023]
Abstract
The perplexing nature of dynamic glycosylation modification plays imperative role in determining the regulatory role of key glycoconjugates involved in immune system. Systematic analysis of change in expression pattern of glycogenes and lectins can bring in a comprehensive understanding of genetic basis of the glycobiological changes occurring in pathological condition. Advancement in the field of glycobiology has capacitated the process of linking gene expression changes of glycogenes with its biological function. This instigated us to systematically analyze changes in expression patterns focusing on glycome genomics under diverse gastrointestinal immune dysfunction background. To necessitate this, as a pilot project, we carefully integrated several publically available databases to construct a glycosylation process associated gene set as well as public expression microarray data associated with gastrointestinal infections into an online database called Glycosylation and Gut Associated Immune Tolerance (GlycoGAIT). Currently the database comprises of 548 well characterized genes belonging to glycogenes and lectins along with gene expression data obtained from human biopsy samples under both H. pylori infection and inflammatory bowel disease (IBD) condition. The user-friendly interface enables the users to quickly compare and interpret changes in expression patterns of glycome genomics under different gut associated inflammatory conditions. The database is available online at: https://apps.connexios.com/glycogait/.
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Affiliation(s)
- Anup Mammen Oommen
- Connexios Life Sciences, Prestige South End, 3rd Floor, South End Road, Basavanagudi, Bangalore 560004, Karnataka, India; Glycoscience Group, National Centre for Biomedical Engineering Science, National University of Ireland Galway, Galway, Ireland.
| | - Neeti Somaiya
- Connexios Life Sciences, Prestige South End, 3rd Floor, South End Road, Basavanagudi, Bangalore 560004, Karnataka, India.
| | - Jisha Vijayan
- Connexios Life Sciences, Prestige South End, 3rd Floor, South End Road, Basavanagudi, Bangalore 560004, Karnataka, India.
| | - Satheesh Kumar
- Connexios Life Sciences, Prestige South End, 3rd Floor, South End Road, Basavanagudi, Bangalore 560004, Karnataka, India.
| | - Suri Venkatachalam
- Connexios Life Sciences, Prestige South End, 3rd Floor, South End Road, Basavanagudi, Bangalore 560004, Karnataka, India.
| | - Lokesh Joshi
- Glycoscience Group, National Centre for Biomedical Engineering Science, National University of Ireland Galway, Galway, Ireland.
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15
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Selectin-mediated leukocyte trafficking during the development of autoimmune disease. Autoimmun Rev 2015; 14:984-95. [DOI: 10.1016/j.autrev.2015.06.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Accepted: 06/18/2015] [Indexed: 12/18/2022]
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16
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Israeli E, Goldin E, Fishman S, Konikoff F, Lavy A, Chowers Y, Melzer E, Lahat A, Mahamid M, Shirin H, Nussinson E, Segol O, Ya'acov AB, Shabbat Y, Ilan Y. Oral administration of non-absorbable delayed release 6-mercaptopurine is locally active in the gut, exerts a systemic immune effect and alleviates Crohn's disease with low rate of side effects: results of double blind Phase II clinical trial. Clin Exp Immunol 2015; 181:362-72. [PMID: 25846055 DOI: 10.1111/cei.12640] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2015] [Revised: 03/17/2015] [Accepted: 03/17/2015] [Indexed: 12/18/2022] Open
Abstract
Therapy for Crohn's disease (CD) with thiopurines is limited by systemic side effects. A novel formulation of fixed-dose, delayed-release 6-mercaptopurine (DR-6MP) was developed, with local effect on the gut immune system and minimal absorption. The aim of this study was to evaluate the safety and efficacy of DR-6MP in patients with moderately severe CD compared to systemically delivered 6-mercaptopurine (Purinethol). Seventy CD patients were enrolled into a 12-week, double-blind controlled trial. The primary end-point was the percentage of subjects with clinical remission [Crohn's Disease Activity Index (CDAI) < 150] or clinical response (100-point CDAI reduction). Twenty-six (56·5%) and 13 (54·2%) subjects from the DR-6MP and Purinethol cohorts, respectively, completed the study. DR-6MP had similar efficacy to Purinethol following 12 weeks of treatment. However, the time to maximal clinical response was 8 weeks for DR-6MP versus 12 weeks for Purinethol. A higher proportion of patients on DR-6MP showed clinical remission at week 8. A greater improvement in Inflammatory Bowel Disease Questionnaire (IBDQ) score was noted in the DR-6MP group. DR-6MP led to a decrease of CD62(+) expression on T cells, implying a reduction of lymphocyte adhesion to site of inflammation. DR-6MP was safer than Purinethol, with significantly fewer adverse events (AEs). There was no evidence of drug-induced leucopenia in the DR-6MP group; the proportion of subjects who developed hepatotoxicity was lower for the DR-6MP. Non-absorbable DR-6MP is safe and biologically active in the gut. It is clinically effective, exerting a systemic immune response with low systemic bioavailability and a low incidence of side effects.
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Affiliation(s)
- E Israeli
- Gastroenterology and Liver Units, Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem
| | - E Goldin
- Department of Gastroenterology, Shaarei Zedek Medical Center, Jerusalem
| | - S Fishman
- Department of Gastroenterology, Tel Aviv-Sourasky Medical Center, Tel Aviv
| | - F Konikoff
- Department of Gastroenterology, Meir Medical Center, Kfar Saba
| | - A Lavy
- Department of Gastroenterology, Bnai Zion Hospital, Haifa
| | - Y Chowers
- Department of Gastroenterology, Rambam Health Care Campus and Bruce Rappaport School of Medicine, Technion Israel Institute of Technology, Haifa
| | - E Melzer
- Department of Gastroenterology, Kaplan Medical Center, Rehovot
| | - A Lahat
- Department of Gastroenterology, Sheba Medical Center, Tel Hashomer
| | - M Mahamid
- Department of Gastroenterology, Holy Family Hospital, Nazareth
| | - H Shirin
- Department of Gastroenterology, Assaf Harofeh Medical Center, Zerifin
| | - E Nussinson
- Department of Gastroenterology, Ha'emek Medical Center, Afula
| | - O Segol
- Department of Gastroenterology, Carmel Medical Center, Haifa, Israel
| | - A Ben Ya'acov
- Gastroenterology and Liver Units, Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem
| | - Y Shabbat
- Gastroenterology and Liver Units, Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem
| | - Y Ilan
- Gastroenterology and Liver Units, Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem
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17
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Theodoratou E, Campbell H, Ventham NT, Kolarich D, Pučić-Baković M, Zoldoš V, Fernandes D, Pemberton IK, Rudan I, Kennedy NA, Wuhrer M, Nimmo E, Annese V, McGovern DPB, Satsangi J, Lauc G. The role of glycosylation in IBD. Nat Rev Gastroenterol Hepatol 2014; 11:588-600. [PMID: 24912389 DOI: 10.1038/nrgastro.2014.78] [Citation(s) in RCA: 121] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
A number of genetic and immunological studies give impetus for investigating the role of glycosylation in IBD. Experimental mouse models have helped to delineate the role of glycosylation in intestinal mucins and to explore the putative pathogenic role of glycosylation in colitis. These experiments have been extended to human studies investigating the glycosylation patterns of intestinal mucins as well as levels of glycans of serum glycoproteins and expression of glycan receptors. These early human studies have generated interesting hypotheses regarding the pathogenic role of glycans in IBD, but have generally been restricted to fairly small underpowered studies. Decreased glycosylation has been observed in the intestinal mucus of patients with IBD, suggesting that a defective inner mucus layer might lead to increased bacterial contact with the epithelium, potentially triggering inflammation. In sera, decreased galactosylation of IgG has been suggested as a diagnostic marker for IBD. Advances in glycoprofiling technology make it technically feasible and affordable to perform high-throughput glycan pattern analyses and to build on previous work investigating a much wider range of glycan parameters in large numbers of patients.
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Affiliation(s)
- Evropi Theodoratou
- Centre for Population Health Sciences, University of Edinburgh, Teviot Place, EH8 9AG, Edinburgh, UK
| | - Harry Campbell
- Centre for Population Health Sciences, University of Edinburgh, Teviot Place, EH8 9AG, Edinburgh, UK
| | - Nicholas T Ventham
- Centre for Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, Edinburgh, UK
| | - Daniel Kolarich
- Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1 OT Golm, 14476, Potsdam, Germany
| | | | - Vlatka Zoldoš
- University of Zagreb, Faculty of Science, Horvatovac 102a, 10000 Zagreb, Croatia
| | | | - Iain K Pemberton
- IP Research Consulting SAS, 34 Rue Carnot, 93160 Noisy-le-Grand, Paris, France
| | - Igor Rudan
- Centre for Population Health Sciences, University of Edinburgh, Teviot Place, EH8 9AG, Edinburgh, UK
| | - Nicholas A Kennedy
- Centre for Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, Edinburgh, UK
| | - Manfred Wuhrer
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, Netherlands
| | - Elaine Nimmo
- Centre for Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, Edinburgh, UK
| | - Vito Annese
- Department of Medical and Surgical Specialities, Division of Gastroenterology, AOU Careggi University Hospital, Largo Brambilla 13, 50139 Florence, Italy
| | - Dermot P B McGovern
- F.Widjaja Family Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Suite D4063, Los Angeles, CA 90048, USA
| | - Jack Satsangi
- Centre for Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, Edinburgh, UK
| | - Gordan Lauc
- Department of Biochemistry and Molecular Biology, University of Zagreb Faculty of Pharmacy and Biochemistry, Trg maršala Tita 14, 10000 Zagreb, Croatia
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Okanishi H, Kagawa Y, Watari T. Expression of selectins and P-selectin glycoprotein ligand-1 in dogs with lymphocytic–plasmacytic enteritis. Vet Immunol Immunopathol 2014; 161:42-8. [DOI: 10.1016/j.vetimm.2014.06.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2014] [Revised: 05/20/2014] [Accepted: 06/26/2014] [Indexed: 12/22/2022]
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Iwaszkiewicz KS, Schneider JJ, Hua S. Targeting peripheral opioid receptors to promote analgesic and anti-inflammatory actions. Front Pharmacol 2013; 4:132. [PMID: 24167491 PMCID: PMC3807052 DOI: 10.3389/fphar.2013.00132] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2013] [Accepted: 10/04/2013] [Indexed: 01/25/2023] Open
Abstract
Mechanisms of endogenous pain control are significant. Increasing studies have clearly produced evidence for the clinical usefulness of opioids in peripheral analgesia. The immune system uses mechanisms of cell migration not only to fight pathogens but also to control pain and inflammation within injured tissue. It has been demonstrated that peripheral inflammatory pain can be effectively controlled by an interaction of immune cell-derived opioid peptides with opioid receptors on peripheral sensory nerve terminals. Experimental and clinical studies have clearly shown that activation of peripheral opioid receptors with exogenous opioid agonists and endogenous opioid peptides are able to produce significant analgesic and anti-inflammatory effects, without central opioid mediated side effects (e.g., respiratory depression, sedation, tolerance, dependence). This article will focus on the role of opioids in peripheral inflammatory conditions and the clinical implications of targeting peripheral opioid receptors.
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Affiliation(s)
- Katerina S Iwaszkiewicz
- The School of Biomedical Sciences and Pharmacy, The University of Newcastle Callaghan, NSW, Australia
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Matos I, Bento AF, Marcon R, Claudino RF, Calixto JB. Preventive and therapeutic oral administration of the pentacyclic triterpene α,β-amyrin ameliorates dextran sulfate sodium-induced colitis in mice: the relevance of cannabinoid system. Mol Immunol 2013; 54:482-92. [PMID: 23454360 DOI: 10.1016/j.molimm.2013.01.018] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2012] [Revised: 01/28/2013] [Accepted: 01/30/2013] [Indexed: 01/23/2023]
Abstract
The pentacyclic triterpene α,β-amyrin has been previously reported as an effective compound in the treatment of several inflammatory conditions. Recent evidence indicates that α,β-amyrin displayed its effects through interaction with the cannabinoid pathway. We assessed the anti-inflammatory effects of the α,β-amyrin in the dextran sulfate sodium (DSS)-induced colitis in mice and investigated whether its effects were associated with the interaction with the cannabinoid system. Our results showed that the oral preventive or therapeutic treatment with α,β-amyrin significantly reduced disease activity, body weight loss, colonic damage, as well as colonic myeloperoxidase and N-acetylglucosaminidase activities. Moreover, α,β-amyrin decreases the colonic pro-inflammatory mediators tumor necrosis factor (TNF)-α, interleukin (IL)-1β and keratinocyte-derived chemokine (CXCL1/KC), while up-regulating the IL-4 levels. Additionally, we also observed that the α,β-amyrin caused a significant reduction of the adhesion molecules mRNA expression for intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), platelet cell adhesion molecule 1 (PCAM-1), β(2)-integrin and protein expression for proliferation marker Ki67, the macrophage molecule CD68 and for adhesion molecule P-selectin. Interestingly, our results also showed that the cannabinoid receptor 1 (CB(1)), but not CB(2), pharmacological blockade significantly reversed the beneficial effects of α,β-amyrin in DSS-induced colitis. Besides, our data demonstrated that mRNA expression for both the endocannabinoid hydrolase monoglyceride lipase 1 (MGL1) and fatty acid amide hydrolase (FAAH) were significantly reduced in the colon of α,β-amyrin-treated mice. Altogether, these results suggest that the α,β-amyrin might possess potential therapeutic interest for the treatment of IBD, and also provide new insights for the underlying mechanisms.
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Affiliation(s)
- Israel Matos
- Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, 88049-900, Florianópolis, SC, Brazil
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Wang H, Machtaler S, Bettinger T, Lutz AM, Luong R, Bussat P, Gambhir SS, Tranquart F, Tian L, Willmann JK. Molecular imaging of inflammation in inflammatory bowel disease with a clinically translatable dual-selectin-targeted US contrast agent: comparison with FDG PET/CT in a mouse model. Radiology 2013; 267:818-29. [PMID: 23371306 DOI: 10.1148/radiol.13122509] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE To develop and test a molecular imaging approach that uses ultrasonography (US) and a clinically translatable dual-targeted (P- and E-selectin) contrast agent (MBSelectin) in the quantification of inflammation at the molecular level and to quantitatively correlate selectin-targeted US with fluorodeoxyglucose (FDG) combined positron emission tomography (PET) and computed tomography (CT) in terms of visualization and quantification of different levels of inflammation in a murine acute colitis model. MATERIALS AND METHODS Animal studies were approved by the Institutional Administrative Panel on Laboratory Animal Care at Stanford University. MBSelectin was developed by covalently binding an analog of the naturally occurring binding ligand P-selectin glycoprotein ligand 1 fused to a human fragment crystallizable(or Fc) domain onto the lipid shell of perfluorobutane and nitrogen-containing MBs. Binding specificity of MBSelectin was assessed in vitro with a flow chamber assay and in vivo with a chemically induced acute colitis murine model. US signal was quantitatively correlated with FDG uptake at PET/CT and histologic grade. Statistical analysis was performed with the Student t test, analysis of variance, and Pearson correlation analysis. RESULTS MBSelectin showed strong attachment to both human and mouse P- and E-selectin compared with MBControl in vitro (P ≤ .002). In vivo, US signal was significantly increased (P < .001) in mice with acute colitis (173.8 arbitrary units [au] ± 134.8 [standard deviation]) compared with control mice (5.0 au ± 4.5). US imaging signal strongly correlated with FDG uptake on PET/CT images (ρ = 0.89, P < .001). Ex vivo analysis enabled confirmation of inflammation in mice with acute colitis and high expression levels of P- and E-selectin in mucosal capillaries (P = .014). CONCLUSION US with MBSelectin specifically enables detection and quantification of inflammation in a murine acute colitis model, leveraging the natural pathway of leukocyte recruitment in inflammatory tissue. US imaging with MBSelectin correlates well with FDG uptake at PET/CT imaging.
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Affiliation(s)
- Huaijun Wang
- Department of Radiology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, 300 Pasteur Dr, Room H1307; Stanford, CA 94305-5621, USA
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Tarlton NJ, Green CM, Lazarus NH, Rott L, Wong AP, Abramson ON, Bremer M, Butcher EC, Abramson T. Plasmablast frequency and trafficking receptor expression are altered in pediatric ulcerative colitis. Inflamm Bowel Dis 2012; 18:2381-91. [PMID: 22488927 PMCID: PMC3404263 DOI: 10.1002/ibd.22962] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2012] [Accepted: 03/05/2012] [Indexed: 12/18/2022]
Abstract
BACKGROUND The incidence of pediatric ulcerative colitis (UC), a chronic autoinflammatory disease of the colon, is on the rise. Although an increased infiltration of B cells from the peripheral blood into the colon occurs in UC, B-cell trafficking is understudied. We hypothesized that the frequency of circulating plasmablasts (PBs) and their trafficking receptor (TR) expression may be indicative of the location and degree of pathology in pediatric UC. METHODS We conducted multicolor flow cytometry analyses of circulating IgA(+/-) PBs and IgA(+) memory B cells (MBCs) in pediatric UC patients with remission, mild, moderate, and severe state of disease (n = 12), and healthy pediatric (n = 2) and adult donors (n = 11). RESULTS Compared to healthy donors the average frequency of PBs among total peripheral blood lymphocytes is increased 30-fold during severe UC activity, and positively correlates with Pediatric Ulcerative Colitis Activity Index score, C-reactive protein level, and erythrocyte sedimentation rate. A greater percent of PBs in severe patients express the gut-homing receptors α4β7 and CCR10, and the inflammatory homing molecule P-selectin ligand (P-sel lig). The percent of IgA(+) MBCs expressing α4β7, however, is reduced. Furthermore, expression of the small intestine TR CCR9 is decreased on α4β7(high) PBs, and on α4β7(high) /CCR10(high) PBs and MBCs in these patients, consistent with preferential cell targeting to the colon. CONCLUSIONS Peripheral blood PBs with a colon-homing phenotype (α4β7/CCR10/P-sel lig) are elevated in children with severe UC. Screening this B-cell subset may provide a complementary approach in monitoring disease activity or therapeutic efficacy in pediatric UC.
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Affiliation(s)
- Nicole J Tarlton
- San Jose State University, Department of Biology, One Washington Square, San Jose, CA 95192
| | - Caroline M Green
- San Jose State University, Department of Biology, One Washington Square, San Jose, CA 95192
| | - Nicole H Lazarus
- Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, California 94305
,Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304
| | - Lusijah Rott
- Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, California 94305
,Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304
| | - Anthony P Wong
- Kaiser Permanente Santa Clara, 710 Lawrence Express Way, Santa Clara, CA 95051
| | - Oren N Abramson
- Kaiser Permanente Santa Clara, 710 Lawrence Express Way, Santa Clara, CA 95051
| | - Martina Bremer
- San Jose State University, Department of Mathematics, One Washington Square, San Jose, CA 95192
| | - Eugene C Butcher
- Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, California 94305
,Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304
| | - Tzvia Abramson
- San Jose State University, Department of Biology, One Washington Square, San Jose, CA 95192
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Van Rees EP, Palmen MJ, Van De Goot FR, Macher BA, Dieleman LA. Leukocyte migration in experimental inflammatory bowel disease. Mediators Inflamm 2012; 6:85-93. [PMID: 18472841 PMCID: PMC2365857 DOI: 10.1080/09629359791776] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Emigration of leukocytes from the circulation into tissue by transendothelial migration, is mediated subsequently by adhesion molecules such as selectins, chemokines and integrins. This multistep paradigm, with multiple molecular choices at each step, provides a diversity in signals. The influx of neutrophils, monocytes and lymphocytes into inflamed tissue is important in the pathogenesis of chronic inflammatory bowel disease. The importance of each of these groups of adhesion molecules in chronic inflammatory bowel disease, either in human disease or in animal models, will be discussed below. Furthermore, the possibilities of blocking these different steps in the process of leukocyte extravasation in an attempt to prevent further tissue damage, will be taken into account.
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Affiliation(s)
- E P Van Rees
- Department of Cell Biology and Immunology Faculty of Medicine Vrije Universiteit Van der Boechorststraat 7 Amsterdam 1081 BT The Netherlands
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24
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Deshpande N, Lutz AM, Ren Y, Foygel K, Tian L, Schneider M, Pai R, Pasricha PJ, Willmann JK. Quantification and monitoring of inflammation in murine inflammatory bowel disease with targeted contrast-enhanced US. Radiology 2011; 262:172-80. [PMID: 22056689 DOI: 10.1148/radiol.11110323] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE To evaluate ultrasonography (US) by using contrast agent microbubbles (MBs) targeted to P-selectin (MB(P-selectin)) to quantify P-selectin expression levels in inflamed tissue and to monitor response to therapy in a murine model of chemically induced inflammatory bowel disease (IBD). MATERIALS AND METHODS All procedures in which laboratory animals were used were approved by the institutional administrative panel on laboratory animal care. Binding affinity and specificity of MB(P-selectin) were tested in cell culture experiments under flow shear stress conditions and compared with control MBs (MB(Control)). In vivo binding specificity of MB(P-selectin) to P-selectin was tested in mice with trinitrobenzenesulfonic acid-induced colitis (n = 22) and control mice (n = 10). Monitoring of anti-tumor necrosis factor α antibody therapy was performed over 5 days in an additional 30 mice with colitis by using P-selectin-targeted US imaging, by measuring bowel wall thickness and perfusion, and by using a clinical disease activity index score. In vivo targeted contrast material-enhanced US signal was quantitatively correlated with ex vivo expression levels of P-selectin as assessed by quantitative immunofluorescence. RESULTS Attachment of MB(P-selectin) to endothelial cells was significantly (P = .0001) higher than attachment of MB(Control) and significantly (ρ = 0.83, P = .04) correlated with expression levels of P-selectin on endothelial cells. In vivo US signal in mice with colitis was significantly higher (P = .0001) with MB(P-selectin) than with MB(Control). In treated mice, in vivo US signal decreased significantly (P = .0001) compared with that in nontreated mice and correlated well with ex vivo P-selectin expression levels (ρ = 0.69; P = .04). Colonic wall thickness (P ≥ .06), bowel wall perfusion (P ≥ .85), and clinical disease activity scoring (P ≥ .06) were not significantly different between treated and nontreated mice at any time. CONCLUSION Targeted contrast-enhanced US imaging enables noninvasive in vivo quantification and monitoring of P-selectin expression in inflammation in murine IBD.
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Affiliation(s)
- Nirupama Deshpande
- Molecular Imaging Program at Stanford, Department of Radiology, Stanford University School of Medicine, 300 Pasteur Dr, Stanford, CA 94305-5621, USA
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Tanida S, Mizoshita T, Mizushima T, Sasaki M, Shimura T, Kamiya T, Kataoka H, Joh T. Involvement of oxidative stress and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in inflammatory bowel disease. J Clin Biochem Nutr 2011; 48:112-6. [PMID: 21373262 PMCID: PMC3045682 DOI: 10.3164/jcbn.10-41] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2010] [Accepted: 06/01/2010] [Indexed: 12/28/2022] Open
Abstract
The pathophysiology of inflammatory bowel disease involves excessive immune effects of inflammatory cells against gut microbes. In genetically predisposed individuals, these effects are considered to contribute to the initiation and perpetuation of mucosal injury. Oxidative stress is a fundamental tissue-destructive mechanisms that can occur due to the reactive oxygen species and reactive nitrogen metabolites which are released in abundance from numerous inflammatory cells that have extravasated from lymphatics and blood vessels to the lamina propria. This extravasation is mediated by interactions between adhesion molecules including mucosal addressin cell adhesion molecule-1 and vascular cell adhesion molecule-1 on the surface of lymphocytes or neutrophils and their ligands on endothelial cells. Thus, reactive oxygen species and adhesion molecules play an important role in the development of inflammatory bowel disease. The present review focuses on the involvement of oxidative stress and adhesion molecules, in particular mucosal addressin cell adhesion molecule-1, in inflammatory bowel disease.
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Affiliation(s)
- Satoshi Tanida
- Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho, Nagoya, Aichi 467-8601, Japan
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26
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Abstract
Targeted nanoparticles have the potential to improve drug delivery efficiencies by more than two orders of magnitude, from the ~ 0.1% which is common today. Most pharmacologically agents on the market today are small drug molecules, which diffuse across the body’s blood-tissue barriers and distribute not only into the lesion, but into almost all organs. Drug actions in the non-lesion organs are an inescapable part of the drug delivery principle, causing “side-effects” which limit the maximally tolerable doses and result in inadequate therapy of many lesions. Nanoparticles only cross barriers by design, so side-effects are not built into their mode of operation. Delivery rates of almost 90% have been reported. This review examines the significance of these statements and checks how far they need qualification. What type of targeting is required? Is a single targeting sufficient? What new types of clinical challenge, such as immunogenicity, might attend the use of targeted nanoparticles?
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27
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Vainer B. Intercellular adhesion molecule-1 (ICAM-1) in ulcerative colitis: presence, visualization, and significance. APMIS 2010:1-43. [PMID: 20653648 DOI: 10.1111/j.1600-0463.2010.02647.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Affiliation(s)
- Ben Vainer
- Department of Pathology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
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28
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Effect of sesame lignans on TNF-alpha-induced expression of adhesion molecules in endothelial cells. Biosci Biotechnol Biochem 2010; 74:1539-44. [PMID: 20699585 DOI: 10.1271/bbb.100095] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The expression of cell adhesion molecules (CAMs) has been implicated as one of the most important causes of the development of inflammatory diseases such as atherosclerosis, and, it is speculated that the prevention of it is an effective approach to the control of atherosclerosis. In the present study, we investigated the effect of sesame lignans on the expression of CAMs in human umbilical vein endothelial cells (HUVECs) induced by tumor necrosis factor-alpha (TNF-alpha). Based on cell-ELISA analysis, we found that sesaminol-6-catechol downregulated the TNF-alpha-induced expression of CAMs in a dose-dependent manner. Moreover, these inhibitory effects were caused to be drastically exerted by downregulating the CAM proteins in TNF-alpha-activated HUVECs at transcriptional level. This suggests, that sesaminol-6-catehcol suppresses the expression of CAMs, and may be an active component of sesame lignans.
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Belmiro CLR, Castelo-Branco MTL, Melim LMC, Schanaider A, Elia C, Madi K, Pavão MSG, de Souza HSP. Unfractionated heparin and new heparin analogues from ascidians (chordate-tunicate) ameliorate colitis in rats. J Biol Chem 2009; 284:11267-78. [PMID: 19258310 DOI: 10.1074/jbc.m807211200] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The anti-inflammatory effect of mammalian heparin analogues, named dermatan sulfate and heparin, isolated from the ascidian Styela plicata was accessed in a TNBS-induced colitis model in rats. Subcutaneous administration of the invertebrate compounds during a 7-day period drastically reduced inflammation as observed by the normalization of the macroscopic and histological characteristics of the colon. At the molecular level, a decrease in the production of TNF-alpha, TGF-beta, and VEGF was observed, as well as a reduction of NF-kappaB and MAPK kinase activation. At the cellular level, the heparin analogues attenuated lymphocyte and macrophage recruitment and epithelial cell apoptosis. A drastic reduction in collagen-mediated fibrosis was also observed. No hemorrhagic events were observed after glycan treatment. These results strongly indicate the potential therapeutic use of these compounds for the treatment of colonic inflammation with a lower risk of hemorrhage when compared with mammalian heparin.
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Affiliation(s)
- Celso L R Belmiro
- Laboratório de Tecido Conjuntivo, Hospital Universitário Clementino Fraga Filho (HUCFF) and Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-913, Brazil
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31
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Eksteen B, Liaskou E, Adams DH. Lymphocyte homing and its role in the pathogenesis of IBD. Inflamm Bowel Dis 2008; 14:1298-312. [PMID: 18393377 DOI: 10.1002/ibd.20453] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Inflammatory bowel disease (IBD) is an idiopathic disorder of chronic inflammation of the gastrointestinal tract. Experimental models of IBD and results from human genomewide linkage studies suggest that the primary defect that leads to IBD is an inappropriate mucosal immune response to normal intestinal microbes. Genetic alterations not only confer increased susceptibility to IBD but also appear to determine the nature and location of the intestinal inflammation, as is evident in patients with genetic alterations of NOD2 and their susceptibility for ileal Crohn's disease. IBD has traditionally been classified into 2 subtypes, namely, ulcerative colitis (UC) and Crohn's disease (CD), based on histological appearance and anatomical distribution. However, an increasing body of data supports the concept that IBD is an umbrella diagnosis encompassing a variety of disorders with distinct genetic, microbial, and environmental determinants that cluster either into a UC or CD phenotype. The shared common pathway is uncontrolled intestinal inflammation. A key element in the pathogenesis of intestinal inflammation in both UC and CD is increased leukocyte recruitment from the circulation, and this provides a potential target for pharmaceutical inhibition. In this article we review the current understanding of the molecules that determine leukocyte trafficking to the gut and highlight opportunities where their inhibition could be exploited to treat IBD.(Inflamm Bowel Dis 2008).
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Affiliation(s)
- Bertus Eksteen
- Liver Research Laboratories, MRC Centre for Immune Regulation, Institute for Biomedical Research, Medical School, University of Birmingham, Birmingham, United Kingdom
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32
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Molecular fingerprints of neutrophil-dependent oxidative stress in inflammatory bowel disease. J Gastroenterol 2007; 42:787-98. [PMID: 17940831 DOI: 10.1007/s00535-007-2096-y] [Citation(s) in RCA: 90] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2007] [Accepted: 07/18/2007] [Indexed: 02/04/2023]
Abstract
Neutrophil accumulation within epithelial crypts and in the intestinal mucosa directly correlates with clinical disease activity and epithelial injury in inflammatory bowel disease (IBD). Current advances have defined the mechanisms by which neutrophils are activated or migrate across endothelial and mucosal epithelial cells. A better understanding of this process will likely provide new insights into novel treatment strategies for IBD. Especially, activated neutrophils produce reactive oxygen and nitrogen species and myeloperoxidase within intestinal mucosa, which induce oxidative stress. Posttranslational modification of proteins generated by these reactive species serves as a "molecular fingerprint" of protein modification by lipid peroxidation-, nitric oxide-, and myeloperoxidase-derived oxidants. Measurement of these modified proteins may serve both as a quantitative index of oxidative stress and an important new biological marker of clinical relevance to IBD. We have succeeded in the clinical development of a novel granulocyte adsorptive apheresis therapy for IBD. In this review, we discuss current advances in defining the role of neutrophil-dependent oxidative stress in IBD.
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Broedl UC, Schachinger V, Lingenhel A, Lehrke M, Stark R, Seibold F, Göke B, Kronenberg F, Parhofer KG, Konrad-Zerna A. Apolipoprotein A-IV is an independent predictor of disease activity in patients with inflammatory bowel disease. Inflamm Bowel Dis 2007; 13:391-7. [PMID: 17206692 DOI: 10.1002/ibd.20078] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND ApoA-IV, an apolipoprotein (apo) with antioxidant, antiatherogenic, and antiinflammatory properties, was recently demonstrated to inhibit dextran sulfate sodium (DSS)-induced experimental colitis in mice. We therefore hypothesized that apoA-IV may be associated with disease activity in patients with inflammatory bowel disease (IBD). METHODS We addressed this question by testing for associations between apoA-IV genotypes, apoA-IV plasma levels, inflammatory parameters, and clinical disease activity in 206 patients with Crohn's disease (CD), 95 subjects with ulcerative colitis (UC), and 157 healthy controls. RESULTS In CD patients, apoA-IV plasma levels were inversely associated with C-reactive protein (CRP) (P = 0.005) and disease activity (P = 0.01) in univariate analysis. In multiple logistic regression analysis, apoA-IV levels were identified as an independent predictor of elevated CRP (odds ratio [OR] 0.956, 95% confidence interval [CI]: 0.916-0.998, P = 0.04) and active disease (OR 0.957, 95% CI: 0.918-0.998, P = 0.04). In UC patients the apoA-IV gene variant 360 His (P = 0.03) but not apoA-IV levels (P = 0.15) were associated with increased disease activity in univariate analysis. This association, however, was lost in multiple logistic regression analysis (OR 3.435, 95% CI 0.995-11.853, P = 0.05). CONCLUSIONS To our knowledge, this is the first study to demonstrate an association of apoA-IV with disease activity in patients with CD. Further studies are needed to define the relationship of apoA-IV to IBD.
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Affiliation(s)
- Uli C Broedl
- Department of Internal Medicine II, University of Munich, Germany.
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34
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Neuman MG. Immune dysfunction in inflammatory bowel disease. Transl Res 2007; 149:173-86. [PMID: 17383591 DOI: 10.1016/j.trsl.2006.11.009] [Citation(s) in RCA: 165] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2006] [Revised: 11/19/2006] [Accepted: 11/21/2006] [Indexed: 02/08/2023]
Abstract
Ulcerative colitis (UC) and Crohn's disease (CD) are idiopathic inflammatory bowel diseases (IBDs) that are characterized by chronic periods of exacerbation and remission. Research into the immunopathogenesis of IBD adds support to the theory that the disease results from a dysfunctional regulation of the immune system that leads to the polarization of intestinal immune cells toward a Th1 (T helper) response. The immunologic factors that mediate alterations in intestinal homeostasis and the development of intestinal mucosal inflammation have been at the forefront of IBD research. Cytokines, which are important regulators of leukocyte trafficking and apoptotic cell death, have emerged as essential immune molecules in the pathogenesis of IBD. In this study, recent advances in the understanding of the dynamism of cytokines and the consequences for mucosal immunity and inflammation in IBD are discussed. Furthermore, this study highlights the potential use of cytokines, anti-cytokine antibodies, and cytokine-related biologic therapies as novel targets for the treatment of IBD.
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Affiliation(s)
- Manuela G Neuman
- Department of Pharmacology and Institute of Drug Research, University of Toronto, Toronto, Ontario, Canada.
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35
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Kayo S, Ikura Y, Suekane T, Shirai N, Sugama Y, Ohsawa M, Adachi K, Watanabe K, Nakamura S, Fujiwara Y, Oshitani N, Higuchi K, Maeda K, Hirakawa K, Arakawa T, Ueda M. Close association between activated platelets and neutrophils in the active phase of ulcerative colitis in humans. Inflamm Bowel Dis 2006; 12:727-35. [PMID: 16917228 DOI: 10.1097/00054725-200608000-00009] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Neutrophils are considered to play a causative role in inflammatory mucosal injury in ulcerative colitis (UC), and an association between platelets and neutrophils may contribute to the progression of the inflammatory processes. To test this hypothesis, we performed immunohistochemical and flow cytometric analyses on tissue and blood samples from patients with UC. MATERIALS AND METHODS Colonic mucosal tissues of patients with active (n = 27) or inactive (n = 16) UC and normal controls (n = 11) were subjected to immunohistochemical staining for markers of activated platelets (glycoprotein IIb/IIIa and P-selectin) and neutrophils (neutrophil elastase, myeloperoxidase, and CD66b). The amounts of stained cells were evaluated by computer-aided morphometry. Peripheral blood samples from patients (n = 8) and healthy volunteers (n = 8) were subjected to comparative flow cytometric analysis of activated platelets. RESULTS P-selectin-positive activated platelets were frequently aggregated in the inflamed mucosa, especially in ulcerative lesions, and were close to regions of dense neutrophil infiltration. An increase in the number of activated platelets in the colonic lesions was associated with an increase in infiltrating neutrophils and was related to the severity of the disease. The flow cytometric analysis indicated that circulating platelets of patients with UC were highly activated. CONCLUSIONS The present study demonstrated that a close association between activated platelets and neutrophils is a prominent pathological change in both the affected colonic mucosa and peripheral blood of patients with active-phase UC. This suggests that platelet-neutrophil association may play an important role in the progression of inflammatory processes in UC.
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Affiliation(s)
- Soichiro Kayo
- Department of Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan
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Anthoni C, Laukoetter MG, Rijcken E, Vowinkel T, Mennigen R, Müller S, Senninger N, Russell J, Jauch J, Bergmann J, Granger DN, Krieglstein CF. Mechanisms underlying the anti-inflammatory actions of boswellic acid derivatives in experimental colitis. Am J Physiol Gastrointest Liver Physiol 2006; 290:G1131-7. [PMID: 16423918 DOI: 10.1152/ajpgi.00562.2005] [Citation(s) in RCA: 86] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Recent clinical trials of the gum resin of Boswellia serrata have shown promising results in patients with ulcerative colitis. The objective of this study was to determine whether a semisynthetic form of acetyl-11-keto-beta-boswellic acid (sAKBA), the most potent anti-inflammatory component of the resin, also confers protection in experimental murine colitis induced by dextran sodium sulfate (DSS) to compare its effects with those standard medications of ulcerative colitis like steroids and to examine whether leukocyte-endothelial cell adhesion is a major target of action of sAKBA. Clinical measurements of disease activity and histology were used to assess disease progression, and intravital microscopy was employed to monitor the adhesion of leukocytes and platelets in postcapillary venules of the inflamed colon. sAKBA treatment significantly blunted disease activity as assessed both grossly and by histology. Similarly, the recruitment of adherent leukocytes and platelets into inflamed colonic venules was profoundly reduced in mice treated with sAKBA. Because previous studies in the DSS model have shown that P-selectin mediates these blood cell-endothelial cell interactions, the expression of P-selectin in the colonic microcirculation was monitored using the dual-radiolabeled antibody technique. The treatment of established colitis with sAKBA largely prevented the P-selectin upregulation normally associated with DSS colitis. All of the protective responses observed with sAKBA were comparable to that realized in mice treated with a corticosteroid. Our findings demonstrated an anti-inflammatory effect of sAKBA and indicated that P-selectin-mediated recruitment of inflammatory cells is a major site of action for this novel anti-inflammatory agent.
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Affiliation(s)
- C Anthoni
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, 71130, USA
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Abstract
The recruitment of leukocytes to inflamed tissues plays an essential role in combating infection and promoting wound healing. However, in autoimmune diseases such as multiple sclerosis and diabetes, leukocytes enter tissues and contribute to inappropriate inflammatory responses, which cause tissue injury and dysfunction. In diseases of this type, lymphocytes play critical roles in initiating and maintaining these aberrant inflammatory responses. The aim of this review is to examine the mechanisms whereby T-lymphocytes enter tissues in autoimmune diseases and to compare these mechanisms between various organs and diseases. An overview of the mechanisms of leukocyte recruitment and the techniques used to study leukocyte trafficking is provided, focusing on the use of intravital microscopy as a tool to assess the functional microvasculature in vivo. We also discuss the series of tissue homing events which allow naïve lymphocytes to first enter lymph nodes and undergo activation, then subsequently to home to the peripheral organ where their cognate antigen is present. Finally, we examine mechanisms of leukocyte recruitment in diseases such as multiple sclerosis, autoimmune diabetes, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease and asthma.
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Affiliation(s)
- M U Norman
- Immunology Research Group, University of Calgary, Calgary, AB, Canada
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Ko JKS, Lam FYL, Cheung APL. Amelioration of experimental colitis by Astragalus membranaceus through anti-oxidation and inhibition of adhesion molecule synthesis. World J Gastroenterol 2005; 11:5787-94. [PMID: 16270386 PMCID: PMC4479677 DOI: 10.3748/wjg.v11.i37.5787] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the protective effects of Astragalus membranaceus (Am) against hapten-induced colitis in male Sprague-Dawley rats as well as its underlying mechanism.
METHODS: Experimental colitis was induced in rats by enema administration of 2,4-dinitrobenzene sulfonic acid (DNBS). Rats were either pretreated with Am extract (2 or 4 g/kg, p.o. once daily) starting from 10 d before DNBS enema, or received Am post-treatment (2 or 4 g/kg, p.o. twice daily) on the three consecutive days following DNBS administration. Colonic lesion area and histological damage were determined, while the activities of myeloperoxidase (MPO) and xanthine oxidase, as well as reduced glutathione (GSH) content were measured in the excised colonic tissues. Besides, protein expression of inducible nitrite oxide synthase (iNOS), intercellular adhesion molecule-1 (ICAM-1) and P-selectin was also detected by Western blot analysis.
RESULTS: Our findings had shown that both macroscopic lesion area and histological colonic damage induced by DNBS were significantly reduced by both Am pre- and post-treatments. These were accompanied by attenuation of the elevated colonic MPO activity and downregulation of the iNOS, P-selectin, and ICAM-1 protein expression. Besides, deprivation of colonic GSH level under colitis condition was also preserved.
CONCLUSION: These results demonstrate that Am possesses both preventive and therapeutic potential in experimental colitis. The anti-inflammatory actions involve anti-oxidation along with inhibition of adhesion molecule synthesis in the colonic tissues.
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Affiliation(s)
- Joshua-Ka-Shun Ko
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.
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Mori M, Salter JW, Vowinkel T, Krieglstein CF, Stokes KY, Granger DN. Molecular determinants of the prothrombogenic phenotype assumed by inflamed colonic venules. Am J Physiol Gastrointest Liver Physiol 2005; 288:G920-6. [PMID: 15550557 DOI: 10.1152/ajpgi.00371.2004] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Although platelets have been implicated in the pathogenesis of human inflammatory bowel diseases, little is known about the magnitude of platelet accumulation in the inflamed bowel, what regulates this process, and its relevance to the overall inflammatory response. In this study, intravital video microscopy was used to monitor the trafficking of platelets and leukocytes and vascular permeability in colonic venules during the development of colonic inflammation induced by 3% dextran sodium sulfate (DSS). Blocking antibodies directed against different adhesion molecules as well as P-selectin-deficient mice were used to define the adhesive determinants of DSS-induced platelet recruitment. DSS induced an accumulation of adherent platelets that was temporally correlated with the appearance of adherent leukocytes and with disease severity. Platelet adhesion and, to a lesser extent, leukocyte adhesion were attenuated by immunoblockade of P-selectin and its ligand P-selectin glycoprotein ligand-1 (PSGL-1), with contributions from both platelet- and endothelial cell-associated P-selectin. DSS induced a rapid and sustained increase in vascular permeability that was greatly attenuated in P-selectin-deficient mice. P-selectin bone marrow chimeras revealed that both endothelial cell- and platelet-associated P-selectin contribute to the P-selectin expression detected in the inflamed colonic microvasculature, with endothelial P-selectin making a larger contribution. Our findings indicate that colonic inflammation is associated with the induction of a prothrombogenic phenotype in the colonic microcirculation, with P-selectin and its ligand PSGL-1 playing a major role in the recruitment of platelets.
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Affiliation(s)
- Mikiji Mori
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, Louisiana 71130-3932, USA
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Sakhalkar HS, Hanes J, Fu J, Benavides U, Malgor R, Borruso CL, Kohn LD, Kurjiaka DT, Goetz DJ. Enhanced adhesion of ligand‐conjugated biodegradable particles to colitic venules. FASEB J 2005; 19:792-4. [PMID: 15764649 DOI: 10.1096/fj.04-2668fje] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The expression of certain endothelial cell adhesion molecules (ECAMs) is increased in the vasculature of the inflamed bowel (e.g., colitis), thereby providing an opportunity for targeted drug delivery. We recently demonstrated that biodegradable particles conjugated with ligands to ECAMs exhibit significant selective adhesion to ECAM expressing endothelium. In the present study, we used a murine model of colitis to determine whether poly(lactic acid)-poly(ethylene glycol) particles conjugated with a VCAM-1 ligand (alpha-V) exhibit enhanced adhesion to colitic vasculature. In post-capillary venules of the colon, significantly more alpha-V particles accumulate in colitic mice relative to (i) control mice (i.e., selectivity) and (ii) particles bearing a control ligand (i.e., ligand efficiency). The selectivity and ligand efficiency of alpha-V particles were a function of the total number of particles infused. The highest selectivity observed within our test regime was 3, while ligand efficiency increased linearly with the number of particles injected to a value of 24. This work represents a significant step towards achieving a targeted drug delivery scheme for the treatment of inflammatory bowel disease and indicates that the efficiency of targeting is dependent on the dose regime.
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Affiliation(s)
- Harshad S Sakhalkar
- Department of Chemical Engineering, Ohio University, Athens, Ohio 45701, USA
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Murthy S, Flanigan A, Osborne BJ, Murthy NS. Inflammatory bowel diseases: a new wave of therapy. Expert Opin Ther Pat 2005. [DOI: 10.1517/13543776.8.7.785] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Koutroubakis IE, Theodoropoulou A, Xidakis C, Sfiridaki A, Notas G, Kolios G, Kouroumalis EA. Association between enhanced soluble CD40 ligand and prothrombotic state in inflammatory bowel disease. Eur J Gastroenterol Hepatol 2004; 16:1147-52. [PMID: 15489574 DOI: 10.1097/00042737-200411000-00011] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Inflammatory bowel disease is associated with an increased incidence of thromboembolic complications. The aim of this study was to investigate the role of the soluble CD40 ligand (sCD40L), which displays prothrombotic properties, in patients with ulcerative colitis (UC) and Crohn's disease (CD) in comparison with inflammatory and healthy controls. METHODS Plasma levels of sCD40L, prothrombin fragment 1+2 (F1+2), thrombin-antithrombin (TAT) complex and soluble P-selectin were measured in 104 inflammatory bowel disease patients (54 ulcerative colitis and 50 Crohn's disease), in 18 cases with other causes of intestinal inflammation and in 80 healthy controls using commercially available enzyme-linked immunosorbent assays. Plasma levels of sCD40L were correlated with disease activity, type, localization and treatment as well as with the measured thrombophilic parameters. RESULTS CD patients had significantly higher sCD40L levels than both groups of controls (CD vs HC P < 0.001; CD vs non-IBD P < 0.05). UC patients had higher but not significantly different sCD40L levels compared with the controls. Both UC and CD patients with active disease had significantly higher sCD40L levels in comparison with patients with inactive disease. Plasma levels of sCD40L were correlated with platelet count (r = 0.27, P = 0.001). They also showed a correlation with prothrombin F1+2 (r = 0.16, r = 0.03) and TAT (r = 0.15, r = 0.04) as well as with P-selectin (r = 0.19, P = 0.01). CONCLUSIONS The increased sCD40L plasma levels may represent, at least in some degree, a molecular link between inflammatory bowel disease and the procoagualant state.
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Affiliation(s)
- Ioannis E Koutroubakis
- Department of Gastroenterology University Hospital Heraklion; and Regional Blood Bank Center Venizelion Hospital Heraklion, Crete, Greece
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Vowinkel T, Mori M, Krieglstein CF, Russell J, Saijo F, Bharwani S, Turnage RH, Davidson WS, Tso P, Granger DN, Kalogeris TJ. Apolipoprotein A-IV inhibits experimental colitis. J Clin Invest 2004; 114:260-9. [PMID: 15254593 PMCID: PMC450164 DOI: 10.1172/jci21233] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2004] [Accepted: 05/25/2004] [Indexed: 12/13/2022] Open
Abstract
The antiatherogenic properties of apoA-IV suggest that this protein may act as an anti-inflammatory agent. We examined this possibility in a mouse model of acute colitis. Mice consumed 3% dextran sulfate sodium (DSS) in their drinking water for 7 days, with or without daily intraperitoneal injections of recombinant human apoA-IV. apoA-IV significantly and specifically delayed the onset, and reduced the severity and extent of, DSS-induced inflammation, as assessed by clinical disease activity score, macroscopic appearance and histology of the colon, and tissue myeloperoxidase activity. Intravital fluorescence microscopy of colonic microvasculature revealed that apoA-IV significantly inhibited DSS-induced leukocyte and platelet adhesive interactions. Furthermore, apoA-IV dramatically reduced the upregulation of P-selectin on colonic endothelium during DSS-colitis. apoA-IV knockout mice exhibited a significantly greater inflammatory response to DSS than did their WT littermates; this greater susceptibility to DSS-induced inflammation was reversed upon exogenous administration of apoA-IV to knockout mice. These results provide the first direct support for the hypothesis that apoA-IV is an endogenous anti-inflammatory protein. This anti-inflammatory effect likely involves the inhibition of P-selectin-mediated leukocyte and platelet adhesive interactions.
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Affiliation(s)
- Thorsten Vowinkel
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport 71130-3932, USA
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Vowinkel T, Mori M, Krieglstein CF, Russell J, Saijo F, Bharwani S, Turnage RH, Davidson WS, Tso P, Granger DN, Kalogeris TJ. Apolipoprotein A-IV inhibits experimental colitis. J Clin Invest 2004. [PMID: 15254593 DOI: 10.1172/jci200421233] [Citation(s) in RCA: 124] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
The antiatherogenic properties of apoA-IV suggest that this protein may act as an anti-inflammatory agent. We examined this possibility in a mouse model of acute colitis. Mice consumed 3% dextran sulfate sodium (DSS) in their drinking water for 7 days, with or without daily intraperitoneal injections of recombinant human apoA-IV. apoA-IV significantly and specifically delayed the onset, and reduced the severity and extent of, DSS-induced inflammation, as assessed by clinical disease activity score, macroscopic appearance and histology of the colon, and tissue myeloperoxidase activity. Intravital fluorescence microscopy of colonic microvasculature revealed that apoA-IV significantly inhibited DSS-induced leukocyte and platelet adhesive interactions. Furthermore, apoA-IV dramatically reduced the upregulation of P-selectin on colonic endothelium during DSS-colitis. apoA-IV knockout mice exhibited a significantly greater inflammatory response to DSS than did their WT littermates; this greater susceptibility to DSS-induced inflammation was reversed upon exogenous administration of apoA-IV to knockout mice. These results provide the first direct support for the hypothesis that apoA-IV is an endogenous anti-inflammatory protein. This anti-inflammatory effect likely involves the inhibition of P-selectin-mediated leukocyte and platelet adhesive interactions.
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Affiliation(s)
- Thorsten Vowinkel
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport 71130-3932, USA
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Dagia NM, Harii N, Meli AE, Sun X, Lewis CJ, Kohn LD, Goetz DJ. Phenyl Methimazole Inhibits TNF-α-Induced VCAM-1 Expression in an IFN Regulatory Factor-1-Dependent Manner and Reduces Monocytic Cell Adhesion to Endothelial Cells. THE JOURNAL OF IMMUNOLOGY 2004; 173:2041-9. [PMID: 15265939 DOI: 10.4049/jimmunol.173.3.2041] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Proinflammatory cytokine (e.g., TNF-alpha)-induced expression of endothelial cell adhesion molecules (ECAMs) on the lumenal surface of the vascular endothelium and a consequent increase in leukocyte adhesion are key aspects of pathological inflammation. A promising therapeutic approach to diminish aberrant leukocyte adhesion is, therefore, to inhibit cytokine-induced ECAM expression at the transcription level. Several studies suggest that methimazole, a compound used clinically to treat autoimmune diseases, such as Graves' disease, may also diminish pathological inflammation by suppressing ECAM expression. In this study we probed the hypothesis that a derivative of methimazole, phenyl methimazole (compound 10), can reduce cytokine-induced ECAM expression and consequent leukocyte adhesion. We found that compound 10 1) dramatically inhibits TNF-alpha-induced VCAM-1 mRNA and protein expression in human aortic endothelial cells (HAEC), has a relatively modest inhibitory effect on TNF-alpha induced E-selectin expression and has no effect on ICAM-1 expression; 2) significantly reduces TNF-alpha-induced monocytic (U937) cell adhesion to HAEC under in vitro flow conditions similar to that present in vivo; 3) inhibits TNF-alpha-induced IFN regulatory factor-1 binding to VCAM-1 promoter; and 4) reduces TNF-alpha-induced IRF-1 expression in HAEC. Combined, the results indicate that phenyl methimazole can reduce TNF-alpha-induced VCAM-1 expression in an IFN regulatory factor-1-dependent manner and that this contributes significantly to reduced monocytic cell adhesion to TNF-alpha-activated HAEC.
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Affiliation(s)
- Nilesh M Dagia
- Department of Chemical Engineering, College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA
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Rijcken EM, Laukoetter MG, Anthoni C, Meier S, Mennigen R, Spiegel HU, Bruewer M, Senninger N, Vestweber D, Krieglstein CF. Immunoblockade of PSGL-1 attenuates established experimental murine colitis by reduction of leukocyte rolling. Am J Physiol Gastrointest Liver Physiol 2004; 287:G115-24. [PMID: 15001428 DOI: 10.1152/ajpgi.00207.2003] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Recruitment of circulating leukocytes into the colonic tissue is a key feature of intestinal inflammation. P-selectin glycoprotein ligand-1 (PSGL-1) and very late antigen-4 (VLA-4) are expressed on leukocytes and play an important role in leukocyte-endothelial cell adhesive interactions. We examined the effects of immunoneutralization of PSGL-1 and VLA-4 on leukocyte recruitment in vivo in the development and treatment of experimental colitis. Chronic colitis was induced in balb/c mice by oral administration of dextran sodium sulfate (DSS). Monoclonal antibodies 2PH1 (anti-PSGL-1) and PS/2 (anti-VLA-4) or the combination of both were injected intravenously, and leukocyte adhesion was observed for 60 min in colonic submucosal venules by intravital microscopy (IVM) under isoflurane/N(2)O anesthesia. In addition, mice with established colitis were treated by daily intraperitoneal injections of 2PH1, PS/2, or the combination of both over 5 days. Disease activity index (DAI), histology, and myeloperoxidase (MPO) levels were compared with sham-treated DSS controls. We found that 2PH1 reduced the number of rolling leukocytes (148.7 +/- 29.8 vs. 36.9 +/- 8.7/0.01 mm(2)/30 s, P < 0.05), whereas leukocyte velocity was increased (24.0 +/- 3.6 vs. 127.8 +/- 11.7 microm/s, P < 0.05). PS/2 reduced leukocyte rolling to a lesser extent. Leukocyte firm adhesion was not influenced by 2PH1 but was strongly reduced by PS/2 (24.1 +/- 2 vs. 4.4 +/- 0.9/0.01 mm(2)/30 s, P < 0.05). Combined application did not cause additional effects on leukocyte adhesion. Treatment of chronic colitis with 2PH1 or PS/2 reduced DAI, mucosal injury, and MPO levels significantly. Combined treatment led to a significantly better reduction of DAI (0.4 +/- 0.1 vs. 2.1 +/- 0.2 points) and histology (9.7 +/- 0.9 vs. 21.4 +/- 4.6 points). In conclusion, PSGL-1 and VLA-4 play an important role for leukocyte recruitment during intestinal inflammation. Therapeutic strategies designed to disrupt interactions mediated by PSGL-1 and/or VLA-4 may prove beneficial in treatment of chronic colitis.
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Affiliation(s)
- Emile M Rijcken
- Dept. of General Surgery, Muenster University Hospital, Waldeyerstrasse 1, D-48149 Muenster, Germany
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Seyfarth HJ, Koksch M. Fibrinogen receptor antagonists induce conformational changes of the human platelet glycoprotein IIb. ACTA ACUST UNITED AC 2004; 62:14-24. [PMID: 15476209 DOI: 10.1002/cyto.b.20026] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
BACKGROUND Controversial results have been reported concerning the ability of fibrinogen receptor antagonists (fibans) to induce conformational changes in the fibrinogen receptor after binding to it as the initial step of fibrinogen binding and platelet activation. METHODS Platelets in citrated whole blood were stained with several pairs of anti-glycoprotein (anti-GP) IIb-directed monoclonal antibodies conjugated to phycoerythrin (PE) or indirectly labeled with Cy5. Pairs of monoclonal antibodies that induced a high-fluorescence resonance energy transfer (FRET) efficiency served as tools to detect activation-dependent changes of GP IIb after addition of adenosine diphosphate and several fibans. RESULTS Using the combination of the clones 5B12-PE and P2-biotin/SA-Cy5, a concentration-dependent alteration of the GP IIb conformation was observed after addition of tirofiban, eptifibatide, and lotrafiban. Magnitude and kinetics differed among the investigated substances. CONCLUSION The newly developed FRET assay allows the direct investigation of conformational changes of GP IIb after addition of platelet agonists or receptor ligands, as shown for three fibans.
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Sakhalkar HS, Dalal MK, Salem AK, Ansari R, Fu J, Kiani MF, Kurjiaka DT, Hanes J, Shakesheff KM, Goetz DJ. Leukocyte-inspired biodegradable particles that selectively and avidly adhere to inflamed endothelium in vitro and in vivo. Proc Natl Acad Sci U S A 2003; 100:15895-900. [PMID: 14668435 PMCID: PMC307664 DOI: 10.1073/pnas.2631433100] [Citation(s) in RCA: 131] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2003] [Accepted: 10/29/2003] [Indexed: 01/31/2023] Open
Abstract
We exploited leukocyte-endothelial cell adhesion chemistry to generate biodegradable particles that exhibit highly selective accumulation on inflamed endothelium in vitro and in vivo. Leukocyte-endothelial cell adhesive particles exhibit up to 15-fold higher adhesion to inflamed endothelium, relative to noninflamed endothelium, under in vitro flow conditions similar to that present in blood vessels, a 6-fold higher adhesion to cytokine inflamed endothelium relative to non-cytokine-treated endothelium in vivo, and a 10-fold enhancement in adhesion to trauma-induced inflamed endothelium in vivo due to the addition of a targeting ligand. The leukocyte-inspired particles have adhesion efficiencies similar to that of leukocytes and were shown to target each of the major inducible endothelial cell adhesion molecules (E-selectin, P-selectin, vascular cell adhesion molecule 1, and intercellular adhesion molecule 1) that are up-regulated at sites of pathological inflammation. The potential for targeted drug delivery to inflamed endothelium has significant implications for the improved treatment of an array of pathologies, including cardiovascular disease, arthritis, inflammatory bowel disease, and cancer.
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Affiliation(s)
- Harshad S Sakhalkar
- Departments of Chemical Engineering and Biological Sciences, Ohio University, Athens, OH 45701, USA
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Folch-Puy E, García-Movtero A, Iovanna JL, Dagorn JC, Prats N, Vaccaro MI, Closa D. The pancreatitis-associated protein induces lung inflammation in the rat through activation of TNFalpha expression in hepatocytes. J Pathol 2003; 199:398-408. [PMID: 12579542 DOI: 10.1002/path.1307] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
The pancreatitis-associated protein (PAP) is a pancreatic stress protein overexpressed during acute pancreatitis, a disease often accompanied by lung inflammation. We investigated whether PAP was involved in the occurrence of this remote complication of pancreatitis and whether the liver might be implicated in the process. PAP was injected into the vena cava of rats (40 or 400 micro g/kg body weight). For comparison, pancreatitis was induced in rats by intraductal administration of sodium taurocholate. Three hours later, parameters of inflammation and mRNA concentrations of TNFalpha, P-selectin, heat shock protein (HSP)-70, and extracellular superoxide dismutase (EC-SOD) were monitored in lung and liver. Significant increases in P-selectin expression, neutrophil infiltration, and oxidative stress revealed that PAP treatment induced lung inflammation in rats and exacerbated inflammation in animals with pancreatitis. Plasma TNFalpha level was increased and TNFalpha mRNA was strongly overexpressed in liver, with concomitant activation of NF-kappaB; in situ hybridization revealed that TNFalpha overexpression was mainly located to hepatocytes. Lung inflammation induced by PAP could be prevented by injection of anti-TNFalpha antibodies. It was concluded that, during pancreatitis, PAP released by the pancreas could mediate lung inflammation through induction of hepatic TNFalpha expression and subsequent increase in circulating TNFalpha.
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