|
1
|
Ávila-Gálvez MÁ, Vico-Padilla A, Schneider C, Espín JC, González-Sarrías A, Giménez-Bastida JA. Angiogenesis as a Therapeutic Target of (Poly)phenols: Tackling Cancer and Vascular-Related Complications. Mol Nutr Food Res 2025:e70110. [PMID: 40370203 DOI: 10.1002/mnfr.70110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 04/01/2025] [Accepted: 04/29/2025] [Indexed: 05/16/2025]
Abstract
Targeting angiogenesis as a strategy for treating cancer or vascular-associated complications is an inspiring field for many investigators. An active area within this discipline is the search for agents capable of modulating angiogenesis in order to ameliorate its structural and functional abnormalities associated with these diseases. (Poly)phenols are a broad group of molecules, many of which fall within the category of natural compounds with therapeutic potential. These potential medicinal effects have launched a considerable number of studies investigating the pro- and(or) anti-angiogenic properties of (poly)phenols in different (patho)physiological settings. The purpose of this review is to summarize the current evidence of the role of (poly)phenols in modulating angiogenesis. This review will guide the reader through preclinical and human investigations describing the pro- and anti-angiogenic effects of these compounds in different pathophysiological context, the cellular and molecular mechanisms associated, the key points in the design and evaluation of the effects described, and suggest new approaches to be considered in future studies to overcome the current limitations.
Collapse
Affiliation(s)
- María Ángeles Ávila-Gálvez
- Laboratory of Food and Health, Research Group on Quality, Safety and Bioactivity of Plant Foods, Department of Food Science and Technology, CEBAS-CSIC, Murcia, Spain
| | - Antonio Vico-Padilla
- Laboratory of Food and Health, Research Group on Quality, Safety and Bioactivity of Plant Foods, Department of Food Science and Technology, CEBAS-CSIC, Murcia, Spain
| | - Claus Schneider
- Division of Clinical Pharmacology, Department of Pharmacology, Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Juan Carlos Espín
- Laboratory of Food and Health, Research Group on Quality, Safety and Bioactivity of Plant Foods, Department of Food Science and Technology, CEBAS-CSIC, Murcia, Spain
| | - Antonio González-Sarrías
- Laboratory of Food and Health, Research Group on Quality, Safety and Bioactivity of Plant Foods, Department of Food Science and Technology, CEBAS-CSIC, Murcia, Spain
| | - Juan Antonio Giménez-Bastida
- Laboratory of Food and Health, Research Group on Quality, Safety and Bioactivity of Plant Foods, Department of Food Science and Technology, CEBAS-CSIC, Murcia, Spain
| |
Collapse
|
|
2
|
Fang Z, Qu S, Ji X, Zheng C, Mo J, Xu J, Zhang J, Shen H. Correlation between PDGF-BB and M1-type macrophage in inflammatory bowel disease: a case-control study. BMC Gastroenterol 2024; 24:417. [PMID: 39567902 PMCID: PMC11580552 DOI: 10.1186/s12876-024-03518-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 11/14/2024] [Indexed: 11/22/2024] Open
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a chronic disease in which macrophages play an important role in its pathogenesis. Platelet-derived growth factor-BB (PDGF-BB) secreted by macrophages is involved in the repair of vascular endothelial injury during inflammatory reactions. METHODS The expression levels of M1 macrophages and PDGF-BB in serum and colonic mucosa of 30 patients with Crohn's disease (CD) and 30 patients with ulcerative colitis (UC) were measured using enzyme-linked immunosorbent assays and immunohistochemistry. Logistic regression was used for univariate and multivariate analyses, and receiver operating characteristic curves were used to evaluate diagnostic value. Associations were evaluated using Spearman correlation analysis. RESULTS The expression of serum PDGF-BB and M1 macrophages with positive CXCL9 expression in patients with active-stage IBD [206.55(160.41,262.90)and 337.30(217.73,472.28) pg/ml] was higher than that in patients with remission stage [153.42(107.02,219.68)and 218.37(144.49,347.33)pg/ml] and controls [156.19(91.16,216.08)and 191.20(121.42,311.76)pg/ml](P < 0.05). The expression of PDGF-BB, CD86, and CXCL9 in the colon of patients with active-stage IBD [0.380(0.266,0.542) 0.663(0.480,0.591) and 0.564(0.378,0.765) /µm2] was higher than that in the remission stage [0.308(0.214,0.420), 0.376(0.206,0.591) and 0.413(0.275,0.570) /µm2] and controls [0.265(0.185,0.384), 0.416(0.269,0.534) and 0.497(0.415,0.642) /µm2] (P < 0.05). A positive correlation was observed between CD86 and PDGF-BB, and CXCL9 and PDGF-BB levels in patients with IBD (P < 0.05). CD86 and PDGF-BB in the colonic mucosa were independent risk factors for active IBD, and the area under the curve for their combined diagnosis was 0.754 (95%CI: 0.654-0.852, P < 0.05). CONCLUSIONS PDGF-BB was associated with M1 macrophages and has a potential diagnostic value for active IBD. TRIAL REGISTRATION Not applicable.
Collapse
Grants
- 2021KY1116 the Zhejiang Provincial Medicine and Health Technology Project
- 2021KY1116 the Zhejiang Provincial Medicine and Health Technology Project
- 2021KY1116 the Zhejiang Provincial Medicine and Health Technology Project
- 2021KY1116 the Zhejiang Provincial Medicine and Health Technology Project
- 2021KY1116 the Zhejiang Provincial Medicine and Health Technology Project
- 2021KY1116 the Zhejiang Provincial Medicine and Health Technology Project
- 2021KY1116 the Zhejiang Provincial Medicine and Health Technology Project
- 2021KY1116 the Zhejiang Provincial Medicine and Health Technology Project
- 2022AD30007 the Science and Technology Bureau of Jiaxing city, Zhejiang, China
- 2022AD30007 the Science and Technology Bureau of Jiaxing city, Zhejiang, China
- 2022AD30007 the Science and Technology Bureau of Jiaxing city, Zhejiang, China
- 2022AD30007 the Science and Technology Bureau of Jiaxing city, Zhejiang, China
- 2022AD30007 the Science and Technology Bureau of Jiaxing city, Zhejiang, China
- 2022AD30007 the Science and Technology Bureau of Jiaxing city, Zhejiang, China
- 2022AD30007 the Science and Technology Bureau of Jiaxing city, Zhejiang, China
- 2022AD30007 the Science and Technology Bureau of Jiaxing city, Zhejiang, China
Collapse
Affiliation(s)
- Zhiyun Fang
- The Second Hospital of Jiaxing, Jiaxing, 314000, China
| | - Siwen Qu
- The Second Hospital of Jiaxing, Jiaxing, 314000, China
| | - Xia Ji
- The Second Hospital of Jiaxing, Jiaxing, 314000, China
| | - Chuwei Zheng
- The Second Hospital of Jiaxing, Jiaxing, 314000, China
| | - Juanfen Mo
- The Second Hospital of Jiaxing, Jiaxing, 314000, China
| | - Jianqiu Xu
- The Second Hospital of Jiaxing, Jiaxing, 314000, China
| | - Jinming Zhang
- The Second Hospital of Jiaxing, Jiaxing, 314000, China.
| | - Haiyan Shen
- The Second Hospital of Jiaxing, Jiaxing, 314000, China.
| |
Collapse
|
|
3
|
Özkan A, LoGrande NT, Feitor JF, Goyal G, Ingber DE. Intestinal organ chips for disease modelling and personalized medicine. Nat Rev Gastroenterol Hepatol 2024; 21:751-773. [PMID: 39192055 DOI: 10.1038/s41575-024-00968-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/10/2024] [Indexed: 08/29/2024]
Abstract
Alterations in intestinal structure, mechanics and physiology underlie acute and chronic intestinal conditions, many of which are influenced by dysregulation of microbiome, peristalsis, stroma or immune responses. Studying human intestinal physiology or pathophysiology is difficult in preclinical animal models because their microbiomes and immune systems differ from those of humans. Although advances in organoid culture partially overcome this challenge, intestinal organoids still lack crucial features that are necessary to study functions central to intestinal health and disease, such as digestion or fluid flow, as well as contributions from long-term effects of living microbiome, peristalsis and immune cells. Here, we review developments in organ-on-a-chip (organ chip) microfluidic culture models of the human intestine that are lined by epithelial cells and interfaced with other tissues (such as stroma or endothelium), which can experience both fluid flow and peristalsis-like motions. Organ chips offer powerful ways to model intestinal physiology and disease states for various human populations and individual patients, and can be used to gain new insight into underlying molecular and biophysical mechanisms of disease. They can also be used as preclinical tools to discover new drugs and then validate their therapeutic efficacy and safety in the same human-relevant model.
Collapse
Affiliation(s)
- Alican Özkan
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
| | - Nina Teresa LoGrande
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
| | - Jessica F Feitor
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
| | - Girija Goyal
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
| | - Donald E Ingber
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.
- Vascular Biology Program and Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
- Harvard John A. Paulson School of Engineering and Applied Sciences, Cambridge, MA, USA.
| |
Collapse
|
|
4
|
Kim KO, Lee SH. [Old and New Biologics and Small Molecules in Inflammatory Bowel Disease: Anti Integrins]. THE KOREAN JOURNAL OF GASTROENTEROLOGY = TAEHAN SOHWAGI HAKHOE CHI 2024; 84:43-50. [PMID: 39176460 DOI: 10.4166/kjg.2024.070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 08/04/2024] [Accepted: 08/12/2024] [Indexed: 08/24/2024]
Abstract
Recently, novel biologics or small molecular drugs have been introduced for overcoming the unmet needs associated with anti-tumor necrosis factor α agents for inflammtory bowel disease (IBD) treatment. Among these novel drugs, anti integrin agents block leukocyte trafficking to the intestine by blocking the interaction between integrin and cell adhesion molecules. Vedolizumab (anti-α4β7) is most widely used anti-integrin approved in both ulcerative colitis and Crohn's disease .It has been shown to be effective in both induction and maintenance therapy with a favorable safety profile due to gut selectivity. Several models incorporating clinical, genetic, immune and gut microbial markers to predict response to vedolizumab in IBD have been developed. Etrolizumab (anti-β7) blocks leukocyte trafficking via α4β7 and cell adhesion via αEβ7 integrins. In addition, the introduction of subcutaneous vedolizumab showed similar efficacy and safety with improved patients' convenience. Other investigational anti-integrin therapies include abrilumab (anti-α4β7 IgG2), PN-943 (orally administered and gut-restricted α4β7 antagonist peptide), AJM300 (orally active small molecule inhibitor of α4), and ontamalimab (anti-MAdCAM-1 IgG).
Collapse
Affiliation(s)
- Kyeong Ok Kim
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Si Hyung Lee
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| |
Collapse
|
|
5
|
Park JS, Cresci GAM. Dysfunctional intestinal microvascular endothelial cells: Insights and therapeutic implications in gastrointestinal inflammation. IMMUNOMETABOLISM (COBHAM, SURREY) 2024; 6:e00043. [PMID: 38818514 PMCID: PMC11136270 DOI: 10.1097/in9.0000000000000043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 05/01/2024] [Indexed: 06/01/2024]
Abstract
The intestinal microvascular endothelium plays a crucial role in orchestrating host responses to inflammation within the gastrointestinal tract. This review delves into the unique aspects of intestinal microvascular endothelial cells, distinct from those of larger vessels, in mediating leukocyte recruitment, maintaining barrier integrity, and regulating angiogenesis during inflammation. Specifically, their role in the pathogenesis of inflammatory bowel diseases, where dysregulated endothelial functions contribute to the disease progression, is reviewed. Furthermore, this review discusses the isolation technique for these cells and commonly used adhesion molecules for in vitro and in vivo experiments. In addition, we reviewed the development and therapeutic implications of a biologic agent targeting the interaction between α4β7 integrin on T lymphocytes and mucosal addressin cellular adhesion molecule-1 on gut endothelium. Notably, vedolizumab, a humanized monoclonal antibody against α4β7 integrin, has shown promising outcomes in inflammatory bowel diseases and other gastrointestinal inflammatory conditions, including chronic pouchitis, immune checkpoint inhibitor-induced colitis, and acute cellular rejection post-intestinal transplantation.
Collapse
Affiliation(s)
- Ji Seok Park
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Gail A. M. Cresci
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cleveland Clinic Children’s Hospital, Cleveland, OH, USA
| |
Collapse
|
|
6
|
Siddiqui MT, Han Y, Shapiro D, West G, Fiocchi C, Cresci GAM. The Postbiotic Butyrate Mitigates Gut Mucosal Disruption Caused by Acute Ethanol Exposure. Int J Mol Sci 2024; 25:1665. [PMID: 38338944 PMCID: PMC10855591 DOI: 10.3390/ijms25031665] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 01/03/2024] [Accepted: 01/11/2024] [Indexed: 02/12/2024] Open
Abstract
We aimed to test how the postbiotic butyrate impacts select gut bacteria, small intestinal epithelial integrity, and microvascular endothelial activation during acute ethanol exposure in mice and primary human intestinal microvascular endothelial cells (HIMECs). Supplementation during an acute ethanol challenge with or without tributyrin, a butyrate prodrug, was delivered to C57BL/6 mice. A separate group of mice received 3 days of clindamycin prior to the acute ethanol challenge. Upon euthanasia, blood endotoxin, cecal bacteria, jejunal barrier integrity, and small intestinal lamina propria dendritic cells were assessed. HIMECs were tested for activation following exposure to ethanol ± lipopolysaccharide (LPS) and sodium butyrate. Tributyrin supplementation protected a butyrate-generating microbe during ethanol and antibiotic exposure. Tributyrin rescued ethanol-induced disruption in jejunal epithelial barrier, elevated plasma endotoxin, and increased mucosal vascular addressin cell-adhesion molecule-1 (MAdCAM-1) expression in intestinal microvascular endothelium. These protective effects of tributyrin coincided with a tolerogenic dendritic response in the intestinal lamina propria. Lastly, sodium butyrate pre- and co-treatment attenuated the direct effects of ethanol and LPS on MAdCAM-1 induction in the HIMECs from a patient with ulcerative colitis. Tributyrin supplementation protects small intestinal epithelial and microvascular barrier integrity and modulates microvascular endothelial activation and dendritic tolerizing function during a state of gut dysbiosis and acute ethanol challenge.
Collapse
Affiliation(s)
- Mohamed Tausif Siddiqui
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195, USA; (M.T.S.); (C.F.)
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Yingchun Han
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - David Shapiro
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Gail West
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Claudio Fiocchi
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195, USA; (M.T.S.); (C.F.)
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Gail A. M. Cresci
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195, USA; (M.T.S.); (C.F.)
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cleveland Clinic Children’s Hospital, Cleveland, OH 44195, USA
| |
Collapse
|
|
7
|
Jingjie W, Jun S. Gut vascular barrier in the pathogenesis and resolution of Crohn's disease: A novel link from origination to therapy. Clin Immunol 2023; 253:109683. [PMID: 37406981 DOI: 10.1016/j.clim.2023.109683] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Revised: 06/07/2023] [Accepted: 06/12/2023] [Indexed: 07/07/2023]
Abstract
The gut vascular barrier (GVB) is the deepest layer of the gut barrier. It mainly comprised gut vascular endothelial cells, enteric glial cells, and pericytes. The GVB facilitates nutrient absorption and blocks bacterial translocation through its size-restricted permeability. Accumulating evidence suggests that dysfunction of this barrier correlates with several clinical pathologies including Crohn's disease (CD). Significant progress has been made to elucidate the mechanism of GVB dysfunction and to confirm the participation of disrupted GVB in the course of CD. However, further analyses are required to pinpoint the specific roles of GVB in CD pathogenesis. Many preclinical models and clinical trials have demonstrated that various agents are effective in protecting the GVB integrity and thus providing a potential CD treatment strategy. Through this review, we established a systemic understanding of the role of GVB in CD pathogenesis and provided novel insights for GVB-targeting strategies in CD treatment.
Collapse
Affiliation(s)
- Wang Jingjie
- Division of Gastroenterology and Hepatology, Baoshan Branch, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center; Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease; 160# Pu Jian Ave, Shanghai 200127, China
| | - Shen Jun
- Division of Gastroenterology and Hepatology, Baoshan Branch, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center; Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease; 160# Pu Jian Ave, Shanghai 200127, China.
| |
Collapse
|
|
8
|
Kolski-Andreaco A, Balut CM, Bertuccio CA, Wilson AS, Rivers WM, Liu X, Gandley RE, Straub AC, Butterworth MB, Binion D, Devor DC. Histone deacetylase inhibitors (HDACi) increase expression of KCa2.3 (SK3) in primary microvascular endothelial cells. Am J Physiol Cell Physiol 2022; 322:C338-C353. [PMID: 35044858 PMCID: PMC8858676 DOI: 10.1152/ajpcell.00409.2021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The small conductance calcium-activated potassium channel (KCa2.3) has long been recognized for its role in mediating vasorelaxation through the endothelium-derived hyperpolarization (EDH) response. Histone deacetylases (HDACs) have been implicated as potential modulators of blood pressure and histone deacetylase inhibitors (HDACi) are being explored as therapeutics for hypertension. Herein, we show that HDACi increase KCa2.3 expression when heterologously expressed in HEK cells and endogenously expressed in primary cultures of human umbilical vein endothelial cells (HUVECs) and human intestinal microvascular endothelial cells (HIMECs). When primary endothelial cells were exposed to HDACi, KCa2.3 transcripts, subunits, and functional current are increased. Quantitative RT-PCR (qPCR) demonstrated increased KCa2.3 mRNA following HDACi, confirming transcriptional regulation of KCa2.3 by HDACs. By using pharmacological agents selective for different classes of HDACs, we discriminated between cytoplasmic and epigenetic modulation of KCa2.3. Biochemical analysis revealed an association between the cytoplasmic HDAC6 and KCa2.3 in immunoprecipitation studies. Specifically inhibiting HDAC6 increases expression of KCa2.3. In addition to increasing the expression of KCa2.3, we show that nonspecific inhibition of HDACs causes an increase in the expression of the molecular chaperone Hsp70 in endothelial cells. When Hsp70 is inhibited in the presence of HDACi, the magnitude of the increase in KCa2.3 expression is diminished. Finally, we show a slower rate of endocytosis of KCa2.3 as a result of exposure of primary endothelial cells to HDACi. These data provide the first demonstrated approach to increase KCa2.3 channel number in endothelial cells and may partially account for the mechanism by which HDACi induce vasorelaxation.
Collapse
Affiliation(s)
| | - Corina M. Balut
- 1Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | | | - Annette S. Wilson
- 2Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - William M. Rivers
- 2Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Xiaoning Liu
- 1Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Robin E. Gandley
- 3Department of Obstetrics and Gynecology and Reproductive Sciences, Magee Womens Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Adam C. Straub
- 4Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | | | - David Binion
- 2Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Daniel C. Devor
- 1Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
| |
Collapse
|
|
9
|
Biological Treatments in Inflammatory Bowel Disease: A Complex Mix of Mechanisms and Actions. BIOLOGICS 2021. [DOI: 10.3390/biologics1020012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Inflammatory bowel disease (IBD) is a chronic disease that requires lifelong medication and whose incidence is increasing over the world. There is currently no cure for IBD, and the current therapeutic objective is to control the inflammatory process. Approximately one third of treated patients do not respond to treatment and refractoriness to treatment is common. Therefore, pharmacological treatments, such as monoclonal antibodies, are urgently needed, and new treatment guidelines are regularly published. Due to the extremely important current role of biologics in the therapy of IBD, herein we have briefly reviewed the main biological treatments currently available. In addition, we have focused on the mechanisms of action of the most relevant groups of biological agents in IBD therapy, which are not completely clear but are undoubtfully important for understanding both their therapeutic efficacy and the adverse side effects they may have. Further studies are necessary to better understand the action mechanism of these drugs, which will in turn help us to understand how to improve their efficacy and safety. These studies will hopefully pave the path for a personalized medicine.
Collapse
|
|
10
|
Dickson K, Malitan H, Lehmann C. Imaging of the Intestinal Microcirculation during Acute and Chronic Inflammation. BIOLOGY 2020; 9:E418. [PMID: 33255906 PMCID: PMC7760140 DOI: 10.3390/biology9120418] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 11/18/2020] [Indexed: 12/12/2022]
Abstract
Because of its unique microvascular anatomy, the intestine is particularly vulnerable to microcirculatory disturbances. During inflammation, pathological changes in blood flow, vessel integrity and capillary density result in impaired tissue oxygenation. In severe cases, these changes can progress to multiorgan failure and possibly death. Microcirculation may be evaluated in superficial tissues in patients using video microscopy devices, but these techniques do not allow the assessment of intestinal microcirculation. The gold standard for the experimental evaluation of intestinal microcirculation is intravital microscopy, a technique that allows for the in vivo examination of many pathophysiological processes including leukocyte-endothelial interactions and capillary blood flow. This review provides an overview of changes in the intestinal microcirculation in various acute and chronic inflammatory conditions. Acute conditions discussed include local infections, severe acute pancreatitis, necrotizing enterocolitis and sepsis. Inflammatory bowel disease and irritable bowel syndrome are included as examples of chronic conditions of the intestine.
Collapse
Affiliation(s)
- Kayle Dickson
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada;
| | - Hajer Malitan
- Department of Anesthesia, Pain and Perioperative Management, Dalhousie University, Halifax, NS B3H 4R2, Canada;
| | - Christian Lehmann
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada;
- Department of Anesthesia, Pain and Perioperative Management, Dalhousie University, Halifax, NS B3H 4R2, Canada;
- Department of Physiology and Biophysics, Dalhousie University, Halifax, NS B3H 4R2, Canada
- Department of Pharmacology, Dalhousie University, Halifax, NS B3H 4R2, Canada
| |
Collapse
|
|
11
|
Kondreddy V, Keshava S, Esmon CT, Pendurthi UR, Rao LVM. A critical role of endothelial cell protein C receptor in the intestinal homeostasis in experimental colitis. Sci Rep 2020; 10:20569. [PMID: 33239717 PMCID: PMC7689504 DOI: 10.1038/s41598-020-77502-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 11/11/2020] [Indexed: 12/28/2022] Open
Abstract
Crohn’s disease and ulcerative colitis are the two forms of disorders of the human inflammatory bowel disease with unknown etiologies. Endothelial cell protein C receptor (EPCR) is a multifunctional and multiligand receptor, which is expressed on the endothelium and other cell types, including epithelial cells. Here, we report that EPCR is expressed in the colon epithelial cells, CD11c+, and CD21+/CD35+ myeloid cells surrounding the crypts in the colon mucosa. EPCR expression was markedly decreased in the colon mucosa during colitis. The loss of EPCR appeared to associate with increased disease index of the experimental colitis in mice. EPCR−/− mice were more susceptible to dextran sulfate sodium (DSS)-induced colitis, manifested by increased weight loss, macrophage infiltration, and inflammatory cytokines in the colon tissue. DSS treatment of EPCR−/− mice resulted in increased bleeding, bodyweight loss, anemia, fibrin deposition, and loss of colon epithelial and goblet cells. Administration of coagulant factor VIIa significantly attenuated the DSS-induced colon length shortening, rectal bleeding, bodyweight loss, and disease activity index in the wild-type mice but not EPCR−/− mice. In summary, our data provide direct evidence that EPCR plays a crucial role in regulating the inflammation in the colon during colitis.
Collapse
Affiliation(s)
- Vijay Kondreddy
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center At Tyler, 11937 US Highway 271, Tyler, TX, 75708-3154, USA
| | - Shiva Keshava
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center At Tyler, 11937 US Highway 271, Tyler, TX, 75708-3154, USA
| | - Charles T Esmon
- Coagulation Biology Laboratory, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Usha R Pendurthi
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center At Tyler, 11937 US Highway 271, Tyler, TX, 75708-3154, USA
| | - L Vijaya Mohan Rao
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center At Tyler, 11937 US Highway 271, Tyler, TX, 75708-3154, USA.
| |
Collapse
|
|
12
|
The risk of cardiovascular complications in inflammatory bowel disease. Clin Exp Med 2020; 20:481-491. [PMID: 32785793 PMCID: PMC7568702 DOI: 10.1007/s10238-020-00639-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Accepted: 06/15/2020] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel disease (IBD) is a chronic, relapsing disease of unknown etiology involving gastrointestinal tract. IBD comprises two main entities: ulcerative colitis and Crohn's disease. Several studies showed increased risk of cardiovascular complications in chronic inflammatory disorders, especially during IBD relapses. Endothelium plays a role in physiologic regulation of vascular tone, cell adhesion, migration and resistance to thrombosis. Also, its dysfunction is associated with increased risk of atherosclerosis development. There are several potential links between chronic IBD-related inflammatory processes and the risk of cardiovascular disease, but insight into pathogenetic pathways remains unclear. We present the current concepts and review of adult and pediatric studies on the risk of CVD in IBD.
Collapse
|
|
13
|
Ferreira-Duarte M, Sousa JB, Diniz C, Sousa T, Duarte-Araújo M, Morato M. Experimental and Clinical Evidence of Endothelial Dysfunction in Inflammatory Bowel Disease. Curr Pharm Des 2020; 26:3733-3747. [PMID: 32611296 DOI: 10.2174/1381612826666200701212414] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 06/04/2020] [Indexed: 02/07/2023]
Abstract
The endothelium has a crucial role in proper hemodynamics. Inflammatory bowel disease (IBD) is mainly a chronic inflammatory condition of the gastrointestinal tract. However, considerable evidence points to high cardiovascular risk in patients with IBD. This review positions the basic mechanisms of endothelial dysfunction in the IBD setting (both clinical and experimental). Furthermore, we review the main effects of drugs used to treat IBD in endothelial (dys)function. Moreover, we leave challenging points for enlarging the therapeutic arsenal for IBD with new or repurposed drugs that target endothelial dysfunction besides inflammation.
Collapse
Affiliation(s)
| | | | - Carmen Diniz
- LAQV@REQUIMTE, University of Porto, Porto, Portugal
| | - Teresa Sousa
- Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal
| | | | | |
Collapse
|
|
14
|
Chen W, Chen H, Fu S, Lin X, Zheng Z, Zhang J. Microbiome characterization and re-design by biologic agents for inflammatory bowel disease insights. Bioprocess Biosyst Eng 2020; 44:929-939. [PMID: 32458051 DOI: 10.1007/s00449-020-02380-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 05/12/2020] [Indexed: 12/14/2022]
Abstract
The therapeutic effect of inflammatory bowel disease has improved in the past decades, but most of patients cannot tolerate, do not respond to drugs, or relapse after treating with conventional therapy. Therefore, new and more effective treatment methods are still needed in treatment of IBD. In this review, we will discuss the relevant mechanisms and the latest research progress of biologics (anti-TNF treatments, interleukin inhibitors, integrin inhibitors, antisense oligonucleotide, and JAK inhibitors) for IBD, focus on the efficacy and safety of drugs for moderate-to-severe IBD, and summarize the clinical status and future development direction of biologics in IBD.
Collapse
Affiliation(s)
- Wenshuo Chen
- Department of Gastrointestinal Surgery, Zhujiang Hospital, Southern Medical University, GuangZhou, 510280, China
| | - Haijin Chen
- Department of Gastrointestinal Surgery, Zhujiang Hospital, Southern Medical University, GuangZhou, 510280, China.
| | - Shudan Fu
- Ophthalmology Department, Zhujiang Hospital, Southern Medical University, GuangZhou, 510280, China
| | - Xiaohua Lin
- Department of Gastrointestinal Surgery, Zhujiang Hospital, Southern Medical University, GuangZhou, 510280, China
| | - Zheng Zheng
- Department of Gastrointestinal Surgery, Zhujiang Hospital, Southern Medical University, GuangZhou, 510280, China
| | - Jinlong Zhang
- Department of Gastrointestinal Surgery, Zhujiang Hospital, Southern Medical University, GuangZhou, 510280, China
| |
Collapse
|
|
15
|
Jing B, Wang ZA, Zhang C, Deng Q, Wei J, Luo Y, Zhang X, Li J, Du Y. Establishment and Application of Peristaltic Human Gut-Vessel Microsystem for Studying Host-Microbial Interaction. Front Bioeng Biotechnol 2020; 8:272. [PMID: 32296697 PMCID: PMC7137556 DOI: 10.3389/fbioe.2020.00272] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 03/16/2020] [Indexed: 12/18/2022] Open
Abstract
Intestinal floras influence a lot of biological functions of the organism. Although animal model are strong tools for researches on the relationship between host and microbe, a physiologically relevant in vitro human gut model was still required. Here, a novel human gut-vessel microfluidic system was established to study the host–microbial interaction. Peristaltic motion of the cells on the chip was driven by a pneumatic pump. When intestinal epithelial cells (Caco2) were co-cultured with vascular endothelial cells (HUVECs) on the peristaltic microfluidic chip, Caco2 showed normal barrier and absorption functions after 5 days cultivation, which generally took 21 days in static Transwell models. Intestinal microvilli and glycocalyx layer were seen after 4 days cultivation, and Lactobacillus casei was successfully co-cultured for a week in the intestinal cavity. A model for intestinal damage and inflammatory responses caused by E. coli was set up on this chip, which were successfully suppressed by Lactobacillus casei or antibiotic. In summary, this human gut-vessel microfluidic system showed a good potential for investigating the host–microbial interaction and the effect and mechanism of microbiome on intestinal diseases in vitro.
Collapse
Affiliation(s)
- Bolin Jing
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China.,Department of Chemistry, University of Chinese Academy of Sciences, Beijing, China
| | - Zhuo A Wang
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China
| | - Chen Zhang
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China
| | - Quanfeng Deng
- Key Laboratory of Fine Chemicals, Department of Chemical Engineering, Dalian University of Technology, Dalian, China
| | - Jinhua Wei
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China
| | - Yong Luo
- Key Laboratory of Fine Chemicals, Department of Chemical Engineering, Dalian University of Technology, Dalian, China
| | - Xiuli Zhang
- College of Pharmaceutical Sciences, Soochow University, Soochow, China
| | - Jianjun Li
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China
| | - Yuguang Du
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China
| |
Collapse
|
|
16
|
Seiler KM, Bajinting A, Alvarado DM, Traore MA, Binkley MM, Goo WH, Lanik WE, Ou J, Ismail U, Iticovici M, King CR, VanDussen KL, Swietlicki EA, Gazit V, Guo J, Luke CJ, Stappenbeck T, Ciorba MA, George SC, Meacham JM, Rubin DC, Good M, Warner BW. Patient-derived small intestinal myofibroblasts direct perfused, physiologically responsive capillary development in a microfluidic Gut-on-a-Chip Model. Sci Rep 2020; 10:3842. [PMID: 32123209 PMCID: PMC7051952 DOI: 10.1038/s41598-020-60672-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 02/13/2020] [Indexed: 02/07/2023] Open
Abstract
The development and physiologic role of small intestine (SI) vasculature is poorly studied. This is partly due to a lack of targetable, organ-specific markers for in vivo studies of two critical tissue components: endothelium and stroma. This challenge is exacerbated by limitations of traditional cell culture techniques, which fail to recapitulate mechanobiologic stimuli known to affect vessel development. Here, we construct and characterize a 3D in vitro microfluidic model that supports the growth of patient-derived intestinal subepithelial myofibroblasts (ISEMFs) and endothelial cells (ECs) into perfused capillary networks. We report how ISEMF and EC-derived vasculature responds to physiologic parameters such as oxygen tension, cell density, growth factors, and pharmacotherapy with an antineoplastic agent (Erlotinib). Finally, we demonstrate effects of ISEMF and EC co-culture on patient-derived human intestinal epithelial cells (HIECs), and incorporate perfused vasculature into a gut-on-a-chip (GOC) model that includes HIECs. Overall, we demonstrate that ISEMFs possess angiogenic properties as evidenced by their ability to reliably, reproducibly, and quantifiably facilitate development of perfused vasculature in a microfluidic system. We furthermore demonstrate the feasibility of including perfused vasculature, including ISEMFs, as critical components of a novel, patient-derived, GOC system with translational relevance as a platform for precision and personalized medicine research.
Collapse
Grants
- R01 HD105301 NICHD NIH HHS
- R01 DK106382 NIDDK NIH HHS
- T32 DK007130 NIDDK NIH HHS
- R01 DK104698 NIDDK NIH HHS
- R01 DK114047 NIDDK NIH HHS
- R03 DK111473 NIDDK NIH HHS
- R01 DK109384 NIDDK NIH HHS
- R01 DK118568 NIDDK NIH HHS
- R01 DK112378 NIDDK NIH HHS
- K08 DK101608 NIDDK NIH HHS
- P30 DK052574 NIDDK NIH HHS
- T32 HD043010 NICHD NIH HHS
- K01 DK109081 NIDDK NIH HHS
- Association for Academic Surgery Foundation (AASF)
- Children’s Discovery Institute of Washington University in St. Louis and St. Louis Children’s Hospital MI-F-2017-629; National Institutes of Health 4T32HD043010-14
- National Institutes of Health 3T32DK007130-45S1
- Givin’ it all for Guts Foundation (https://givinitallforguts.org/), Lawrence C. Pakula MD IBD Research, Innovation, and Education Fund, National Institutes of Health R01DK109384
- National Institutes of Health R03DK111473, R01DK118568, and K08DK101608, Children’s Discovery Institute of Washington University in St. Louis and St. Louis Children’s Hospital MI-FR-2017-596, March of Dimes Foundation Grant No. 5-FY17-79, Department of Pediatrics at Washington University School of Medicine, St. Louis
Collapse
Affiliation(s)
- Kristen M Seiler
- Division of Pediatric Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, United States
| | - Adam Bajinting
- Division of Pediatric Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, United States
- Saint Louis University School of Medicine, St. Louis, Missouri, United States
| | - David M Alvarado
- Division of Gastroenterology and the Inflammatory Bowel Diseases Center, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, United States
| | - Mahama A Traore
- Department of Biomedical Engineering, Washington University, St. Louis, Missouri, United States
| | - Michael M Binkley
- Department of Mechanical Engineering & Materials Science, Washington University McKelvey School of Engineering, St. Louis, MO, United States
| | - William H Goo
- Washington University, St. Louis, Missouri, United States
| | - Wyatt E Lanik
- Division of Newborn Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, United States
| | - Jocelyn Ou
- Division of Newborn Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, United States
| | - Usama Ismail
- Department of Mechanical Engineering & Materials Science, Washington University McKelvey School of Engineering, St. Louis, MO, United States
| | - Micah Iticovici
- Division of Gastroenterology and the Inflammatory Bowel Diseases Center, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, United States
| | - Cristi R King
- Division of Pediatric Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, United States
| | - Kelli L VanDussen
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Elzbieta A Swietlicki
- Division of Gastroenterology and the Inflammatory Bowel Diseases Center, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, United States
| | - Vered Gazit
- Division of Gastroenterology and the Inflammatory Bowel Diseases Center, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, United States
| | - Jun Guo
- Division of Pediatric Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, United States
| | - Cliff J Luke
- Division of Newborn Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, United States
| | - Thaddeus Stappenbeck
- Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri, United States
| | - Matthew A Ciorba
- Division of Gastroenterology and the Inflammatory Bowel Diseases Center, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, United States
| | - Steven C George
- Department of Biomedical Engineering, University of California, Davis, California, United States
| | - J Mark Meacham
- Department of Mechanical Engineering & Materials Science, Washington University McKelvey School of Engineering, St. Louis, MO, United States
| | - Deborah C Rubin
- Division of Gastroenterology and the Inflammatory Bowel Diseases Center, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, United States
| | - Misty Good
- Division of Newborn Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, United States
| | - Brad W Warner
- Division of Pediatric Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, United States.
| |
Collapse
|
|
17
|
Cao F, Liu J, Sha BX, Pan HF. Natural Products: Experimental Efficient Agents for Inflammatory Bowel Disease Therapy. Curr Pharm Des 2020; 25:4893-4913. [DOI: 10.2174/1381612825666191216154224] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Accepted: 12/12/2019] [Indexed: 02/06/2023]
Abstract
:
Inflammatory bowel disease (IBD) is a chronic, elusive disorder resulting in relapsing inflammation of
intestine with incompletely elucidated etiology, whose two representative forms are ulcerative colitis (UC) and
Crohn’s disease (CD). Accumulating researches have revealed that the individual genetic susceptibility, environmental
risk elements, intestinal microbial flora, as well as innate and adaptive immune system are implicated in
the pathogenesis and development of IBD. Despite remarkable progression of IBD therapy has been achieved by
chemical drugs and biological therapies such as aminosalicylates, corticosteroids, antibiotics, anti-tumor necrosis
factor (TNF)-α, anti-integrin agents, etc., healing outcome still cannot be obtained, along with inevitable side
effects. Consequently, a variety of researches have focused on exploring new therapies, and found that natural
products (NPs) isolated from herbs or plants may serve as promising therapeutic agents for IBD through antiinflammatory,
anti-oxidant, anti-fibrotic and anti-apoptotic effects, which implicates the modulation on nucleotide-
binding domain (NOD) like receptor protein (NLRP) 3 inflammasome, gut microbiota, intestinal microvascular
endothelial cells, intestinal epithelia, immune system, etc. In the present review, we will summarize the research
development of IBD pathogenesis and current mainstream therapy, as well as the therapeutic potential and
intrinsic mechanisms of NPs in IBD.
Collapse
Affiliation(s)
- Fan Cao
- Department of Clinical Medicine, The Second School of Clinical Medicine, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, China
| | - Jie Liu
- School of Traditional Chinese Medicine, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu, China
| | - Bing-Xian Sha
- Department of Clinical Medicine, Tongji University, 50 Chifeng Road, Shanghai, China
| | - Hai-Feng Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, China
| |
Collapse
|
|
18
|
Bian Y, Dong Y, Sun J, Sun M, Hou Q, Lai Y, Zhang B. Protective Effect of Kaempferol on LPS-Induced Inflammation and Barrier Dysfunction in a Coculture Model of Intestinal Epithelial Cells and Intestinal Microvascular Endothelial Cells. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2020; 68:160-167. [PMID: 31825618 DOI: 10.1021/acs.jafc.9b06294] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of intestinal mucosa and submucosa, characterized by the disruption of the intestinal epithelial barrier, increased production of inflammatory mediators, and excessive tissue injury. Intestinal epithelial cells, as well as microvascular endothelial cells, play important roles in IBD. To study the potential effects of kaempferol in IBD progress, we established a novel epithelial-endothelial cells coculture model to investigate the intestinal inflammation and barrier function. Data demonstrated an obvious increased transepithelial electrical resistance (TEER) (1222 ± 60.40 Ω cm2 vs 1371 ± 38.77 Ω cm2), decreased flux of FITC (180.8 ± 20.06 μg/mL vs 136.7 ± 14.78 μg/mL), and up-regulated occludin and claudin-2 expression in Caco-2 that was specifically cocultured with endothelial cells. Meanwhile, 80 μM kaempferol alleviated the drop of TEER, the increase of FITC flux, and the overexpression of interleukin-8 (IL-8) induced by 1 μg/mL lipopolysaccharide (LPS). Additionally, kaempferol also ameliorated the LPS-induced decrease of protein expression of zonula occludens-1 (ZO-1), occludin, and claudin-2, together with the inhibited protein expressions of the phosphorylation level of NF-κB and I-κB induced by LPS. Our results suggest that kaempferol alleviates the IL-8 secretion and barrier dysfunction of the Caco-2 monolayer in the LPS-induced epithelial-endothelial coculture model via inhibiting the NF-κB signaling pathway activation.
Collapse
Affiliation(s)
- Yifei Bian
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology , China Agricultural University , Yuanmingyuan West Road , Haidian District, Beijing , 100193 , China
| | - Yuanyang Dong
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology , China Agricultural University , Yuanmingyuan West Road , Haidian District, Beijing , 100193 , China
| | - Jingjing Sun
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology , China Agricultural University , Yuanmingyuan West Road , Haidian District, Beijing , 100193 , China
| | - Meng Sun
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology , China Agricultural University , Yuanmingyuan West Road , Haidian District, Beijing , 100193 , China
| | - Qihang Hou
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology , China Agricultural University , Yuanmingyuan West Road , Haidian District, Beijing , 100193 , China
| | - Yujiao Lai
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology , China Agricultural University , Yuanmingyuan West Road , Haidian District, Beijing , 100193 , China
| | - Bingkun Zhang
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology , China Agricultural University , Yuanmingyuan West Road , Haidian District, Beijing , 100193 , China
| |
Collapse
|
|
19
|
Abstract
Introduction: The mucosal addressin cell adhesion molecule-1 (MAdCAM-1) plays a key role in the endothelial adhesion and migration of lymphocytes to sites of inflammation in inflammatory bowel disease. Therapies that target this pathway appear to be a promising therapeutic approach in the management of ulcerative colitis (UC).Areas covered: This review provides a summary of the preclinical and available clinical data on the safety and efficacy of ontamalimab (SHP647), a fully human monoclonal antibody that binds and inhibits the action of MAdCAM-1.Expert opinion: Intestinal immune cell trafficking is emerging as an important component in the pathogenesis of UC. Ontamalimab (SHP647) inhibits this process by preventing the binding of integrins found on the surface of lymphocytes and the endothelial ligand adhesion molecule MAdCAM-1. This monoclonal antibody has already demonstrated safety and efficacy in phase II clinical trials. Its targeted mechanism of action suggests a superior safety profile as compared with the current systemic immunosuppressive therapies. Results from the phase III trials are awaited to establish ontamalimab (SHP647) as a therapeutic option in the management of UC.
Collapse
Affiliation(s)
- Sherman Picardo
- Inflammatory Bowel Disease Unit, Department of Gastroenterology, University of Calgary, Calgary, AB, Canada
| | - Remo Panaccione
- Inflammatory Bowel Disease Unit, Department of Gastroenterology, University of Calgary, Calgary, AB, Canada
| |
Collapse
|
|
20
|
A Pharmacological Approach to Managing Inflammatory Bowel Disease During Conception, Pregnancy and Breastfeeding: Biologic and Oral Small Molecule Therapy. Drugs 2019; 79:1053-1063. [PMID: 31183768 DOI: 10.1007/s40265-019-01141-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The inflammatory bowel diseases commonly affect individuals during their peak reproductive years. Patients are often concerned about the impact of medical therapies on their ability to conceive, effect on the fetus, as well as the ability to breastfeed, which has led to poor medical adherence during pregnancy. However, most medications are safe, and discontinuation may lead to active disease, which is associated with adverse materno-fetal outcomes. The anti-TNF biologic therapies, infliximab and adalimumab have been extensively studied in the context of pregnancy. They are actively transferred to the placenta during the second and third trimesters; these have not been associated with an increased rate of congenital abnormalities or fetal death. The minimal amounts of drug that are transferred to breast milk are proteolyzed by the infant's digestive system with no reported short- or long-term adverse effects. There is a paucity of clinical data for the other approved anti-TNF agents or newer anti-integrin (vedolizumab) and anti-interleukin (ustekinumab) therapies used in the management of inflammatory bowel disease; however, no significant safety signals have been documented thus far. The new oral small molecule therapy, tofacitinib is teratogenic in animal models and is contra-indicated in patients attempting pregnancy. It is important that patients, as well as physicians managing patients with these conditions, be aware of the impact of these medical therapies during pregnancy.
Collapse
|
|
21
|
Petrey AC, Obery DR, Kessler SP, Zawerton A, Flamion B, de la Motte CA. Platelet hyaluronidase-2 regulates the early stages of inflammatory disease in colitis. Blood 2019; 134:765-775. [PMID: 31262781 PMCID: PMC6716076 DOI: 10.1182/blood.2018893594] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 06/12/2019] [Indexed: 12/31/2022] Open
Abstract
Platelets are specialized cells essential for hemostasis that also function as crucial effectors capable of mediating inflammatory and immune responses. These sentinels continually survey their environment and discriminate between homeostatic and danger signals such as modified components of the extracellular matrix. The glycosaminoglycan hyaluronan (HA) is a major extracellular matrix component that coats the vascular lumen and, under normal conditions, restricts access of inflammatory cells. In response to tissue damage, the endothelial HA matrix enhances leukocyte recruitment and regulates the early stages of the inflammatory response. We have shown that platelets can degrade HA from the surface of activated endothelial cells via the enzyme hyaluronidase-2 (HYAL2) and that HYAL2 is deficient in platelets isolated from patients with inflammatory bowel disease (IBD). Platelets are known to be involved in the pathogenesis of several chronic disease states, including IBD, but they have been largely overlooked in the context of intestinal inflammation. We therefore wanted to define the mechanism by which platelet HYAL2 regulates the inflammatory response during colitis. In this study, we provide evidence that HA catabolism is disrupted in human intestinal microvascular endothelial cells isolated from patients with IBD. Furthermore, mice deficient in HYAL2 are more susceptible to an acute model of colitis, and this increased susceptibility is abrogated by transfusion of HYAL2-competent platelets. Finally, we show that platelets, via HYAL2-dependent degradation of endothelial HA, regulate the early stages of inflammation in colitis by limiting leukocyte extravasation.
Collapse
Affiliation(s)
- Aaron C Petrey
- Department of Inflammation and Immunity, Cleveland Clinic Lerner Research Institute, Cleveland, OH; and
| | - Dana R Obery
- Department of Inflammation and Immunity, Cleveland Clinic Lerner Research Institute, Cleveland, OH; and
| | - Sean P Kessler
- Department of Inflammation and Immunity, Cleveland Clinic Lerner Research Institute, Cleveland, OH; and
| | - Ash Zawerton
- Department of Inflammation and Immunity, Cleveland Clinic Lerner Research Institute, Cleveland, OH; and
| | - Bruno Flamion
- Molecular Physiology Research Unit, Namur Research Institute for Life Sciences, University of Namur, Namur, Belgium
| | - Carol A de la Motte
- Department of Inflammation and Immunity, Cleveland Clinic Lerner Research Institute, Cleveland, OH; and
| |
Collapse
|
|
22
|
Formes H, Reinhardt C. The gut microbiota - a modulator of endothelial cell function and a contributing environmental factor to arterial thrombosis. Expert Rev Hematol 2019; 12:541-549. [PMID: 31159610 DOI: 10.1080/17474086.2019.1627191] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Introduction: There is emerging evidence linking the commensal gut microbiota with the development of cardiovascular disease and arterial thrombosis. In immunothrombosis, the host clotting system protects against the dissemination of invading microbes, not considering the huge number of microbes that interact with host physiology in a mutualistic fashion. Areas covered: Interestingly, recent research revealed that colonizing gut microbes profoundly influence host innate immune pathways that support arterial thrombus growth. The gut microbiota promotes arterial thrombus formation by enhancing the pro-adhesive capacity of the vascular endothelium, triggering hepatic von Willebrand factor synthesis and its release by Weibel-Palade body exocytosis, resulting in elevated von Willebrand factor levels and enhancing FVIII stability in plasma. Furthermore, the metabolic capacity of gut resident microbes promotes agonist-induced platelet activation and deposition. Here, we give an overview, with a focus on the vascular endothelium, on how this gut-resident microbial ecosystem contributes to arterial thrombus formation. Expert opinion: The gut microbiota and its metabolites not only act on agonist-induced platelet reactivity, but also influence the hepatic endothelial phenotype via remote signaling, facilitating arterial thrombus growth at the arterial injury site.
Collapse
Affiliation(s)
- Henning Formes
- a Center for Thrombosis and Hemostasis (CTH) , University Medical Center Mainz, Johannes Gutenberg University Mainz , Mainz , Germany
| | - Christoph Reinhardt
- a Center for Thrombosis and Hemostasis (CTH) , University Medical Center Mainz, Johannes Gutenberg University Mainz , Mainz , Germany.,b German Center for Cardiovascular Research (DZHK), University Medical Center Mainz, Partner Site RheinMain , Mainz , Germany
| |
Collapse
|
|
23
|
Aljadi Z, Kalm F, Ramachandraiah H, Nopp A, Lundahl J, Russom A. Microfluidic Immunoaffinity Basophil Activation Test for Point-of-Care Allergy Diagnosis. J Appl Lab Med 2019; 4:152-163. [PMID: 31639660 DOI: 10.1373/jalm.2018.026641] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 03/14/2019] [Indexed: 02/02/2023]
Abstract
BACKGROUND The flow cytometry-based basophil activation test (BAT) is used for the diagnosis of allergic response. However, flow cytometry is time-consuming, requiring skilled personnel and cumbersome processing, which has limited its use in the clinic. Here, we introduce a novel microfluidic-based immunoaffinity BAT (miBAT) method. METHODS The microfluidic device, coated with anti-CD203c, was designed to capture basophils directly from whole blood. The captured basophils are activated by anti-FcεRI antibody followed by optical detection of CD63 expression (degranulation marker). The device was first characterized using a basophil cell line followed by whole blood experiments. We evaluated the device with ex vivo stimulation of basophils in whole blood from healthy controls and patients with allergies and compared it with flow cytometry. RESULTS The microfluidic device was capable of capturing basophils directly from whole blood followed by in vitro activation and quantification of CD63 expression. CD63 expression was significantly higher (P = 0.0002) in on-chip activated basophils compared with nonactivated cells. The difference in CD63 expression on anti-FcεRI-activated captured basophils in microfluidic chip was significantly higher (P = 0.03) in patients with allergies compared with healthy controls, and the results were comparable with flow cytometry analysis (P = 0.04). Furthermore, there was no significant difference of CD63% expression in anti-FcεRI-activated captured basophils in microfluidic chip compared with flow cytometry. CONCLUSIONS We report on the miBAT. This device is capable of isolating basophils directly from whole blood for on-chip activation and detection. The new miBAT method awaits validation in larger patient populations to assess performance in diagnosis and monitoring of patients with allergies at the point of care.
Collapse
Affiliation(s)
- Zenib Aljadi
- Division of Nanobiotechnology, Department of Protein Science, Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Stockholm, Sweden.,Department of Clinical Science and Education, Karolinska Institutet and Södersjukhuset, Stockholm, Sweden
| | - Frida Kalm
- Division of Nanobiotechnology, Department of Protein Science, Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Stockholm, Sweden.,Department of Clinical Science and Education, Karolinska Institutet and Södersjukhuset, Stockholm, Sweden
| | - Harisha Ramachandraiah
- Division of Nanobiotechnology, Department of Protein Science, Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Anna Nopp
- Department of Clinical Science and Education, Karolinska Institutet and Södersjukhuset, Stockholm, Sweden
| | - Joachim Lundahl
- Department of Clinical Science and Education, Karolinska Institutet and Södersjukhuset, Stockholm, Sweden
| | - Aman Russom
- Division of Nanobiotechnology, Department of Protein Science, Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Stockholm, Sweden;
| |
Collapse
|
|
24
|
Schirbel A, Rebert N, Sadler T, West G, Rieder F, Wagener C, Horst A, Sturm A, de la Motte C, Fiocchi C. Mutual Regulation of TLR/NLR and CEACAM1 in the Intestinal Microvasculature: Implications for IBD Pathogenesis and Therapy. Inflamm Bowel Dis 2019; 25:294-305. [PMID: 30295747 PMCID: PMC6327233 DOI: 10.1093/ibd/izy316] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2018] [Indexed: 12/16/2022]
Abstract
Background Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) displays multiple activities, among which pathogen binding and angiogenesis are particularly prominent. These same functions are also exerted by Toll- and NOD-like receptors (TLRs and NLRs), which are critical mediators of innate immune responses. We investigated whether a functional inter-relationship exists between CEACAM1 and TLRs and NLRs and its potential impact on induction of intestinal angiogenesis. Methods This hypothesis was tested using human intestinal microvascular endothelial cells, a unique cell population exposed to microbial products under physiological and pathological conditions. Results The results show that activation of TLR2/4, TLR4, NOD1, and NOD2 by specific bacterial ligands selectively and differentially upregulates the levels of cellular and soluble CEACAM1 produced by intestinal microvascular endothelial cells. The results also show that CEACAM1 regulates the migration, transmigration, and tube formation of these endothelial cells and mediates vessel sprouting induced by specific TLR and NLR bacterial ligands. Combined, these results demonstrate a close and reciprocal regulatory interaction between CEACAM1 and bacterial products in mediating multiple functions essential to new vessel formation in the gut mucosa. Conclusions A coordinated and reciprocal interaction of CEACAM1 and microbiota-derived factors is necessary to optimize angiogenesis in the gut mucosa. This suggests that a coordination of endogenous and exogenous innate immune responses is necessary to promote intestinal angiogenesis under physiological and inflammatory conditions such as inflammatory bowel disease.
Collapse
Affiliation(s)
- Anja Schirbel
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany
- Department of Inflammation and Immunity, Lerner Research Institute, Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio
| | - Nancy Rebert
- Department of Inflammation and Immunity, Lerner Research Institute, Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio
| | - Tammy Sadler
- Department of Inflammation and Immunity, Lerner Research Institute, Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio
| | - Gail West
- Department of Inflammation and Immunity, Lerner Research Institute, Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio
| | - Florian Rieder
- Department of Inflammation and Immunity, Lerner Research Institute, Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio
| | | | - Andrea Horst
- University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andreas Sturm
- DRK Kliniken Berlin, Schwerpunkt Gastroenterologie, Berlin, Germany
| | - Carol de la Motte
- Department of Inflammation and Immunity, Lerner Research Institute, Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio
| | - Claudio Fiocchi
- Department of Inflammation and Immunity, Lerner Research Institute, Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio
| |
Collapse
|
|
25
|
Bian Y, Liu P, Zhong J, Hu Y, Fan Y, Zhuang S, Liu Z. Kaempferol inhibits multiple pathways involved in the secretion of inflammatory mediators from LPS‑induced rat intestinal microvascular endothelial cells. Mol Med Rep 2018; 19:1958-1964. [PMID: 30569099 DOI: 10.3892/mmr.2018.9777] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 11/08/2018] [Indexed: 11/06/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic, idiopathic inflammatory disease of the small and/or large intestine. Endothelial expression of inflammatory mediators, including cytokines and adhesion molecules, serves a critical role in the initiation and progression of IBD. The dietary flavonoid, kaempferol, has been reported to inhibit expression of inflammatory mediators; however, the underlying mechanisms require further investigation. In the present study, a novel molecular mechanism of kaempferol against IBD was identified. The potential anti‑inflammatory effect of kaempferol in a cellular model of intestinal inflammation was assessed using lipopolysaccharide (LPS)‑induced rat intestinal microvascular endothelial cells (RIMVECs), and an underlying key molecular mechanism was identified. RIMVECs were pretreated with kaempferol of various concentrations (12.5, 25 and 50 µM) followed by LPS (10 µg/ml) stimulation. ELISA was used to examine the protein levels of tumor necrosis factor‑α (TNF‑α), interleukin‑1β (IL‑1β), IL‑6, intercellular adhesion molecule-1 (ICAM‑1) and vascular cell adhesion molecule-1 (VCAM‑1) in the supernatant. Protein expression levels of Toll‑like receptor 4 (TLR4), nuclear factor‑κB (NF‑κB) p65, inhibitor of NF‑κB, mitogen‑activated protein kinase p38 and signal transducer and activator of transcription (STAT) in cells were measured by western blotting. Kaempferol significantly reduced the overproduction of TNF‑α, IL‑1β, interleukin‑6, ICAM‑1 and VCAM‑1 induced by LPS, indicating the negative regulation of kaempferol in TLR4, NF‑κB and STAT signaling underlying intestinal inflammation. The present results provide support for the potential use of kaempferol as an effective therapeutic agent for IBD treatment.
Collapse
Affiliation(s)
- Yifei Bian
- Division of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing 100193, P.R. China
| | - Ping Liu
- Division of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing 100193, P.R. China
| | - Jia Zhong
- Division of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing 100193, P.R. China
| | - Yusheng Hu
- Division of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing 100193, P.R. China
| | - Yingsai Fan
- Division of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing 100193, P.R. China
| | - Shen Zhuang
- Division of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing 100193, P.R. China
| | - Zhongjie Liu
- Division of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing 100193, P.R. China
| |
Collapse
|
|
26
|
Clostridium difficile toxins induce VEGF-A and vascular permeability to promote disease pathogenesis. Nat Microbiol 2018; 4:269-279. [PMID: 30510170 DOI: 10.1038/s41564-018-0300-x] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2015] [Accepted: 10/22/2018] [Indexed: 01/15/2023]
Abstract
Clostridium difficile infection (CDI) is mediated by two major exotoxins, toxin A (TcdA) and toxin B (TcdB), that damage the colonic epithelial barrier and induce inflammatory responses. The function of the colonic vascular barrier during CDI has been relatively understudied. Here we report increased colonic vascular permeability in CDI mice and elevated vascular endothelial growth factor A (VEGF-A), which was induced in vivo by infection with TcdA- and/or TcdB-producing C. difficile strains but not with a TcdA-TcdB- isogenic mutant. TcdA or TcdB also induced the expression of VEGF-A in human colonic mucosal biopsies. Hypoxia-inducible factor signalling appeared to mediate toxin-induced VEGF production in colonocytes, which can further stimulate human intestinal microvascular endothelial cells. Both neutralization of VEGF-A and inhibition of its signalling pathway attenuated CDI in vivo. Compared to healthy controls, CDI patients had significantly higher serum VEGF-A that subsequently decreased after treatment. Our findings indicate critical roles for toxin-induced VEGF-A and colonic vascular permeability in CDI pathogenesis and may also point to the pathophysiological significance of the gut vascular barrier in response to virulence factors of enteric pathogens. As an alternative to pathogen-targeted therapy, this study may enable new host-directed therapeutic approaches for severe, refractory CDI.
Collapse
|
|
27
|
Bian Y, Liu P, Zhong J, Hu Y, Zhuang S, Fan K, Liu Z. Quercetin Attenuates Adhesion Molecule Expression in Intestinal Microvascular Endothelial Cells by Modulating Multiple Pathways. Dig Dis Sci 2018; 63:3297-3304. [PMID: 30076503 DOI: 10.1007/s10620-018-5221-2] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Accepted: 07/20/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND In inflammatory bowel disease, activation of microvascular endothelial cells and adhesion of immune cells are required for the initiation and maintenance of inflammation. We evaluated the effects and mechanisms of quercetin, a flavone identified in a wide variety of dietary sources, in LPS-induced rat intestinal microvascular endothelial cells (RIMVECs). METHODS RIMVECs were pretreated with quercetin of various concentrations (20, 40 and 80 μM) followed by LPS (10 μg/ml) stimulation. ELISA was used to examine protein levels of intercellular adhesion molecules-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in the supernatant. Protein levels of Toll-like receptor 4 (TLR4), nuclear transcription factor kappa B (NF-κB) p65, inhibitors of NF-κB (IκB-α), extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), mitogen-activated protein kinase (MAPK) p38 and signal transducer and activator of transcription (STAT) in cells were measured by Western blot. RESULTS Quercetin significantly suppressed protein levels of ICAM-1 and VCAM-1 induced by LPS. Quercetin also inhibited TLR4 expression, NF-κB p65, ERK, JNK and STAT phosphorylation and decreased IκB-α degradation. Moreover, the MAPK p38 signal does not contribute to the anti-inflammatory effects on RIMVECs, although LPS significantly increases its phosphorylation. CONCLUSIONS These results indicate that quercetin may have an anti-inflammatory effect by inhibiting expression of ICAM-1 and VCAM-1 in RIMVECs by suppressing TLR4, NF-κB, ERK, JNK and STAT but not the p38 signaling pathway.
Collapse
Affiliation(s)
- Yifei Bian
- Division of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Yuan Ming Yuan West Road No. 2, Haidian District, Beijing, 100193, People's Republic of China
| | - Ping Liu
- Division of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Yuan Ming Yuan West Road No. 2, Haidian District, Beijing, 100193, People's Republic of China
| | - Jia Zhong
- Division of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Yuan Ming Yuan West Road No. 2, Haidian District, Beijing, 100193, People's Republic of China
| | - Yusheng Hu
- Division of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Yuan Ming Yuan West Road No. 2, Haidian District, Beijing, 100193, People's Republic of China
| | - Shen Zhuang
- Division of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Yuan Ming Yuan West Road No. 2, Haidian District, Beijing, 100193, People's Republic of China
| | - Kai Fan
- Division of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Yuan Ming Yuan West Road No. 2, Haidian District, Beijing, 100193, People's Republic of China
| | - Zhongjie Liu
- Division of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Yuan Ming Yuan West Road No. 2, Haidian District, Beijing, 100193, People's Republic of China.
| |
Collapse
|
|
28
|
Allocca M, Gilardi D, Fiorino G, Furfaro F, Argollo M, Peyrin-Biroulet L, Danese S. PF-00547659 for the treatment of Crohn's disease and ulcerative colitis. Expert Opin Investig Drugs 2018; 27:623-629. [PMID: 29985060 DOI: 10.1080/13543784.2018.1494722] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Gut-specific homing is mainly mediated by the expression of MAdCAM-1 on endothelial cells. An increase in MAdCAM-1 expression has been shown in patients with inflammatory bowel disease (IBD). Areas covered: PF-00547659 is a fully human monoclonal antibody (mAb) toward MAdCAM-1 on endothelial cells, blocking its binding with the α4β7 integrin on leukocytes. This review discusses the available data on effectiveness and safety of PF-00547659 in IBD. Expert opinion: A phase II study in moderate-to-severe ulcerative colitis (UC) patients, both naïve and previously exposed to anti-tumor necrosis factors, showed that PF-00547659 was superior to placebo for induction of remission, response, and mucosal healing at week 12. In contrast, preliminary results in a similar study in Crohn's disease (CD) did not show a superiority of PF-00547659, suggesting that PF-00547659 may have limited impact over CD outcomes. However, the time frame needed to evaluate clinical effectiveness of PF-00547659 may be longer in CD patients, given its transmural characteristic. In addition, it should be taken into consideration the possibility of incorporating new tools and more objective parameters in disease assessment that are proven to better correlate with inflammation. Future randomized-controlled trials are needed to confirm the efficacy of PF-00547659 in CD.
Collapse
Affiliation(s)
| | - Daniela Gilardi
- a IBD Centre, Humanitas Clinical and Research Centre , Milan , Italy
| | - Gionata Fiorino
- a IBD Centre, Humanitas Clinical and Research Centre , Milan , Italy
| | - Federica Furfaro
- a IBD Centre, Humanitas Clinical and Research Centre , Milan , Italy
| | - Marjorie Argollo
- a IBD Centre, Humanitas Clinical and Research Centre , Milan , Italy
| | | | - Silvio Danese
- a IBD Centre, Humanitas Clinical and Research Centre , Milan , Italy.,c Department of Biomedical Sciences , Humanitas University , Milan , Italy
| |
Collapse
|
|
29
|
Park SC, Jeen YT. Anti-integrin therapy for inflammatory bowel disease. World J Gastroenterol 2018; 24:1868-1880. [PMID: 29740202 PMCID: PMC5937204 DOI: 10.3748/wjg.v24.i17.1868] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Revised: 04/23/2018] [Accepted: 04/26/2018] [Indexed: 02/06/2023] Open
Abstract
In inflammatory bowel disease (IBD), tumor necrosis factor plays an important role in mediating inflammation, but several other pathways are also involved in eliciting an inflammatory response. One such pathway is the invasion of the intestinal mucosa by leukocytes. Leukocytes within the systemic circulation move to sites of inflammation, and blocking this pathway could be an important treatment strategy for IBD. Anti-integrin therapy blocks the action of integrin on the surface of circulating immune cells and endothelial cell adhesion molecules, thereby inhibiting the interactions between leukocytes and intestinal blood vessels. Natalizumab, which acts on α4-integrin, was the first such drug to be approved for Crohn’s disease, but its use is limited due to the risk of progressive multifocal leukoencephalopathy. Vedolizumab produces few systemic adverse effects because it acts on gut-trophic α4β7 integrin, and has been approved and is being used to treat IBD. Currently, several anti-integrin drugs, including etrolizumab, which acts on β7-integrin, and PF-00547569, which targets mucosal addressin cell adhesion molecule-1, are undergoing clinical trials and the results are being closely watched.
Collapse
Affiliation(s)
- Sung Chul Park
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon 24289, South Korea
| | - Yoon Tae Jeen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul 02841, South Korea
| |
Collapse
|
|
30
|
Burkovskiy I, Zhou J, Lehmann C. Experimental Cannabinoid 2 Receptor Inhibition in CNS Injury-Induced Immunodeficiency Syndrome. Microcirculation 2018; 23:283-92. [PMID: 26999797 DOI: 10.1111/micc.12276] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Accepted: 03/14/2016] [Indexed: 01/15/2023]
Abstract
OBJECTIVE Severe CNS injury, such as stroke, traumatic brain injury, or spinal cord injury, is known to increase susceptibility to infections. The increased susceptibility to infection is due to an impaired immune response and is referred to as CIDS. The CB2 receptor on immune cells presents a potential therapeutic target in CIDS as activation of this receptor has been shown to be involved in immunosuppression. The main purpose of this study was to determine the impact of CB2 receptor inhibition on leukocyte activation within the microcirculation following endotoxin challenge in an experimental stroke model. METHODS Five experimental groups (male C57BL/6 mice, age: 6-8 weeks) were subjected to the following treatments: control; endotoxemia (LPS 5 mg/kg, i.v.); transient cerebral hypoxia-ischemia (HI) + endotoxemia; HI + endotoxemia + CB2 receptor antagonist (AM630 2.5 mg/kg, i.v.). HI was induced by unilateral carotid artery occlusion, followed by 50 minute exposure to a low oxygen atmosphere (8% O2 ). The CB2 receptor antagonist was given 15 min prior to LPS administration. Intravital microscopy (IVM) was carried out 2h after LPS administration. Brains were extracted and stained with tetrazolium chloride (TTC) to measure infarct volume. RESULTS Compared to endotoxemic animals without CNS injury, mice subjected to HI displayed reduced leukocyte activation in intestinal submucosal venules indicative of CIDS. Administration of the CB2 receptor antagonist in animals with CIDS challenged with endotoxin restored peripheral leukocyte recruitment without a detrimental impact on infarct size. CONCLUSION We conclude that the ECS is involved in the impaired immune response following CNS injury. Future studies should further explore the CB2 receptor pathway to develop novel therapies for CIDS.
Collapse
Affiliation(s)
- Ian Burkovskiy
- Department of Anaesthesia, Dalhousie University, Halifax, Nova Scotia, Canada.,Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Juan Zhou
- Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.,Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Christian Lehmann
- Department of Anaesthesia, Dalhousie University, Halifax, Nova Scotia, Canada.,Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.,Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
| |
Collapse
|
|
31
|
Park KH, Kim J, Lee EH, Lee TH. Cynandione A inhibits lipopolysaccharide-induced cell adhesion via suppression of the protein expression of VCAM‑1 in human endothelial cells. Int J Mol Med 2018; 41:1756-1764. [PMID: 29328438 DOI: 10.3892/ijmm.2018.3376] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Accepted: 01/08/2018] [Indexed: 11/06/2022] Open
Abstract
Cynandione A (CA) is one of the most active compounds in the roots of Cynanchum wilfordii, the extracts of which have been used extensively in East Asia to treat various diseases including anti‑ischemic stroke. In the present study, the anti‑adherent activity of CA in lipopolysaccharide (LPS)‑stimulated human umbilical vascular endothelial cells (HUVECs) was investigated. CA markedly reduced the expression of vascular adhesion molecule‑1 (VCAM‑1) by LPS in HUVECs. The results also demonstrated that CA significantly reduced the expression of pro‑inflammatory and chemoattractant cytokines, including interleukin (IL)‑1β, IL‑6, IL‑8, monocyte chemoattractant protein‑1 and tumor necrosis factor‑α, in LPS‑activated human endothelial cells. CA inhibited the phosphorylation of mitogen‑activated protein kinases, including the extracellular signal‑regulated kinase 1/2 and p38 kinases. It was found that CA decreased the IKK/IκB‑α phosphorylation of inhibitor of nuclear factor (NF)‑κB kinase/inhibitor of NF‑κB‑α, suppressed translocation of the NF‑κB p65 subunit into the nucleus and inhibited the transcriptional activity of NF‑κB. CA also decreased human monocyte cell adhesion to endothelial cells in LPS‑stimulated conditions. These results demonstrated that CA inhibited the protein expression of VCAM‑1 and pro‑inflammatory cytokines by suppressing the transcriptional activity of NF‑κB. The results also suggested that CA may be important in the development of anti‑inflammatory drugs by inhibiting the expression of cell adhesion molecules.
Collapse
Affiliation(s)
- Keun Hyung Park
- Graduate School of Biotechnology and College of Life Science, Kyung Hee University, Yongin, Gyeonggi 446‑701, Republic of Korea
| | - Jiyoung Kim
- Graduate School of Biotechnology and College of Life Science, Kyung Hee University, Yongin, Gyeonggi 446‑701, Republic of Korea
| | - Eunjoo H Lee
- Graduate School of East‑West Medical Sciences, Kyung Hee University, Yongin, Gyeonggi 446‑701, Republic of Korea
| | - Tae Hoon Lee
- Graduate School of Biotechnology and College of Life Science, Kyung Hee University, Yongin, Gyeonggi 446‑701, Republic of Korea
| |
Collapse
|
|
32
|
Toullec A, Buard V, Rannou E, Tarlet G, Guipaud O, Robine S, Iruela-Arispe ML, François A, Milliat F. HIF-1α Deletion in the Endothelium, but Not in the Epithelium, Protects From Radiation-Induced Enteritis. Cell Mol Gastroenterol Hepatol 2017; 5:15-30. [PMID: 29276749 PMCID: PMC5738457 DOI: 10.1016/j.jcmgh.2017.08.001] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Accepted: 08/08/2017] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS Radiation therapy in the pelvic area is associated with side effects that impact the quality of life of cancer survivors. Interestingly, the gastrointestinal tract is able to adapt to significant changes in oxygen availability, suggesting that mechanisms related to hypoxia sensing help preserve tissue integrity in this organ. However, hypoxia-inducible factor (HIF)-dependent responses to radiation-induced gut toxicity are unknown. Radiation-induced intestinal toxicity is a complex process involving multiple cellular compartments. Here, we investigated whether epithelial or endothelial tissue-specific HIF-1α deletion could affect acute intestinal response to radiation. METHODS Using constitutive and inducible epithelial or endothelial tissue-specific HIF-1α deletion, we evaluated the consequences of epithelial or endothelial HIF-1α deletion on radiation-induced enteritis after localized irradiation. Survival, radiation-induced tissue injury, molecular inflammatory profile, tissue hypoxia, and vascular injury were monitored. RESULTS Surprisingly, epithelium-specific HIF-1α deletion does not alter radiation-induced intestinal injury. However, irradiated VECad-Cre+/-HIF-1αFL/FL mice present with lower radiation-induced damage, showed a preserved vasculature, reduced hypoxia, and reduced proinflammatory response compared with irradiated HIF-1αFL/FL mice. CONCLUSIONS We demonstrate in vivo that HIF-1α impacts radiation-induced enteritis and that this role differs according to the targeted cell type. Our work provides a new role for HIF-1α and endothelium-dependent mechanisms driving inflammatory processes in gut mucosae. Results presented show that effects on normal tissues have to be taken into account in approaches aiming to modulate hypoxia or hypoxia-related molecular mechanisms.
Collapse
Key Words
- EndoMT, endothelial-to-mesenchymal transition
- Endothelium
- HIF, hypoxia-inducible factor
- HIF-1α
- HIF-1αFl/FL, HIF-1α floxed mice
- HIMEC, human intestinal microvascular endothelial cells
- HUVEC, human umbilical vein endothelial cells
- IL, interleukin
- PAI-1, plasminogen activator inhibitor type-1
- PCR, polymerase chain reaction
- ROSA, ROSA26R LacZ reporter mice
- Radiation
- Sham-IR, sham-irradiation
- TBI, total body irradiation
- VECad-Cre, VE-cadherin-Cre mice
Collapse
Affiliation(s)
- Aurore Toullec
- Research Laboratory of Radiobiology and Radiopathology, Institute for Radiological Protection and Nuclear Safety, Fontenay-aux-Roses, France
| | - Valérie Buard
- Research Laboratory of Radiobiology and Radiopathology, Institute for Radiological Protection and Nuclear Safety, Fontenay-aux-Roses, France
| | - Emilie Rannou
- Research Laboratory of Radiobiology and Radiopathology, Institute for Radiological Protection and Nuclear Safety, Fontenay-aux-Roses, France
- Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, California
| | - Georges Tarlet
- Research Laboratory of Radiobiology and Radiopathology, Institute for Radiological Protection and Nuclear Safety, Fontenay-aux-Roses, France
| | - Olivier Guipaud
- Research Laboratory of Radiobiology and Radiopathology, Institute for Radiological Protection and Nuclear Safety, Fontenay-aux-Roses, France
| | | | - M. Luisa Iruela-Arispe
- Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, California
| | - Agnès François
- Research Laboratory of Radiobiology and Radiopathology, Institute for Radiological Protection and Nuclear Safety, Fontenay-aux-Roses, France
| | - Fabien Milliat
- Research Laboratory of Radiobiology and Radiopathology, Institute for Radiological Protection and Nuclear Safety, Fontenay-aux-Roses, France
- Correspondence Address correspondence to: Fabien Milliat, PhD, Research Laboratory of Radiobiology and Radiopathology, Institute for Radiological Protection and Nuclear Safety, 92265 Fontenay-aux-Roses, France.Research Laboratory of Radiobiology and RadiopathologyInstitute for Radiological Protection and Nuclear Safety92265 Fontenay-aux-RosesFrance
| |
Collapse
|
|
33
|
Wang P, Zhang X, Li F, Yuan K, Li M, Zhang J, Li B, Liang W. MiR-130b attenuates vascular inflammation via negatively regulating tumor progression locus 2 (Tpl2) expression. Int Immunopharmacol 2017; 51:9-16. [PMID: 28759810 DOI: 10.1016/j.intimp.2017.07.020] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Revised: 07/09/2017] [Accepted: 07/20/2017] [Indexed: 12/14/2022]
Abstract
Endothelial cell (EC) activation and dysfunction have been linked to a wide variety of vascular inflammatory diseases. However, the role of microRNAs in EC activation and inflammation remains largely unknown. In this study, we found that miR-130b was significantly decreased in human umbilical vein endothelial cells (HUVECs) after lipopolysaccharides (LPS) treatment. Forced expression of miR-130b inhibited the LPS-induced activation of extracellular signal-regulated kinase (ERK) and the inflammatory genes expression, such as interleukin (IL)-6 and tumor necrosis factor alpha (TNF-α). Furthermore, we identified that tumor progression locus 2 (Tpl2) is a direct target of miR-130b. Finally, in vivo overexpression of miR-130b via miR-130b agomir attenuates acute lung vascular inflammation in the LPS-induced sepsis mouse model. Taken together, our data demonstrated that miR-130b represses vascular inflammation via targeting Tpl2, suggesting that miR-130b mimics might be a promising therapeutic strategy for treatment of vascular inflammatory diseases.
Collapse
Affiliation(s)
- Peng Wang
- Department of Vascular Surgery, South Campus, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, China
| | - Xue Zhang
- Department of Vascular Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, China
| | - Fulun Li
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Kai Yuan
- Department of Vascular Surgery, South Campus, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, China
| | - Maoran Li
- Department of Vascular Surgery, South Campus, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, China
| | - Jiwei Zhang
- Department of Vascular Surgery, South Campus, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, China
| | - Bin Li
- Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China; Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Wei Liang
- Department of Vascular Surgery, South Campus, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, China.
| |
Collapse
|
|
34
|
Vadstrup K, Galsgaard ED, Jensen H, Lanier LL, Ryan JC, Chen SY, Nolan GP, Vester-Andersen MK, Pedersen JS, Gerwien J, Jensen T, Bendtsen F. NKG2D ligand expression in Crohn's disease and NKG2D-dependent stimulation of CD8 + T cell migration. Exp Mol Pathol 2017; 103:56-70. [PMID: 28684217 DOI: 10.1016/j.yexmp.2017.06.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Revised: 05/24/2017] [Accepted: 06/30/2017] [Indexed: 12/15/2022]
Abstract
Interaction between the activating NKG2D receptor on lymphocytes and its ligands MICA, MICB, and ULBP1-6 modulate T and NK cell activity and may contribute to the pathogenesis of Crohn's disease (CD). NKG2D ligands are generally not expressed on the cell surface of normal, non-stressed cells, but expression of MICA and MICB in CD intestine has been reported. In this exploratory study, we further characterize the expression of NKG2D and its ligands, including the less well-described ULBP4-6, in CD, and test if NKG2D ligand interactions are involved in the migration of activated T cells into the affected mucosal compartments. Intestinal tissue from CD patients and healthy controls were analyzed by flow cytometry, mass cytometry, and immunohistochemistry for expression of NKG2D and ligands, and for cytokine release. Furthermore, NKG2D-dependent chemotaxis of activated CD8+ T cells across a monolayer of ligand-expressing human intestinal endothelial cells was examined. Activated lymphocytes down-regulated NKG2D expression upon accumulation in inflamed CD intestine. NKG2D expression on CD56+ T and γδ T cells from inflamed tissue seemed inversely correlated with CRP levels and cytokine release. B cells, monocytes, mucosal epithelium, and vascular endothelium expressed NKG2D ligands in inflamed CD intestine. The expression of NKG2D ligands was correlated with cytokine release, but was highly variable between patients. Stimulation of vascular intestinal endothelial cells in vitro induced expression of NKG2D ligands, including MICA/B and ULBP2/6. Blockade of NKG2D on CD8+ T cells inhibited the migration over ligand-expressing endothelial cells. Intestinal induction of NKG2D ligands and ligand-induced down-regulation of NKG2D in CD suggest that the NKG2D-ligand interaction may be involved in both the activation and recruitment of NKG2D+ lymphocytes into the inflamed CD intestine.
Collapse
Affiliation(s)
- Kasper Vadstrup
- Gastrounit, Medical Division, Hvidovre University Hospital, DK-2650 Hvidovre, Denmark; Faculty of Health Sciences, The Panum Institute, University of Copenhagen, DK-2200 Copenhagen N, Denmark; Biopharmaceutical Research Unit, Novo Nordisk A/S, DK-2760 Maaloev, Denmark; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
| | | | - Helle Jensen
- Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Lewis L Lanier
- Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA
| | - James C Ryan
- Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Medicine, Veterans Affairs Medical Center and University of California San Francisco, San Francisco, CA, USA
| | - Shih-Yu Chen
- Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA
| | - Garry P Nolan
- Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA
| | | | - Julie Steen Pedersen
- Gastrounit, Medical Division, Hvidovre University Hospital, DK-2650 Hvidovre, Denmark
| | - Jens Gerwien
- Biopharmaceutical Research Unit, Novo Nordisk A/S, DK-2760 Maaloev, Denmark
| | - Teis Jensen
- Biopharmaceutical Research Unit, Novo Nordisk A/S, DK-2760 Maaloev, Denmark
| | - Flemming Bendtsen
- Gastrounit, Medical Division, Hvidovre University Hospital, DK-2650 Hvidovre, Denmark; Faculty of Health Sciences, The Panum Institute, University of Copenhagen, DK-2200 Copenhagen N, Denmark
| |
Collapse
|
|
35
|
Kasper JY, Hermanns MI, Cavelius C, Kraegeloh A, Jung T, Danzebrink R, Unger RE, Kirkpatrick CJ. The role of the intestinal microvasculature in inflammatory bowel disease: studies with a modified Caco-2 model including endothelial cells resembling the intestinal barrier in vitro. Int J Nanomedicine 2016; 11:6353-6364. [PMID: 27994454 PMCID: PMC5153260 DOI: 10.2147/ijn.s92608] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The microvascular endothelium of the gut barrier plays a crucial role during inflammation in inflammatory bowel disease. We have modified a commonly used intestinal cell model based on the Caco-2 cells by adding microvascular endothelial cells (ISO-HAS-1). Transwell filters were used with intestinal barrier-forming Caco-2 cells on top and the ISO-HAS-1 on the bottom of the filter. The goal was to determine whether this coculture mimics the in vivo situation more closely, and whether the model is suitable to evaluate interactions of, for example, prospective nanosized drug vehicles or contrast agents with this coculture in a physiological and inflamed state as it would occur in inflammatory bowel disease. We monitored the inflammatory responsiveness of the cells (release of IL-8, soluble intercellular adhesion molecule 1, and soluble E-selectin) after exposure to inflammatory stimuli (lipopolysaccharide, TNF-α, INF-γ, IL1-β) and a nanoparticle (Ba/Gd: coprecipitated BaSO4 and Gd(OH)3), generally used as contrast agents. The barrier integrity of the coculture was evaluated via the determination of transepithelial electrical resistance and the apparent permeability coefficient (Papp) of NaFITC. The behavior of the coculture Caco-1/ISO-HAS-1 was compared to the respective monocultures Caco-2 and ISO-HAS-1. Based on transepithelial electrical resistance, the epithelial barrier integrity of the coculture remained stable during incubation with all stimuli, whereas the Papp decreased after exposure to the cytokine mixture (TNF-α, INF-γ, IL1-β, and Ba/Gd). Both the endothelial and epithelial monocultures showed a high inflammatory response in both the upper and lower transwell-compartments. However, in the coculture, inflammatory mediators were only detected on the epithelial side and not on the endothelial side. Thus in the coculture, based on the Papp, the epithelial barrier appears to prevent a potential inflammatory overreaction in the underlying endothelial cells. In summary, this coculture model exhibits in vivo-like features, which cannot be observed in conventional monocultures, making the former more suitable to study interactions with external stimuli.
Collapse
Affiliation(s)
| | | | | | | | - Thomas Jung
- NanoGate AG, Goettelborn, Saarbrücken, Germany
| | | | - Ronald E Unger
- Institute of Pathology, University Medical Center, Mainz
| | | |
Collapse
|
|
36
|
Coskun M, Vermeire S, Nielsen OH. Novel Targeted Therapies for Inflammatory Bowel Disease. Trends Pharmacol Sci 2016; 38:127-142. [PMID: 27916280 DOI: 10.1016/j.tips.2016.10.014] [Citation(s) in RCA: 144] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Revised: 10/21/2016] [Accepted: 10/26/2016] [Indexed: 02/07/2023]
Abstract
Our growing understanding of the immunopathogenesis of inflammatory bowel disease (IBD) has opened new avenues for developing targeted therapies. These advances in treatment options targeting different mechanisms of action offer new hope for personalized management. In this review we highlight emerging novel and easily administered therapeutics that may be viable candidates for the management of IBD, such as antibodies against interleukin 6 (IL-6) and IL-12/23, small molecules including Janus kinase inhibitors, antisense oligonucleotide against SMAD7 mRNA, and inhibitors of leukocyte trafficking to intestinal sites of inflammation (e.g., sphingosine 1-phosphate receptor modulators). We also provide an update on the current status in clinical development of these new classes of therapeutics.
Collapse
Affiliation(s)
- Mehmet Coskun
- Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Denmark; The Bioinformatics Centre, Department of Biology, and Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Denmark
| | - Severine Vermeire
- Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium
| | - Ole Haagen Nielsen
- Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Denmark.
| |
Collapse
|
|
37
|
Raad MA, Chams NH, Sharara AI. New and Evolving Immunotherapy in Inflammatory Bowel Disease. Inflamm Intest Dis 2016; 1:85-95. [PMID: 29922662 PMCID: PMC5988105 DOI: 10.1159/000445986] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Accepted: 03/22/2016] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Crohn's disease and ulcerative colitis are chronic inflammatory disorders associated with a dysregulated adaptive and innate immune response to gut commensals in genetically susceptible individuals. The pathogenesis of inflammatory bowel disease is complex, and the disease is characterized by significant phenotypic and genotypic heterogeneity. SUMMARY The introduction of anti-TNF biologics has resulted in improved clinical outcomes in patients with severe and moderately severe disease, but the current treatment paradigm continues to depend on systemic immunosuppression (steroids and immunomodulators) and surgical intervention in a significant number of patients, underscoring a significant unmet need. More recently, a number of genetic and immunologic abnormalities have been unraveled including aberrant intestinal mucosal defense function, abnormal intestinal permeability, dysregulated bacterial antigen processing by macrophages and presentation to T cells, cellular immune regulation and signaling, cytokine production, and leukocyte trafficking. KEY MESSAGES Understanding these molecular mechanisms and effector pathways presents an opportunity for the development of new and improved targeted therapies.
Collapse
Affiliation(s)
- Mohamad A. Raad
- School of Medicine, American University of Beirut, Beirut, Lebanon
| | - Nour H. Chams
- School of Medicine, American University of Beirut, Beirut, Lebanon
| | - Ala I. Sharara
- Division of Gastroenterology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| |
Collapse
|
|
38
|
Baumgart DC, Bokemeyer B, Drabik A, Stallmach A, Schreiber S. Vedolizumab induction therapy for inflammatory bowel disease in clinical practice--a nationwide consecutive German cohort study. Aliment Pharmacol Ther 2016; 43:1090-102. [PMID: 27038247 DOI: 10.1111/apt.13594] [Citation(s) in RCA: 150] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Revised: 02/01/2016] [Accepted: 03/02/2016] [Indexed: 12/13/2022]
Abstract
BACKGROUND Vedolizumab (VDZ) is a humanised monoclonal IgG1 antibody targeting α4 β7 integrin. AIM To investigate the real-world efficacy of vedolizumab for the treatment of Crohn's disease (CD) and ulcerative colitis (UC). METHODS A consecutive cohort of 212 adult IBD patients with active disease (HBI >7/partial Mayo >4) newly receiving VDZ was prospectively recruited from 7 academic and 17 community centres. The primary endpoint was clinical remission (CRM) (CD HBI ≤4, UC pMayo ≤1) in week 14. Secondary endpoints included steroid-free remission (SFCRM), clinical response (CRS) (HBI/pMayo score drop ≥3), vedolizumab impact on CRP, calprotectin and haemoglobin. RESULTS Data of 97 CD (71.1% female, HBI 11) and 115 UC (42.6% female, pMayo 6) patients were analysed. Only 5.2% CD and 24.3% UC were anti-TNFα naïve. Most had extensive mucosal involvement (Montreal L3 69.1%/E3 53.9%). At week 14, 23.7% vs. 23.5% of CD vs. UC patients achieved CRM, 19.6% vs. 19.1% SFCRM and 60.8% vs. 57.4% CRS, respectively (all based on NRI). Week 14 CRM in CD was significantly associated with no history of extraintestinal manifestations (P = 0.019), no prior adalimumab use (P = 0.011), no hospitalisation in the past 12 months (P = 0.015) and low HBI score (P = 0.02) and in UC with active or previous smoking (P = 0.044/0.028) and no anti-TNFα (P = 0.023) use. Low HBI (P = 0.019) and no hospitalisation in the past 12 months (P = 0.01) predict CD CRM. The three most common AE were joint pain, acne and nasopharyngitis. CONCLUSION Vedolizumab is effective in routine use.
Collapse
Affiliation(s)
- D C Baumgart
- Department of Gastroenterology and Hepatology, Charité Medical School, Humboldt-University of Berlin, Berlin, Germany
| | | | - A Drabik
- Biostatistics Consulting, Münster, Germany
| | - A Stallmach
- Department of Internal Medicine IV (Gastroenterology, Hepatology and Infectious Diseases), University Hospital Jena, Jena, Germany
| | - S Schreiber
- Department Internal Medicine I, University Hospital Schleswig-Holstein Campus, Kiel University of Schleswig-Holstein, Kiel, Germany
| | | |
Collapse
|
|
39
|
Cibor D, Domagala-Rodacka R, Rodacki T, Jurczyszyn A, Mach T, Owczarek D. Endothelial dysfunction in inflammatory bowel diseases: Pathogenesis, assessment and implications. World J Gastroenterol 2016; 22:1067-1077. [PMID: 26811647 PMCID: PMC4716020 DOI: 10.3748/wjg.v22.i3.1067] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Revised: 08/24/2015] [Accepted: 11/30/2015] [Indexed: 02/06/2023] Open
Abstract
Endothelial dysfunction is considered one of the etiological factors of inflammatory bowel disease (IBD). An inflammatory process leads to functional and structural changes in the vascular endothelium. An increase of leukocyte adhesiveness and leukocyte diapedesis, as well as an increased vascular smooth muscle tone and procoagulant activity is observed. Structural changes of the vascular endothelium comprise as well capillary and venule remodeling and proliferation of endothelial cells. Hypoxia in the inflammatory area stimulates angiogenesis by up-regulation of vascular endothelial growth factor, fibroblast growth factor and tumor necrosis factor-α. Inflammatory mediators also alter the lymphatic vessel function and impair lymph flow, exacerbating tissue edema and accumulation of dead cells and bacteria. The endothelial dysfunction might be diagnosed by the use of two main methods: physical and biochemical. Physical methods are based on the assessment of large arteries vasodilatation in response to an increased flow and receptors stimulation. Flow-mediated vasodilatation (FMD) is the method that is the most widely used; however, it is less sensitive in detecting early changes of the endothelium function. Most of the studies demonstrated a decrease of FMD in IBD patients but no changes in the carotic intima-media thickness. Biochemical methods of detecting the endothelial dysfunction are based on the assessment of the synthesis of compounds produced both by the normal and damaged endothelium. The endothelial dysfunction is considered an initial step in the pathogenesis of atherosclerosis in the general population. In IBD patients, the risk of cardiovascular diseases is controversial. Large, prospective studies are needed to establish the role of particular medications or dietary elements in the endothelial dysfunction as well to determine the real risk of cardiovascular diseases.
Collapse
|
|
40
|
Lean QY, Gueven N, Eri RD, Bhatia R, Sohal SS, Stewart N, Peterson GM, Patel RP. Heparins in ulcerative colitis: proposed mechanisms of action and potential reasons for inconsistent clinical outcomes. Expert Rev Clin Pharmacol 2015; 8:795-811. [PMID: 26308504 DOI: 10.1586/17512433.2015.1082425] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Current drug therapies for ulcerative colitis (UC) are not completely effective in managing moderate-to-severe UC and approximately 20% of patients with severe UC require surgical interventions. Heparins, polydisperse mixtures of non-anticoagulant and anticoagulant oligosaccharides, are widely used as anticoagulants. However, heparins are also reported to have anti-inflammatory properties. Unfractionated heparin was initially used in patients with UC for the treatment of rectal microthrombi. Surprisingly, it was found to be effective in reducing UC-associated symptoms. Since then, several pre-clinical and clinical studies have reported promising outcomes of heparins in UC. In contrast, some controlled clinical trials demonstrated no or only limited benefits, thus the potential of heparins for the treatment of UC remains uncertain. This review discusses potential mechanisms of action of heparins, as well as proposed reasons for their contradictory clinical effectiveness in the treatment of UC.
Collapse
Affiliation(s)
- Qi Ying Lean
- a 1 Division of Pharmacy, School of Medicine, Faculty of Health, University of Tasmania , Hobart, Tasmania, Australia.,b 2 Faculty of Pharmacy, University of Technology MARA, Puncak Alam , Selangor, Malaysia
| | - Nuri Gueven
- a 1 Division of Pharmacy, School of Medicine, Faculty of Health, University of Tasmania , Hobart, Tasmania, Australia
| | - Rajaraman D Eri
- c 3 School of Health Sciences, Faculty of Health, University of Tasmania, Launceston , Tasmania, Australia
| | - Rajesh Bhatia
- d 4 Royal Hobart Hospital , Hobart, Tasmania, Australia
| | - Sukhwinder Singh Sohal
- c 3 School of Health Sciences, Faculty of Health, University of Tasmania, Launceston , Tasmania, Australia.,e 5 Breathe Well Centre of Research Excellence for Chronic Respiratory Disease and Lung Ageing, School of Medicine, Faculty of Health, University of Tasmania , Hobart, Tasmania, Australia
| | - Niall Stewart
- a 1 Division of Pharmacy, School of Medicine, Faculty of Health, University of Tasmania , Hobart, Tasmania, Australia
| | - Gregory M Peterson
- a 1 Division of Pharmacy, School of Medicine, Faculty of Health, University of Tasmania , Hobart, Tasmania, Australia.,e 5 Breathe Well Centre of Research Excellence for Chronic Respiratory Disease and Lung Ageing, School of Medicine, Faculty of Health, University of Tasmania , Hobart, Tasmania, Australia.,f 6 Health Services Innovation Tasmania, School of Medicine, Faculty of Health, University of Tasmania , Hobart, Tasmania, Australia
| | - Rahul P Patel
- a 1 Division of Pharmacy, School of Medicine, Faculty of Health, University of Tasmania , Hobart, Tasmania, Australia
| |
Collapse
|
|
41
|
Mintet E, Rannou E, Buard V, West G, Guipaud O, Tarlet G, Sabourin JC, Benderitter M, Fiocchi C, Milliat F, François A. Identification of Endothelial-to-Mesenchymal Transition as a Potential Participant in Radiation Proctitis. THE AMERICAN JOURNAL OF PATHOLOGY 2015; 185:2550-62. [PMID: 26185013 DOI: 10.1016/j.ajpath.2015.04.028] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/30/2014] [Revised: 04/22/2015] [Accepted: 04/29/2015] [Indexed: 01/09/2023]
Abstract
The endothelial-to-mesenchymal transition (EndoMT) is a crucial cellular process during heart development necessary to the formation of cardiac valves. This embryonic process reappears in several pathological situations, such as vascular injury or organ fibrosis of various etiologies, as a mediator of extracellular matrix-producing cells. Because radiation induces both vascular damage and fibrosis, we investigated whether radiation exposure induces EndoMT in primary human intestinal microvascular endothelial cells (HIMECs) and whether EndoMT contributes to radiation-induced rectal damage in humans and in a preclinical model of radiation proctitis in mice. Irradiated HIMECs show phenotypic hallmarks of radiation-induced endothelial cell activation in vitro. Moreover, HIMECs undergo changes in molecular expression pattern compatible with EndoMT, with up-regulation of mesenchymal markers and down-regulation of endothelial markers via transforming growth factor/Smad pathway activation. In vivo, EndoMT readily occurs in the human rectum after radiation therapy for rectal adenocarcinoma. Finally, EndoMT was observed in rectal mucosal and submucosal microvessels in a preclinical model of radiation proctitis in Tie2-green fluorescent protein reporter-expressing mice all along radiation proctitis development, also associated with transforming growth factor/Smad pathway activation. In conclusion, radiation-induced cell activation and tissue inflammation constitute a setting that fosters the phenotypic conversion of endothelial cells into mesenchymal cells. Therefore, EndoMT is identified as a potential participant in radiation-induced gut damage and may represent an interesting therapeutic target in cases of radiation-induced pelvic disease.
Collapse
Affiliation(s)
- Elodie Mintet
- Department of Radiobiology and Epidemiology, Radiobiology and Radiopathology Research Laboratory, Fontenay-aux-Roses, France
| | - Emilie Rannou
- Department of Radiobiology and Epidemiology, Radiobiology and Radiopathology Research Laboratory, Fontenay-aux-Roses, France
| | - Valérie Buard
- Department of Radiobiology and Epidemiology, Radiobiology and Radiopathology Research Laboratory, Fontenay-aux-Roses, France
| | - Gail West
- Department of Pathobiology, Digestive Disease Institute, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Olivier Guipaud
- Department of Radiobiology and Epidemiology, Radiobiology and Radiopathology Research Laboratory, Fontenay-aux-Roses, France
| | - Georges Tarlet
- Department of Radiobiology and Epidemiology, Radiobiology and Radiopathology Research Laboratory, Fontenay-aux-Roses, France
| | | | - Marc Benderitter
- Department of Radiobiology and Epidemiology, Institut de Radioprotection et de Sûreté Nucléaire, Fontenay-aux-Roses, France
| | - Claudio Fiocchi
- Department of Pathobiology, Digestive Disease Institute, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Fabien Milliat
- Department of Radiobiology and Epidemiology, Radiobiology and Radiopathology Research Laboratory, Fontenay-aux-Roses, France
| | - Agnès François
- Department of Radiobiology and Epidemiology, Radiobiology and Radiopathology Research Laboratory, Fontenay-aux-Roses, France.
| |
Collapse
|
|
42
|
Hagan M, Cross RK. Safety of vedolizumab in the treatment of Crohn's disease and ulcerative colitis. Expert Opin Drug Saf 2015; 14:1473-9. [PMID: 26138111 DOI: 10.1517/14740338.2015.1063612] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
INTRODUCTION Vedolizumab is the latest FDA-approved anti-integrin therapy for treatment of moderate-to-severe inflammatory bowel disease (IBD). The safety and efficacy of vedolizumab have been studied in short-term clinical trials. AREAS COVERED This paper reviews the safety profile of vedolizumab compared with other biologics. It also highlights the mechanism of action of the medication. We discuss the current position of vedolizumab in our current algorithm for IBD management and comment on future prospects of the drug. EXPERT OPINION Vedolizumab appears to be a safe and effective option in the treatment of moderate-to-severe IBD in the short term. Long-term observational studies and post-marketing safety data are needed to ascertain the long-term efficacy and side effect profile.
Collapse
Affiliation(s)
- Matilda Hagan
- a 1 University of Maryland, Division of Gastroenterology and Hepatology, Department of Medicine , 100 North Greene Street, Lower Level, Baltimore, MD 21201, USA
| | | |
Collapse
|
|
43
|
Tanida S, Ozeki K, Mizoshita T, Tsukamoto H, Katano T, Kataoka H, Kamiya T, Joh T. Managing refractory Crohn's disease: challenges and solutions. Clin Exp Gastroenterol 2015; 8:131-40. [PMID: 25914555 PMCID: PMC4401331 DOI: 10.2147/ceg.s61868] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The goals of treatment for active Crohn’s disease (CD) are to achieve clinical remission and improve quality of life. Conventional therapeutics for moderate-to-severe CD include 5-aminosalicylic acid, corticosteroids, purine analogs, azathioprine, and 6-mercaptopurine. Patients who fail to respond to conventional therapy are treated with tumor necrosis factor (TNF)-α inhibitors such as infliximab and adalimumab, but their efficacy is limited due to primary nonresponse or loss of response. It is suggested that this requires switch to another TNF-α inhibitor, a combination therapy with TNF-α blockade plus azathioprine, or granulocyte and monocyte adsorptive apheresis, and that other therapeutic options having different mechanisms of action, such as blockade of inflammatory cytokines or adhesion molecules, are needed. Natalizumab and vedolizumab are neutralizing antibodies directed against integrin α4 and α4β7, respectively. Ustekinumab is a neutralizing antibody directed against the receptors for interleukin-12 and interleukin-23. Here, we provide an overview of therapeutic treatments that are effective and currently available for CD patients, as well as some that likely will be available in the near future. We also discuss the advantages of managing patients with refractory CD using a combination of TNF-α inhibitors plus azathioprine or intensive monocyte adsorptive apheresis.
Collapse
Affiliation(s)
- Satoshi Tanida
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Aichi Prefecture, Japan
| | - Keiji Ozeki
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Aichi Prefecture, Japan
| | - Tsutomu Mizoshita
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Aichi Prefecture, Japan
| | - Hironobu Tsukamoto
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Aichi Prefecture, Japan
| | - Takahito Katano
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Aichi Prefecture, Japan
| | - Hiromi Kataoka
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Aichi Prefecture, Japan
| | - Takeshi Kamiya
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Aichi Prefecture, Japan
| | - Takashi Joh
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Aichi Prefecture, Japan
| |
Collapse
|
|
44
|
Scarpa M, Kessler S, Sadler T, West G, Homer C, McDonald C, de la Motte C, Fiocchi C, Stylianou E. The epithelial danger signal IL-1α is a potent activator of fibroblasts and reactivator of intestinal inflammation. THE AMERICAN JOURNAL OF PATHOLOGY 2015; 185:1624-37. [PMID: 25864926 DOI: 10.1016/j.ajpath.2015.02.018] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Revised: 01/26/2015] [Accepted: 02/03/2015] [Indexed: 12/19/2022]
Abstract
Intestinal epithelial cell (IEC) death is typical of inflammatory bowel disease (IBD). We investigated: i) whether IEC-released necrotic cell products (proinflammatory mediators) amplify mucosal inflammation, ii) the capacity of necrotic cell lysates from HT29 cells or human IECs to induce human intestinal fibroblasts' (HIF) production of IL-6 and IL-8, and iii) whether IL-1α, released by injured colonocytes, exacerbated experimental IBD. Necrotic cell lysates potently induced HIF IL-6 and IL-8 production independent of Toll-like receptors 2 and 4, receptor for advanced glycation end-products, high-mobility group box 1, uric acid, IL-33, or inflammasome activation. IL-1α was the key IEC-derived necrotic cell product involved in HIF cytokine production. IL-1α-positive cells were identified in the epithelium in human IBD and dextran sulfate sodium (DSS)-induced colitis. IL-1α was detected in the stool of colitic mice before IL-1β. IL-1α enemas reactivated inflammation after DSS colitis recovery, induced IL-1 receptor expression in subepithelial fibroblasts, and activated de novo inflammation even in mice without overt colitis, after the administration of low-dose DSS. IL-1α amplifies gut inflammation by inducing cytokine production by mesenchymal cells. IL-1α-mediated IEC-fibroblast interaction may be involved in amplifying and perpetuating inflammation, even without obvious intestinal damage. IL-1α may be a target for treating early IBD or preventing the reactivation of IBD.
Collapse
Affiliation(s)
- Melania Scarpa
- Department of Pathobiology, Lerner Research Institute, Cleveland, Ohio
| | - Sean Kessler
- Department of Pathobiology, Lerner Research Institute, Cleveland, Ohio
| | - Tammy Sadler
- Department of Pathobiology, Lerner Research Institute, Cleveland, Ohio
| | - Gail West
- Department of Pathobiology, Lerner Research Institute, Cleveland, Ohio
| | - Craig Homer
- Department of Pathobiology, Lerner Research Institute, Cleveland, Ohio
| | - Christine McDonald
- Department of Pathobiology, Lerner Research Institute, Cleveland, Ohio; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio
| | - Carol de la Motte
- Department of Pathobiology, Lerner Research Institute, Cleveland, Ohio; Department of Gastroenterology & Hepatology, Digestive Disease Institute, Cleveland, Ohio
| | - Claudio Fiocchi
- Department of Pathobiology, Lerner Research Institute, Cleveland, Ohio; Department of Gastroenterology & Hepatology, Digestive Disease Institute, Cleveland, Ohio
| | - Eleni Stylianou
- Department of Pathobiology, Lerner Research Institute, Cleveland, Ohio; Department of Gastroenterology & Hepatology, Digestive Disease Institute, Cleveland, Ohio.
| |
Collapse
|
|
45
|
Hua S, Marks E, Schneider JJ, Keely S. Advances in oral nano-delivery systems for colon targeted drug delivery in inflammatory bowel disease: selective targeting to diseased versus healthy tissue. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2015; 11:1117-32. [PMID: 25784453 DOI: 10.1016/j.nano.2015.02.018] [Citation(s) in RCA: 349] [Impact Index Per Article: 34.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/08/2014] [Revised: 02/02/2015] [Accepted: 02/25/2015] [Indexed: 12/15/2022]
Abstract
UNLABELLED Colon targeted drug delivery is an active area of research for local diseases affecting the colon, as it improves the efficacy of therapeutics and enables localized treatment, which reduces systemic toxicity. Targeted delivery of therapeutics to the colon is particularly advantageous for the treatment of inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease. Advances in oral drug delivery design have significantly improved the bioavailability of drugs to the colon; however in order for a drug to have therapeutic efficacy during disease, considerations must be made for the altered physiology of the gastrointestinal (GI) tract that is associated with GI inflammation. Nanotechnology has been used in oral dosage formulation design as strategies to further enhance uptake into diseased tissue within the colon. This review will describe some of the physiological challenges faced by orally administered delivery systems in IBD, the important developments in orally administered nano-delivery systems for colon targeting, and the future advances of this research. FROM THE CLINICAL EDITOR Inflammatory Bowel Disease (IBD) poses a significant problem for a large number of patients worldwide. Current medical therapy mostly aims at suppressing the active inflammatory episodes. In this review article, the authors described and discussed the various approaches current nano-delivery systems can offer in overcoming the limitations of conventional drug formulations.
Collapse
Affiliation(s)
- Susan Hua
- The School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia.
| | - Ellen Marks
- The School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia; Gastrointestinal Research Group, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Jennifer J Schneider
- The School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia
| | - Simon Keely
- The School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia; Gastrointestinal Research Group, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| |
Collapse
|
|
46
|
Bravatà I, Fiorino G, Allocca M, Repici A, Danese S. New targeted therapies such as anti-adhesion molecules, anti-IL-12/23 and anti-Janus kinases are looking toward a more effective treatment of inflammatory bowel disease. Scand J Gastroenterol 2015; 50:113-20. [PMID: 25523561 DOI: 10.3109/00365521.2014.993700] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Antitumor necrosis factor α agents have dramatically changed the management of inflammatory bowel disease (IBD). However, a significant proportion of patients does not respond or lose response over time. Hence, there is an urgent need for new molecules, with different mechanisms of action, and with a targeted and more effective approach. These new drugs include either small molecules or biological agents. We describe the three most promising classes of molecules in the field of IBD: anti-adhesion, anti-interleukin 12/23 and anti-Janus Kinases therapies.
Collapse
Affiliation(s)
- Ivana Bravatà
- Department of Gastroenterology, Endoscopy Unit, Humanitas Research Hospital , Rozzano, Milan , Italy
| | | | | | | | | |
Collapse
|
|
47
|
Krupka N, Baumgart DC. Designing biologic selectivity for inflammatory bowel disease--role of vedolizumab. DRUG DESIGN DEVELOPMENT AND THERAPY 2014; 9:147-54. [PMID: 25552903 PMCID: PMC4277125 DOI: 10.2147/dddt.s50348] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Crohn's disease and ulcerative colitis are two chronic inflammatory bowel conditions. Current approved biologic therapies are limited to blocking tumor necrosis factor alpha. Unfortunately, some patients are primary nonresponders, experiencing a loss of response, intolerance, or side effects. This defines an unmet need for novel therapeutic strategies. The rapid recruitment and inappropriate retention of leukocytes is a hallmark of chronic inflammation and a potentially promising therapeutic target. Here we discuss the clinical trial results of vedolizumab (anti-α4β7, LDP-02, MLN-02, and MLN0002) and its impact on future management of inflammatory bowel disease.
Collapse
Affiliation(s)
- Niklas Krupka
- Division of Gastroenterology and Hepatology, Department of Medicine, Charité Medical School, Humboldt-University of Berlin, Berlin, Germany
| | - Daniel C Baumgart
- Division of Gastroenterology and Hepatology, Department of Medicine, Charité Medical School, Humboldt-University of Berlin, Berlin, Germany
| |
Collapse
|
|
48
|
Danese S, Panés J. Development of drugs to target interactions between leukocytes and endothelial cells and treatment algorithms for inflammatory bowel diseases. Gastroenterology 2014; 147:981-9. [PMID: 25220794 DOI: 10.1053/j.gastro.2014.08.044] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2014] [Revised: 08/23/2014] [Accepted: 08/26/2014] [Indexed: 12/22/2022]
Abstract
Increased understanding of the pathogenesis of inflammatory bowel diseases (IBDs) has led to new therapeutic strategies. One of these is to target the molecules that regulate interactions between leukocytes and endothelial cells at sites of inflammation (mainly leukocyte integrins and endothelial cell adhesion molecules of the immunoglobulin superfamily). These molecules have been validated as therapeutic targets for IBD; several have shown efficacy, and 2 have been approved by the Food and Drug Administration for treatment of IBD. Natalizumab, the first anti-integrin antibody tested for treatment of IBD, blocks the α4 subunit. Although it is effective, its clinical use has been limited by its association with risk of progressive multifocal leukoencephalopathy. Other, allegedly more selective drugs that affect leukocyte recruitment in the gastrointestinal tract have been developed or are under investigation and could increase safety. These include vedolizumab and AMG 181 (antibodies against α4β7), etrolizumab (anti-β7), and PF-00547659 (anti-mucosal vascular addressin cell adhesion molecule 1). Other agents have been developed to block α4 (the small molecule AJM300), CCR9 (the small molecule CCX282-B), and CXCL10 (the antibody eldelumab). We review the scientific rationale for inhibiting interactions between leukocytes and endothelial cells to reduce intestinal inflammation and analyze the clinical studies that have been performed to test these new molecules, with particular attention to safety. We propose an evidence-based clinical positioning of this class of drugs.
Collapse
Affiliation(s)
- Silvio Danese
- IBD Center, Department of Gastroenterology, Humanitas Research Hospital, Milan, Italy.
| | - Julián Panés
- Gastroenterology Department, Hospital Clínic Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| |
Collapse
|
|
49
|
Medda R, Lyros O, Schmidt JL, Jovanovic N, Nie L, Link BJ, Otterson MF, Stoner GD, Shaker R, Rafiee P. Anti inflammatory and anti angiogenic effect of black raspberry extract on human esophageal and intestinal microvascular endothelial cells. Microvasc Res 2014; 97:167-80. [PMID: 25446010 DOI: 10.1016/j.mvr.2014.10.008] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Revised: 10/17/2014] [Accepted: 10/20/2014] [Indexed: 01/05/2023]
Abstract
Polyphenolic compounds (anthocyanins, flavonoid glycosides) in berries prevent the initiation, promotion, and progression of carcinogenesis in rat's digestive tract and esophagus, in part, via anti-inflammatory pathways. Angiogenesis has been implicated in the pathogenesis of chronic inflammation and tumorigenesis. In this study, we investigated the anti-inflammatory and anti-angiogenic effects of black raspberry extract (BRE) on two organ specific primary human intestinal microvascular endothelial cells, (HIMEC) and human esophageal microvascular endothelial cells (HEMEC), isolated from surgically resected human intestinal and donor discarded esophagus, respectively. HEMEC and HIMEC were stimulated with TNF-α/IL-1β with or without BRE. The anti-inflammatory effects of BRE were assessed based upon COX-2, ICAM-1 and VCAM-1 gene and protein expression, PGE2 production, NFκB p65 subunit nuclear translocation as well as endothelial cell-leukocyte adhesion. The anti-angiogenic effects of BRE were assessed on cell migration, proliferation and tube formation following VEGF stimulation as well as on activation of Akt, MAPK and JNK signaling pathways. BRE inhibited TNF-α/IL-1β-induced NFκB p65 nuclear translocation, PGE2 production, up-regulation of COX-2, ICAM-1 and VCAM-1 gene and protein expression and leukocyte binding in HEMEC but not in HIMEC. BRE attenuated VEGF-induced cell migration, proliferation and tube formation in both HEMEC and HIMEC. The anti-angiogenic effect of BRE is mediated by inhibition of Akt, MAPK and JNK phosphorylations. BRE exerted differential anti-inflammatory effects between HEMEC and HIMEC following TNF-α/IL-1β activation whereas demonstrated similar anti-angiogenic effects following VEGF stimulation in both cell lines. These findings may provide more insight into the anti-tumorigenic capacities of BRE in human disease and cancer.
Collapse
Affiliation(s)
- Rituparna Medda
- Department of Surgery, The Medical College of Wisconsin, Milwaukee, WI, USA
| | - Orestis Lyros
- Division of Gastroenterology/Hepatology, The Medical College of Wisconsin, Milwaukee, WI, USA
| | - Jamie L Schmidt
- Division of Gastroenterology/Hepatology, The Medical College of Wisconsin, Milwaukee, WI, USA
| | - Nebojsa Jovanovic
- Division of Gastroenterology/Hepatology, The Medical College of Wisconsin, Milwaukee, WI, USA
| | - Linghui Nie
- Department of Surgery, The Medical College of Wisconsin, Milwaukee, WI, USA
| | - Benjamin J Link
- Department of Surgery, The Medical College of Wisconsin, Milwaukee, WI, USA
| | - Mary F Otterson
- Department of Surgery, The Medical College of Wisconsin, Milwaukee, WI, USA
| | - Gary D Stoner
- Cancer Center, The Medical College of Wisconsin, Milwaukee, WI, USA
| | - Reza Shaker
- Division of Gastroenterology/Hepatology, The Medical College of Wisconsin, Milwaukee, WI, USA
| | - Parvaneh Rafiee
- Department of Surgery, The Medical College of Wisconsin, Milwaukee, WI, USA.
| |
Collapse
|
|
50
|
Bakirtzi K, West G, Fiocchi C, Law IKM, Iliopoulos D, Pothoulakis C. The neurotensin-HIF-1α-VEGFα axis orchestrates hypoxia, colonic inflammation, and intestinal angiogenesis. THE AMERICAN JOURNAL OF PATHOLOGY 2014; 184:3405-14. [PMID: 25307345 DOI: 10.1016/j.ajpath.2014.08.015] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Revised: 07/25/2014] [Accepted: 08/05/2014] [Indexed: 01/14/2023]
Abstract
The expression of neurotensin (NT) and its receptor (NTR1) is up-regulated in experimental colitis and inflammatory bowel disease; NT/NTR1 interactions regulate gut inflammation. During active inflammation, metabolic shifts toward hypoxia lead to the activation of hypoxia-inducible factor (HIF)-1, which enhances vascular endothelial growth factor (VEGF) expression, promoting angiogenesis. We hypothesized that NT/NTR1 signaling regulates intestinal manifestations of hypoxia and angiogenesis by promoting HIF-1 transcriptional activity and VEGFα expression in experimental colitis. We studied NTR1 signaling in colitis-associated angiogenesis using 2,4,6-trinitrobenzenesulfonic acid-treated wild-type and NTR1-knockout mice. The effects of NT on HIF-1α and VEGFα were assessed on human colonic epithelial cells overexpressing NTR1 (NCM460-NTR1) and human intestinal microvascular-endothelial cells. NTR1-knockout mice had reduced microvascular density and mucosal integrity score compared with wild-type mice after 2,4,6-trinitrobenzenesulfonic acid treatment. VEGFα mRNA levels were increased in NCM460-NTR1 cells treated with 10(-7) mol/L NT, at 1 and 6 hours post-treatment. NT exposure in NCM460-NTR1 cells caused stabilization, nuclear translocation, and transcriptional activity of HIF-1α in a diacylglycerol kinase-dependent manner. NT did not stimulate tube formation in isolated human intestinal macrovascular endothelial cells but did so in human intestinal macrovascular endothelial cells cocultured with NCM460-NTR1 cells. Our results demonstrate the importance of an NTR1-HIF-1α-VEGFα axis in intestinal angiogenic responses and in the pathophysiology of colitis and inflammatory bowel disease.
Collapse
Affiliation(s)
- Kyriaki Bakirtzi
- Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
| | - Gail West
- Department of Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio; Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Claudio Fiocchi
- Department of Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio; Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Ivy Ka Man Law
- Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
| | - Dimitrios Iliopoulos
- Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Charalabos Pothoulakis
- Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California.
| |
Collapse
|