|
1
|
Yang L, Wang N, Wang Y, Li W, Kong Z, Zhang B, Bian Y. Integrated Bioinformatics Analysis and Target Drug Prediction of Inflammatory Bowel Disease Co-existent Diabetes Mellitus. Curr Comput Aided Drug Des 2025; 21:129-141. [PMID: 38173213 PMCID: PMC12079310 DOI: 10.2174/0115734099282247231211111219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 11/24/2023] [Accepted: 12/05/2023] [Indexed: 01/05/2024]
Abstract
INTRODUCTION Inflammatory bowel disease (IBD) has become one of the public problems worldwide and its incidence rate is increasing year by year. Its concomitant disease i.e. diabetes mellitus (DM) has attracted more and more attention due to DM altering the progression of IBD and leading to long periods of intermittent recurrence and deterioration. The common mechanism and potential target drug of IBD with comorbid chronic conditions of DM were explored. METHODS Gene expression profile data were downloaded from the Gene Expression Omnibus (GEO) public database. The differentially expressed genes (DEGs) were identified by R software. GO annotation and pathway enrichment were performed, a protein-protein interaction (PPI) network was constructed, associated lncRNAs were predicted and drug prediction targeting key genes was made. Additionally, the regulatory network among core genes, associated pathways, and predicted lncRNA in IBD with coexistent DM were visualized. RESULTS We identified the critical gene MMP3 with lncRNA CDKN2BAS involved in the PPAR pathway, which uncovered the underlying regulatory mechanism of IBD with coexistent DM. We also predicted the potential therapeutic compound ZINC05905909 acting on MMP3. CONCLUSION Our findings revealed the regulatory mechanism chain of critical gene MMP3, lncRNA CDKN2BAS, and PPAR pathway and provided potential therapeutic compound ZINC05905909 for drug therapy to treat comorbid IBD DM.
Collapse
Affiliation(s)
- Lili Yang
- Jingwen Library, Nanjing University of Chinese Medicine, Nanjing, 210023, China
- Jiangsu Provincial Engineering Center of TCM External Medication Researching and Industrializing, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Ning Wang
- School of Acupuncture-Moxibustion and Tuina, School of Health Preservation and Rehabilitation, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yutong Wang
- School of Acupuncture-Moxibustion and Tuina, School of Health Preservation and Rehabilitation, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Wen Li
- School of Acupuncture-Moxibustion and Tuina, School of Health Preservation and Rehabilitation, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Ziyang Kong
- School of Acupuncture-Moxibustion and Tuina, School of Health Preservation and Rehabilitation, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Bin Zhang
- Department of Gastroenterology, Ningbo Municipal Hospital of TCM, Affiliated Hospital of Zhejiang Chinese Medical University, Ningbo, 315012, China
| | - Yaoyao Bian
- Jiangsu Provincial Engineering Center of TCM External Medication Researching and Industrializing, Nanjing University of Chinese Medicine, Nanjing, 210023, China
- School of Acupuncture-Moxibustion and Tuina, School of Health Preservation and Rehabilitation, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| |
Collapse
|
|
2
|
Kanika, Ahmad A, Kumar A, Rahul, Mishra RK, Ali N, Navik U, Parvez S, Khan R. Leveraging thiol-functionalized biomucoadhesive hybrid nanoliposome for local therapy of ulcerative colitis. Biomaterials 2025; 312:122747. [PMID: 39142219 DOI: 10.1016/j.biomaterials.2024.122747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 07/06/2024] [Accepted: 08/04/2024] [Indexed: 08/16/2024]
Abstract
Directly administering medication to inflamed intestinal sites for treating ulcerative colitis (UC), poses significant challenges like retention time, absorption variability, side effects, drug stability, and non-specific delivery. Recent advancements in therapy to treat colitis aim to improve local drug availability that is enema therapy at the site of inflammation, thereby reducing systemic adverse effects. Nevertheless, a key limitation lies in enemas' inability to sustain medication in the colon due to rapid peristaltic movement, diarrhea, and poor local adherence. Therefore, in this work, we have developed site-specific thiolated mucoadhesive anionic nanoliposomes to overcome the limitations of conventional enema therapy. The thiolated delivery system allows prolonged residence of the delivery system at the inflamed site in the colon, confirmed by the adhesion potential of thiolated nanoliposomes using in-vitro and in-vivo models. To further provide therapeutic efficacy thiolated nanoliposomes were loaded with gallic acid (GA), a natural compound known for its antibacterial, antioxidant, and potent anti-inflammatory properties. Consequently, Gallic Acid-loaded Thiolated 2,6 DALP DMPG (GATh@APDL) demonstrates the potential for targeted adhesion to the inflamed colon, facilitated by their small size 100 nm and anionic nature. Therapeutic studies indicate that this formulation offers protective effects by mitigating colonic inflammation, downregulating the expression of NF-κB, HIF-1α, and MMP-9, and demonstrating superior efficacy compared to the free GA enema. The encapsulated GA inhibits the NF-κB expression, leading to enhanced expression of MUC2 protein, thereby promoting mucosal healing in the colon. Furthermore, GATh@APDL effectively reduces neutrophil infiltration and regulates immune cell quantification in colonic lamina propria. Our findings suggest that GATh@APDL holds promise for alleviating UC and addressing the limitations of conventional enema therapy.
Collapse
Affiliation(s)
- Kanika
- Chemical Biology Unit, Institute of Nano Science and Technology, Sector 81, Knowledge City, Sahibzada Ajit Singh Nagar, Mohali, Punjab, 140306, India
| | - Anas Ahmad
- Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, T2N4N1, Canada
| | - Ajay Kumar
- Chemical Biology Unit, Institute of Nano Science and Technology, Sector 81, Knowledge City, Sahibzada Ajit Singh Nagar, Mohali, Punjab, 140306, India
| | - Rahul
- Department of Chemistry, Malaviya National Institute of Technology, Jaipur, Rajasthan, 302017, India
| | - Rakesh Kumar Mishra
- Department of Pharmaceutical Sciences, School of Health Sciences and Technology, UPES, Dehradun, India
| | - Nemat Ali
- Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia
| | - Umashanker Navik
- Department of Pharmacology, Central University of Punjab, Bathinda, Ghudda, Punjab, 151401, India
| | - Suhel Parvez
- Department of Toxicology, School of Chemical & Life Sciences, Jamia Hamdard, New Delhi, 110062, India
| | - Rehan Khan
- Chemical Biology Unit, Institute of Nano Science and Technology, Sector 81, Knowledge City, Sahibzada Ajit Singh Nagar, Mohali, Punjab, 140306, India.
| |
Collapse
|
|
3
|
de Paulo CB, Miglino MA, Castelucci P. Perspectives on the extracellular matrix in inflammatory bowel disease and bowel decellularization protocols. World J Exp Med 2024; 14:97179. [PMID: 39713079 PMCID: PMC11551702 DOI: 10.5493/wjem.v14.i4.97179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 09/15/2024] [Accepted: 10/15/2024] [Indexed: 10/31/2024] Open
Abstract
The extracellular matrix (ECM) is a non-cellular three-dimensional structure present in all tissues that is essential for the intestinal maintenance, function and structure, as well as for providing physical support for tissue integrity and elasticity. ECM enables the regulation of various processes involved in tissue homeostasis, being vital for healing, growth, migration and cell differentiation. Structurally, ECM is composed of water, polysaccharides and proteins, such as collagen fibers and proteoglycans, which are specifically arranged for each tissue. In pathological scenarios, such as inflammatory bowel disease (IBD), the deposition and remodeling of the ECM can be altered in relation to the homeostatic composition. IBD, such as Ulcerative colitis and Crohn's disease, can be differentiated according to ECM alterations, such as circulating levels of collagen, laminin and vimentin neoepitopes. In this context, ECM presents particularities in both physiological and pathological processes, however, exploring methods of tissue decellularization is emerging as a promising frontier for new therapeutic interventions and clinical protocols, promoting the development of new approaches to intestinal diseases.
Collapse
Affiliation(s)
- Caroline Bures de Paulo
- Department of Surgery, School of Veterinary Medicine and Animal Sciences, University of São Paulo, São Paulo 05508-270, São Paulo, Brazil
| | - Maria Angelica Miglino
- Laboratório de Medicina Regenerativa, Universidade de Marilia, Marilia 00000, São Paulo, Brazil
| | | |
Collapse
|
|
4
|
Biel C, Faber KN, Bank RA, Olinga P. Matrix metalloproteinases in intestinal fibrosis. J Crohns Colitis 2024; 18:462-478. [PMID: 37878770 PMCID: PMC10906956 DOI: 10.1093/ecco-jcc/jjad178] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 10/03/2023] [Accepted: 10/24/2023] [Indexed: 10/27/2023]
Abstract
Intestinal fibrosis is a common complication in patients with inflammatory bowel disease [IBD], in particular Crohn's disease [CD]. Unfortunately, at present intestinal fibrosis is not yet preventable, and cannot be treated by interventions other than surgical removal. Intestinal fibrosis is characterized by excessive accumulation of extracellular matrix [ECM], which is caused by activated fibroblasts and smooth muscle cells. Accumulation of ECM results from an imbalanced production and degradation of ECM. ECM degradation is mainly performed by matrix metalloproteinases [MMPs], enzymes that are counteracted by tissue inhibitors of MMPs [TIMPs]. In IBD patients, MMP activity [together with other protease activities] is increased. At the same time, CD patients have a generally lower MMP activity compared to ulcerative colitis patients, who usually do not develop intestinal strictures or fibrosis. The exact regulation and role[s] of these MMPs in fibrosis are far from understood. Here, we review the current literature about ECM remodelling by MMPs in intestinal fibrosis and their potential role as biomarkers for disease progression or druggable targets.
Collapse
Affiliation(s)
- Carin Biel
- Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, the Netherlands
| | - Klaas Nico Faber
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands
| | - Ruud A Bank
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands
| | - Peter Olinga
- Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, the Netherlands
| |
Collapse
|
|
5
|
Flannigan KL, Nieves KM, Szczepanski HE, Serra A, Lee JW, Alston LA, Ramay H, Mani S, Hirota SA. The Pregnane X Receptor and Indole-3-Propionic Acid Shape the Intestinal Mesenchyme to Restrain Inflammation and Fibrosis. Cell Mol Gastroenterol Hepatol 2023; 15:765-795. [PMID: 36309199 PMCID: PMC9883297 DOI: 10.1016/j.jcmgh.2022.10.014] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 10/18/2022] [Accepted: 10/19/2022] [Indexed: 01/31/2023]
Abstract
BACKGROUND & AIMS Fibrosis is a common complication of inflammatory bowel diseases (IBDs). The pregnane X receptor (PXR) (encoded by NR1I2) suppresses intestinal inflammation and has been shown to influence liver fibrosis. In the intestine, PXR signaling is influenced by microbiota-derived indole-3-propionic acid (IPA). Here, we sought to assess the role of the PXR in regulating intestinal inflammation and fibrosis. METHODS Intestinal inflammation was induced using dextran sulfate sodium (DSS). Fibrosis was assessed in wild-type (WT), Nr1i2-/-, epithelial-specific Nr1i2-/-, and fibroblast-specific Nr1i2-/- mice. Immune cell influx was quantified by flow cytometry and cytokines by Luminex. Myofibroblasts isolated from WT and Nr1i2-/- mice were stimulated with cytomix or lipopolysaccharide, and mediator production was assessed by quantitative polymerase chain reaction and Luminex. RESULTS After recovery from DSS-induced colitis, WT mice exhibited fibrosis, a response that was exacerbated in Nr1i2-/- mice. This was correlated with greater neutrophil infiltration and innate cytokine production. Deletion of the PXR in fibroblasts, but not the epithelium, recapitulated this phenotype. Inflammation and fibrosis were reduced by IPA administration, whereas depletion of the microbiota exaggerated intestinal fibrosis. Nr1i2-deficient myofibroblasts were hyperresponsive to stimulation, producing increased levels of inflammatory mediators compared with WT cells. In biopsies from patients with active Crohn's disease (CD) and ulcerative colitis (UC), expression of NR1I2 was reduced, correlating with increased expression of fibrotic and innate immune genes. Finally, both CD and UC patients exhibited reduced levels of fecal IPA. CONCLUSIONS These data highlight a role for IPA and its interactions with the PXR in regulating the mesenchyme and the development of inflammation and fibrosis, suggesting microbiota metabolites may be a vital determinant in the progression of fibrotic complications in IBD.
Collapse
Affiliation(s)
- Kyle L Flannigan
- Department of Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada; Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada
| | - Kristoff M Nieves
- Department of Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada; Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada
| | - Holly E Szczepanski
- Department of Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada; Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada
| | - Alex Serra
- Department of Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada; Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada
| | - Joshua W Lee
- Department of Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada; Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada
| | - Laurie A Alston
- Department of Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada; Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada
| | - Hena Ramay
- International Microbiome Centre, University of Calgary, AB, Canada
| | - Sridhar Mani
- Department of Medicine, Albert Einstein College of Medicine, Bronx, New York
| | - Simon A Hirota
- Department of Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada; Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada; Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, AB, Canada.
| |
Collapse
|
|
6
|
Porras AM, Zhou H, Shi Q, Xiao X, Longman R, Brito IL. Inflammatory Bowel Disease-Associated Gut Commensals Degrade Components of the Extracellular Matrix. mBio 2022; 13:e0220122. [PMID: 36445085 PMCID: PMC9765649 DOI: 10.1128/mbio.02201-22] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 11/02/2022] [Indexed: 12/03/2022] Open
Abstract
Extracellular matrix (ECM) remodeling has emerged as a key feature of inflammatory bowel disease (IBD), and ECM fragments have been proposed as markers of clinical disease severity. Recent studies report increased protease activity in the gut microbiota of IBD patients. Nonetheless, the relationship between gut microbiota and ECM remodeling has remained unexplored. We hypothesized that members of the human gut microbiome could degrade the host ECM and that bacteria-driven remodeling, in turn, could enhance colonic inflammation. Through a variety of in vitro assays, we first confirmed that multiple bacterial species found in the human gut are capable of degrading specific ECM components. Clinical stool samples obtained from ulcerative colitis patients also exhibited higher levels of proteolytic activity in vitro, compared to those of their healthy counterparts. Furthermore, culture supernatants from bacteria species that are capable of degrading human ECM accelerated inflammation in dextran sodium sulfate (DSS)-induced colitis. Finally, we identified several of the bacterial proteases and carbohydrate degrading enzymes (CAZymes) that are potentially responsible for ECM degradation in vitro. Some of these protease families and CAZymes were also found in increased abundance in a metagenomic cohort of IBD. These results demonstrate that some commensal bacteria in the gut are indeed capable of degrading components of human ECM in vitro and suggest that this proteolytic activity may be involved in the progression of IBD. A better understanding of the relationship between nonpathogenic gut microbes, host ECM, and inflammation could be crucial to elucidating some of the mechanisms underlying host-bacteria interactions in IBD and beyond. IMPORTANCE Healthy gut epithelial cells form a barrier that keeps bacteria and other substances from entering the blood or tissues of the body. Those cells sit on scaffolding that maintains the structure of the gut and informs our immune system about the integrity of this barrier. In patients with inflammatory bowel disease (IBD), breaks are formed in this cellular barrier, and bacteria gain access to the underlying tissue and scaffolding. In our study, we discovered that bacteria that normally reside in the gut can modify and disassemble the underlying scaffolding. Additionally, we discovered that changes to this scaffolding affect the onset of IBD in mouse models of colitis as well as the abilities of these mice to recover. We propose that this new information will reveal how breaks in the gut wall lead to IBD and will open up new avenues by which to treat patients with IBD.
Collapse
Affiliation(s)
- Ana Maria Porras
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA
| | - Hao Zhou
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York, USA
| | - Qiaojuan Shi
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York, USA
| | - Xieyue Xiao
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York, USA
| | - JRI Live Cell Bank
- Jill Roberts Institute for IBD Research, Weill Cornell Medicine, New York, New York, USA
| | - Randy Longman
- Jill Roberts Institute for IBD Research, Weill Cornell Medicine, New York, New York, USA
| | - Ilana Lauren Brito
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York, USA
| |
Collapse
|
|
7
|
Householder S, Picoraro JA. Diagnosis and Classification of Fistula from Inflammatory Bowel Disease and Inflammatory Bowel Disease-Related Surgery. Gastrointest Endosc Clin N Am 2022; 32:631-650. [PMID: 36202507 DOI: 10.1016/j.giec.2022.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Fistula in inflammatory bowel disease (IBD) is a well-known yet poorly understood phenotype. Pathophysiology is largely based on the activation of the epithelial-mesenchymal transition (EMT); however, interactions with the microbiome, genetics, mechanical stress and the presence of stricturing disease, and surgical complications play a role. Perianal penetrating disease represents a more severe phenotype in IBD. Pouch-associated fistula can arise as a result of an anastomotic leak, surgical complications, or Crohn's disease (CD) of the pouch. Classification is site-dependent, includes a range of severity, and informs management. It is important to determine associated symptoms and recognize the complex interplay of underlying etiologies to form the basis of appropriate care.
Collapse
Affiliation(s)
| | - Joseph A Picoraro
- Columbia University Irving Medical Center, NewYork-Presbyterian Morgan Stanley Children's Hospital, 622 West 168th Street, PH17-105, New York, NY 10032, USA.
| |
Collapse
|
|
8
|
de Negreiros LMV, Pascoal LB, Genaro LM, Silva JF, Rodrigues BL, Camargo MG, Martinez CAR, Coy CSR, Ayrizono MDLS, Fagundes JJ, Leal RF. Pouchitis: insight into the pathogenesis and clinical aspects. Am J Transl Res 2022; 14:4406-4425. [PMID: 35958439 PMCID: PMC9360866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 05/26/2022] [Indexed: 06/15/2023]
Abstract
Ulcerative colitis (UC) is a chronic intestinal inflammatory disease and familial adenomatous polyposis (FAP) is an autosomal dominant inherited disease. Both diseases, despite being different, may require the same surgical procedure: proctocolectomy with ileal pouch-anal anastomosis (IPAA). The main complication after this procedure is pouch inflammation (pouchitis). This inflammatory complication can affect up to 60 percent of patients who receive IPAA for UC, and a very small percentage of the FAP patients. The purpose of this review was to determine the current molecular mechanisms in its pathogenesis and detail the risk factors involved in pouchitis, its diagnosis, and treatment.
Collapse
Affiliation(s)
- Leandro Minatel Vidal de Negreiros
- Inflammatory Bowel Disease Research Laboratory, Colorectal Surgery Unit, Department of Surgery, School of Medical Sciences, University of Campinas (Unicamp) Campinas, Brazil
| | - Lívia Bitencourt Pascoal
- Inflammatory Bowel Disease Research Laboratory, Colorectal Surgery Unit, Department of Surgery, School of Medical Sciences, University of Campinas (Unicamp) Campinas, Brazil
| | - Lívia Moreira Genaro
- Inflammatory Bowel Disease Research Laboratory, Colorectal Surgery Unit, Department of Surgery, School of Medical Sciences, University of Campinas (Unicamp) Campinas, Brazil
| | - Julian Furtado Silva
- Inflammatory Bowel Disease Research Laboratory, Colorectal Surgery Unit, Department of Surgery, School of Medical Sciences, University of Campinas (Unicamp) Campinas, Brazil
| | - Bruno Lima Rodrigues
- Inflammatory Bowel Disease Research Laboratory, Colorectal Surgery Unit, Department of Surgery, School of Medical Sciences, University of Campinas (Unicamp) Campinas, Brazil
| | - Michel Gardere Camargo
- Inflammatory Bowel Disease Research Laboratory, Colorectal Surgery Unit, Department of Surgery, School of Medical Sciences, University of Campinas (Unicamp) Campinas, Brazil
| | - Carlos Augusto Real Martinez
- Inflammatory Bowel Disease Research Laboratory, Colorectal Surgery Unit, Department of Surgery, School of Medical Sciences, University of Campinas (Unicamp) Campinas, Brazil
| | - Cláudio Saddy Rodrigues Coy
- Inflammatory Bowel Disease Research Laboratory, Colorectal Surgery Unit, Department of Surgery, School of Medical Sciences, University of Campinas (Unicamp) Campinas, Brazil
| | - Maria de Lourdes Setsuko Ayrizono
- Inflammatory Bowel Disease Research Laboratory, Colorectal Surgery Unit, Department of Surgery, School of Medical Sciences, University of Campinas (Unicamp) Campinas, Brazil
| | - João José Fagundes
- Inflammatory Bowel Disease Research Laboratory, Colorectal Surgery Unit, Department of Surgery, School of Medical Sciences, University of Campinas (Unicamp) Campinas, Brazil
| | - Raquel Franco Leal
- Inflammatory Bowel Disease Research Laboratory, Colorectal Surgery Unit, Department of Surgery, School of Medical Sciences, University of Campinas (Unicamp) Campinas, Brazil
| |
Collapse
|
|
9
|
Sanguinarine-Chelerythrine Fraction of Coptis chinensis Exerts Anti-inflammatory Activity in Carrageenan Paw Oedema Test in Rats and Reveals Reduced Gastrotoxicity. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:1504929. [PMID: 35340213 PMCID: PMC8942652 DOI: 10.1155/2022/1504929] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 02/18/2022] [Accepted: 03/03/2022] [Indexed: 01/24/2023]
Abstract
Inflammatory diseases are a common therapeutic problem and nonsteroidal anti-inflammatory drugs are not deprived of side effects, of which ulcerogenic activity is one of the most frequent. The aim of the study was to evaluate the anti-inflammatory activity of the sanguinarine-chelerythrine (SC) fraction of Coptis chinensis and its influence on the integrity of gastric mucosa. The study was conducted on sixty male rats randomly divided into six experimental groups: two control groups (a negative control group CON and a positive control group CAR); three groups receiving an investigational fraction of C. chinensis (1, 5, 10 mg/kg i.g.) named SC1, SC5, and SC10, respectively; and a group receiving indomethacin (IND) (10 mg/kg i.g.) as a reference drug. In all animals, the carrageenan-induced paw oedema was measured; PGE2 release, TNFα production, and MMP-9 concentration in inflamed tissue were determined. Additionally, the macroscopic and microscopic damage of gastric mucosa was evaluated. Administration of SC dose-dependently inhibited the second phase of carrageenan rat paw oedema and PGE2 release, decreased the production of TNFα, and reduced the concentration of MMP-9, and the efficacy of the highest dose was comparable to the effect of IND. Contrary to IND, no gastrotoxic activity of SC was detected. The investigated sanguinarine-chelerythrine fraction of C. chinensis seems to be a promising candidate for further research on new anti-inflammatory and analgesic drugs characterized with a safer gastric profile compared to existing NSAIDs.
Collapse
|
|
10
|
Gough NR, Xiang X, Mishra L. TGF-β Signaling in Liver, Pancreas, and Gastrointestinal Diseases and Cancer. Gastroenterology 2021; 161:434-452.e15. [PMID: 33940008 PMCID: PMC8841117 DOI: 10.1053/j.gastro.2021.04.064] [Citation(s) in RCA: 122] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 04/05/2021] [Accepted: 04/25/2021] [Indexed: 02/06/2023]
Abstract
Genetic alterations affecting transforming growth factor-β (TGF-β) signaling are exceptionally common in diseases and cancers of the gastrointestinal system. As a regulator of tissue renewal, TGF-β signaling and the downstream SMAD-dependent transcriptional events play complex roles in the transition from a noncancerous disease state to cancer in the gastrointestinal tract, liver, and pancreas. Furthermore, this pathway also regulates the stromal cells and the immune system, which may contribute to evasion of the tumors from immune-mediated elimination. Here, we review the involvement of the TGF-β pathway mediated by the transcriptional regulators SMADs in disease progression to cancer in the digestive system. The review integrates human genomic studies with animal models that provide clues toward understanding and managing the complexity of the pathway in disease and cancer.
Collapse
Affiliation(s)
- Nancy R. Gough
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research & Cold Spring Harbor Laboratory, Department of Medicine, Division of Gastroenterology and Hepatology, Northwell Health, Manhasset, New York
| | - Xiyan Xiang
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research & Cold Spring Harbor Laboratory, Department of Medicine, Division of Gastroenterology and Hepatology, Northwell Health, Manhasset, New York
| | - Lopa Mishra
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research & Cold Spring Harbor Laboratory, Department of Medicine, Division of Gastroenterology and Hepatology, Northwell Health, Manhasset, New York; Center for Translational Medicine, Department of Surgery, The George Washington University, Washington, District of Columbia.
| |
Collapse
|
|
11
|
Integrated omics profiling of dextran sodium sulfate-induced colitic mice supplemented with Wolfberry ( Lycium barbarum). NPJ Sci Food 2020; 4:5. [PMID: 32258419 PMCID: PMC7109062 DOI: 10.1038/s41538-020-0065-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 02/14/2020] [Indexed: 12/11/2022] Open
Abstract
We used a multi-omics profiling approach to investigate the suppressive effects of 2% Wolfberry (WOL)-enriched diets on dextran sodium sulfate (DSS)-induced colitis in mice. It was observed that in mice fed the WOL diet, the disease activity index, colon shortening, plasma concentrations of matrix metalloproteinase-3 and relative mesenteric fat weight were significantly improved as compared to the DSS group. Results from colon transcriptome and proteome profiles showed that WOL supplementation significantly ameliorated the expression of genes and proteins associated with the integrity of the colonic mucosal wall and colonic inflammation. Based on the hepatic transcriptome, proteome and metabolome data, genes involved in fatty acid metabolism, proteins involved in inflammation and metabolites related to glycolysis were downregulated in WOL mice, leading to lowered inflammation and changes in these molecules may have led to improvement in body weight loss. The integrated nutrigenomic approach thus revealed the molecular mechanisms underlying the ameliorative effect of whole WOL fruit consumption on inflammatory bowel disease.
Collapse
|
|
12
|
Lucafò M, Pugnetti L, Bramuzzo M, Curci D, Di Silvestre A, Marcuzzi A, Bergamo A, Martelossi S, Villanacci V, Bozzola A, Cadei M, De Iudicibus S, Decorti G, Stocco G. Long Non-Coding RNA GAS5 and Intestinal MMP2 and MMP9 Expression: A Translational Study in Pediatric Patients with IBD. Int J Mol Sci 2019; 20:5280. [PMID: 31652976 PMCID: PMC6862115 DOI: 10.3390/ijms20215280] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 10/16/2019] [Accepted: 10/21/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND The long non-coding RNA (lncRNA) growth arrest-specific transcript 5 (GAS5) seems to be involved in the regulation of mediators of tissue injury, in particular matrix metalloproteinases (MMPs), implicated in the pathogenesis of inflammatory bowel disease (IBD). We investigated the role of GAS5 in regulating MMP2 and MMP9 expression in pediatric patients with IBD and in vitro. METHODS In total, 25 IBD patients were enrolled: For each patient paired inflamed and non-inflamed biopsies were collected. RNA was extracted and GAS5, MMP2, and MMP9 were quantified by TaqMan assay. The expression of GAS5 and MMPs was also determined in the human monocytic THP1 cells differentiated into macrophages and stimulated with lipopolysaccharide (LPS). The function of GAS5 was assessed by overexpressing the lncRNA and evaluating the MMPs levels. RESULTS Real-time PCR results demonstrated a downregulation of GAS5 and an upregulation of both MMPs in inflamed tissues. In vitro data confirmed the trend observed in patients for the three genes: The stimulation with LPS promoted a downregulation of GAS5 while an increase of MMPs was observed. Overexpression experiments showed that higher levels of GAS5 lead to a decrease of both enzymes. CONCLUSION These results provide new information about the role of GAS5 in IBD: The lncRNA could mediate tissue damage by modulating the expression of MMPs.
Collapse
Affiliation(s)
- Marianna Lucafò
- Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", 34137 Trieste, Italy.
| | - Letizia Pugnetti
- PhD School in Science of Reproduction and Development, University of Trieste, 34127 Trieste, Italy.
| | - Matteo Bramuzzo
- Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", 34137 Trieste, Italy.
| | - Debora Curci
- PhD School in Science of Reproduction and Development, University of Trieste, 34127 Trieste, Italy.
| | - Alessia Di Silvestre
- PhD School in Science of Reproduction and Development, University of Trieste, 34127 Trieste, Italy.
| | - Annalisa Marcuzzi
- Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", 34137 Trieste, Italy.
| | | | | | | | - Anna Bozzola
- Pathology Section, Spedali Civili, 25123 Brescia, Italy.
| | - Moris Cadei
- Pathology Section, Spedali Civili, 25123 Brescia, Italy.
| | - Sara De Iudicibus
- Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", 34137 Trieste, Italy.
| | - Giuliana Decorti
- Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", 34137 Trieste, Italy.
- Department of Medicine, Surgery and Health Sciences, University of Trieste, 34127 Trieste, Italy.
| | - Gabriele Stocco
- Department of Life Sciences, University of Trieste, 34127 Trieste, Italy.
| |
Collapse
|
|
13
|
Ostrowski J, Dabrowska M, Lazowska I, Paziewska A, Balabas A, Kluska A, Kulecka M, Karczmarski J, Ambrozkiewicz F, Piatkowska M, Goryca K, Zeber-Lubecka N, Kierkus J, Socha P, Lodyga M, Klopocka M, Iwanczak B, Bak-Drabik K, Walkowiak J, Radwan P, Grzybowska-Chlebowczyk U, Korczowski B, Starzynska T, Mikula M. Redefining the Practical Utility of Blood Transcriptome Biomarkers in Inflammatory Bowel Diseases. J Crohns Colitis 2019; 13:626-633. [PMID: 30541017 PMCID: PMC6486489 DOI: 10.1093/ecco-jcc/jjy205] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS The study investigates the practical utility of whole-blood gene expression profiling to diagnose inflammatory bowel diseases [IBDs]. METHODS The discovery cohorts included 102 and 51 paediatric IBD patients and controls, and 95 and 46 adult IBD patients and controls, respectively. The replication cohorts included 447 and 76 paediatric IBD patients and controls, and 271 and 108 adult IBD patients and controls, respectively. In the discovery phase, RNA samples extracted from whole peripheral blood were analysed using RNA-Seq, and the predictive values of selected biomarkers were validated using quantitative polymerase chain reaction [qPCR]. RESULTS In all, 15 differentially expressed transcripts [adjusted p ≤0.05] were selected from the discovery sequencing datasets. The receiver operating characteristic curves and area under the curve [ROC-AUC] in replication analyses showed high discriminative power [AUC range, 0.91-0.98] for 11 mRNAs in paediatric patients with active IBD. By contrast, the AUC-ROC values ranged from 0.63 to 0.75 in comparison among inactive paediatric IBDs and active/inactive adult IBDs, indicating a lack of discriminative power. The best multi-mRNA diagnostic classifier showed moderate discriminative power [AUC = 0.81] for paediatric inactive IBD, but was not able to discriminate active or inactive adult IBD patients from controls. The AUC-ROC values did not confirm an ability of the mRNAs abundances to discriminate between active ulcerative colitis and active Crohn's disease in paediatric or adult populations. CONCLUSIONS This study identifies and validates blood transcriptional biomarkers that could be used in clinical settings as diagnostic predictors of IBD clinical activity in paediatric, but not adult, IBD patients.
Collapse
Affiliation(s)
- Jerzy Ostrowski
- Department of Genetics, Maria Sklodowska-Curie Institute – Oncology Centre, Warsaw, Poland,Department of Gastroenterology and Hepatology, Medical Center for Postgraduate Education, Warsaw, Poland,Corresponding author: Jerzy Ostrowski, MD, PhD; Cancer Center-Institute, Roentgena 5, 02-781 Warsaw, Poland. Tel.: +48 225462575; e-mail:
| | - Michalina Dabrowska
- Department of Genetics, Maria Sklodowska-Curie Institute – Oncology Centre, Warsaw, Poland
| | - Izabella Lazowska
- Department of Pediatric Gastroenterology and Nutrition, Medical University of Warsaw, Warsaw, Poland
| | - Agnieszka Paziewska
- Department of Gastroenterology and Hepatology, Medical Center for Postgraduate Education, Warsaw, Poland
| | - Aneta Balabas
- Department of Genetics, Maria Sklodowska-Curie Institute – Oncology Centre, Warsaw, Poland
| | - Anna Kluska
- Department of Genetics, Maria Sklodowska-Curie Institute – Oncology Centre, Warsaw, Poland
| | - Maria Kulecka
- Department of Gastroenterology and Hepatology, Medical Center for Postgraduate Education, Warsaw, Poland
| | - Jakub Karczmarski
- Department of Genetics, Maria Sklodowska-Curie Institute – Oncology Centre, Warsaw, Poland
| | - Filip Ambrozkiewicz
- Department of Genetics, Maria Sklodowska-Curie Institute – Oncology Centre, Warsaw, Poland
| | - Magdalena Piatkowska
- Department of Genetics, Maria Sklodowska-Curie Institute – Oncology Centre, Warsaw, Poland
| | - Krzysztof Goryca
- Department of Genetics, Maria Sklodowska-Curie Institute – Oncology Centre, Warsaw, Poland
| | - Natalia Zeber-Lubecka
- Department of Gastroenterology and Hepatology, Medical Center for Postgraduate Education, Warsaw, Poland
| | - Jaroslaw Kierkus
- Department of Gastroenterology, Hepatology and Feeding Disorders, Children’s Memorial Health Institute, Warsaw, Poland
| | - Piotr Socha
- Department of Gastroenterology, Hepatology and Feeding Disorders, Children’s Memorial Health Institute, Warsaw, Poland
| | - Michal Lodyga
- Department of Internal Medicine and Gastroenterology with IBD Subdivision, Central Clinical Hospital of the Ministry of the Interior, Warsaw, Poland
| | - Maria Klopocka
- Vascular Diseases and Internal Medicine, Nicolaus Copernicus University in Torun, Collegium Medicum, Bydgoszcz, Poland
| | - Barbara Iwanczak
- Department of Pediatrics, Gastroenterology and Nutrition, Wroclaw Medical University, Wroclaw, Poland
| | - Katarzyna Bak-Drabik
- Department of Pediatrics, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Jaroslaw Walkowiak
- Department of Pediatric Gastroenterology & Metabolic Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - Piotr Radwan
- Department of Gastroenterology, Medical University of Lublin, Lublin, Poland
| | | | | | - Teresa Starzynska
- Department of Gastroenterology, Pomeranian Medical University, Szczecin, Poland
| | - Michal Mikula
- Department of Genetics, Maria Sklodowska-Curie Institute – Oncology Centre, Warsaw, Poland
| |
Collapse
|
|
14
|
Gupta N, Quah SY, Yeo JF, Ferreira J, Tan KS, Hong CHL. Role of oral flora in chemotherapy-induced oral mucositis in vivo. Arch Oral Biol 2019; 101:51-56. [PMID: 30889505 DOI: 10.1016/j.archoralbio.2019.03.008] [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] [Received: 01/04/2019] [Revised: 03/06/2019] [Accepted: 03/10/2019] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To determine if commensal oral microflora impacts the severity of chemotherapy-induced oral mucositis (OM). DESIGN Specific-pathogen-free (SPF) and germ-free Swiss Webster mice in the experimental groups were dosed with 5-fluorouracil (5-FU) to induce OM. Mice in the control group received phosphate buffered saline. Comparative analyses of the epithelial thickness and cell proliferation/turnover rates, as well as the expression levels of metalloproteinases and pro-inflammatory mediators in the oral mucosa between the control and experimental groups were determined by histopathological and immunohistochemical analyses. RESULTS 5-FU-treated SPF and germ-free mice showed characteristic features of OM with reduced oral epithelial thickness, presence of inflammatory cells in the connective tissues, and increased levels of expression of metalloproteinases and pro-inflammatory cytokines compared to the respective control groups. When 5-FU-treated SPF and germ-free mice were compared, 5-FU-treated germ-free mice exhibited less severe epithelial destruction with higher expression of the cell proliferation marker Ki67, coupled with lower expression levels of metalloproteinases and pro-inflammatory cytokine in the oral mucosa. CONCLUSION This study provides the first histopathological evidence that oral flora has a detrimental effect on chemotherapy-induced OM in vivo.
Collapse
Affiliation(s)
- N Gupta
- Faculty of Dentistry, National University of Singapore, Singapore
| | - S Y Quah
- Faculty of Dentistry, National University of Singapore, Singapore
| | - J F Yeo
- Faculty of Dentistry, National University of Singapore, Singapore
| | - J Ferreira
- Faculty of Dentistry, National University of Singapore, Singapore
| | - K S Tan
- Faculty of Dentistry, National University of Singapore, Singapore.
| | - C H L Hong
- Faculty of Dentistry, National University of Singapore, Singapore.
| |
Collapse
|
|
15
|
Fecal Matrix Metalloprotease-9 and Lipocalin-2 as Biomarkers in Detecting Endoscopic Activity in Patients With Inflammatory Bowel Diseases. J Clin Gastroenterol 2018; 52:e53-e62. [PMID: 28723856 DOI: 10.1097/mcg.0000000000000837] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Fecal biomarkers are emerging tools in the assessment of mucosal healing in inflammatory bowel diseases (IBD). GOALS We aimed to evaluate the accuracy of fecal matrix metalloprotease-9 (MMP-9) and fecal lipocalin-2 (LCN-2) compared with calprotectin in detecting endoscopic activity in IBD STUDY:: Overall, 86 IBD adults underwent colonoscopy consecutively and prospectively, with Crohn's disease Endoscopic Index of Severity (CDEIS) in Crohn's disease (CD) patients or Mayo endoscopic subscore calculation for ulcerative colitis (UC) patients, and stool collection. Fecal calprotectin was measured using quantitative immunochromatographic testing. Fecal MMP-9 and LCN-2 was quantified by enzyme-linked immunosorbent assay. MMP-9 and LCN-2 thresholds were determined using receiver operating curves. RESULTS In 54 CD patients, fecal calprotectin, MMP-9 and LCN-2 correlated with CDEIS and were significantly increased in patients with endoscopic ulcerations. MMP-9 >350 ng/g detected endoscopic ulceration in CD with a sensitivity of 90.0% and a specificity of 63.6%, compared with fecal calprotectin >250 μg/g (sensitivity=90.5% and specificity=59.1%). Fecal LCN-2 demonstrated lower performances than the 2 other biomarkers (sensitivity=85.7% and specificity=45.5%).In 32 UC patients, fecal MMP-9, LCN-2, and calprotectin levels were significantly increased in patients with endoscopic activity. In UC patients, fecal MMP-9 >900 ng/g had the best efficacy to detect endoscopic activity (sensitivity=91.0% and specificity=80.0%, compared with fecal calprotectin >250 μg/g (sensitivity=86.4% and specificity=80.0%) and LCN-2 >6700 ng/g (sensitivity=82.0% and specificity=80.0%). CONCLUSIONS Fecal MMP-9 is a reliable biomarker in detecting endoscopic activity in both UC and CD patients.
Collapse
|
|
16
|
Van Spaendonk H, Ceuleers H, Witters L, Patteet E, Joossens J, Augustyns K, Lambeir AM, De Meester I, De Man JG, De Winter BY. Regulation of intestinal permeability: The role of proteases. World J Gastroenterol 2017; 23:2106-2123. [PMID: 28405139 PMCID: PMC5374123 DOI: 10.3748/wjg.v23.i12.2106] [Citation(s) in RCA: 130] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Revised: 01/20/2017] [Accepted: 03/02/2017] [Indexed: 02/06/2023] Open
Abstract
The gastrointestinal barrier is - with approximately 400 m2 - the human body's largest surface separating the external environment from the internal milieu. This barrier serves a dual function: permitting the absorption of nutrients, water and electrolytes on the one hand, while limiting host contact with noxious luminal antigens on the other hand. To maintain this selective barrier, junction protein complexes seal the intercellular space between adjacent epithelial cells and regulate the paracellular transport. Increased intestinal permeability is associated with and suggested as a player in the pathophysiology of various gastrointestinal and extra-intestinal diseases such as inflammatory bowel disease, celiac disease and type 1 diabetes. The gastrointestinal tract is exposed to high levels of endogenous and exogenous proteases, both in the lumen and in the mucosa. There is increasing evidence to suggest that a dysregulation of the protease/antiprotease balance in the gut contributes to epithelial damage and increased permeability. Excessive proteolysis leads to direct cleavage of intercellular junction proteins, or to opening of the junction proteins via activation of protease activated receptors. In addition, proteases regulate the activity and availability of cytokines and growth factors, which are also known modulators of intestinal permeability. This review aims at outlining the mechanisms by which proteases alter the intestinal permeability. More knowledge on the role of proteases in mucosal homeostasis and gastrointestinal barrier function will definitely contribute to the identification of new therapeutic targets for permeability-related diseases.
Collapse
|
|
17
|
Early Transcriptomic Changes in the Ileal Pouch Provide Insight into the Molecular Pathogenesis of Pouchitis and Ulcerative Colitis. Inflamm Bowel Dis 2017; 23:366-378. [PMID: 28221248 PMCID: PMC5988644 DOI: 10.1097/mib.0000000000001027] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND Ulcerative colitis (UC) only involves the colonic mucosa. Yet, nearly 50% of patients with UC who undergo total proctocolectomy with ileal pouch anal anastomosis develop UC-like inflammation of the ileal pouch (pouchitis). By contrast, patients with familial adenomatous polyposis (FAP) with ileal pouch anal anastomosis develop pouchitis far less frequently. We hypothesized that pathogenic events associated with the development of UC are recapitulated by colonic-metaplastic transcriptomic reprogramming of the UC pouch. METHODS We prospectively sampled pouch and prepouch ileum mucosal biopsies in patients with UC with ileal pouch anal anastomosis 4, 8, and 12 months after their pouch was in continuity. Mucosal samples were also obtained from patients with FAP. Transcriptional profiles of the UC and FAP pouch and prepouch ileum were investigated via RNA sequencing and compared with data from a previously published microarray study. RESULTS Unlike patients with FAP, subjects with UC exhibited a large set of differentially expressed genes between the pouch and prepouch ileum as early as 4 months after pouch functionalization. Functional pathway analysis of differentially expressed genes in the UC pouch revealed an enhanced state of immune/inflammatory response and extracellular matrix remodeling. Moreover, >70% of differentially expressed genes mapped to published inflammatory bowel diseases microarray data sets displayed directional changes consistent with active UC but not with Crohn's disease. CONCLUSIONS The UC pouch, well before histologic inflammation, already displays a systems-level gain of colon-associated genes and loss of ileum-associated genes. Patients with UC exhibit a unique transcriptomic response to ileal pouch creation that can be observed well before disease and may in part explain their susceptibility to the development of pouchitis.
Collapse
|
|
18
|
de Bruyn M, Vandooren J, Ugarte-Berzal E, Arijs I, Vermeire S, Opdenakker G. The molecular biology of matrix metalloproteinases and tissue inhibitors of metalloproteinases in inflammatory bowel diseases. Crit Rev Biochem Mol Biol 2016; 51:295-358. [PMID: 27362691 DOI: 10.1080/10409238.2016.1199535] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
|
|
19
|
Decreased Fibrogenesis After Treatment with Pirfenidone in a Newly Developed Mouse Model of Intestinal Fibrosis. Inflamm Bowel Dis 2016; 22:569-82. [PMID: 26848518 DOI: 10.1097/mib.0000000000000716] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Fibrosis as a common problem in patients with Crohn's disease is a result of an imbalance toward excessive tissue repair. At present, there is no specific treatment option. Pirfenidone is approved for the treatment of idiopathic pulmonary fibrosis with both antifibrotic and anti-inflammatory effects. We subsequently investigated the impact of pirfenidone treatment on development of fibrosis in a new mouse model of intestinal fibrosis. METHODS Small bowel resections from donor mice were transplanted subcutaneously into the neck of recipients. Animals received either pirfenidone (100 mg/kg, three times daily, orally) or vehicle. RESULTS After administration of pirfenidone, a significantly decreased collagen layer thickness was revealed as compared to vehicle (9.7 ± 1.0 versus 13.5 ± 1.5 µm, respectively, **P < 0.001). Transforming growth factor-β and matrix metalloproteinase-9 were significantly decreased after treatment with pirfenidone as confirmed by real-time PCR (0.42 ± 0.13 versus 1.00 ± 0.21 and 0.46 ± 0.24 versus 1.00 ± 0.62 mRNA expression level relative to GAPDH, respectively, *P < 0.05). Significantly decreased transforming growth factor-β after administration of pirfenidone was confirmed by Western blotting. CONCLUSION In our mouse model, intestinal fibrosis can be reliably induced and is developed within 7 days. Pirfenidone partially prevented the development of fibrosis, making it a potential treatment option against Crohn's disease-associated fibrosis.
Collapse
|
|
20
|
Expressions of Matrix Metalloproteinases (MMP-2, MMP-7, and MMP-9) and Their Inhibitors (TIMP-1, TIMP-2) in Inflammatory Bowel Diseases. Gastroenterol Res Pract 2016; 2016:2456179. [PMID: 27034654 PMCID: PMC4789560 DOI: 10.1155/2016/2456179] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Revised: 12/21/2015] [Accepted: 01/27/2016] [Indexed: 12/30/2022] Open
Abstract
Crohn's disease (CD) and ulcerative colitis (UC) belong to a group of inflammatory bowel diseases (IBD). The aim of our study was to evaluate the expression of MMP-2, MMP-7, MMP-9, TIMP-1, and TIMP-2 in ulcerative colitis and Crohn's disease. The study group comprised 34 patients with UC and 10 patients with CD. Evaluation of MMP-2, MMP-7, MMP-9, TIMP-1, and TIMP-2 expression in tissue samples was performed using immunohistochemistry. The overexpression of MMP-9 and TIMP-1 was dominant in both the glandular epithelium and inflammatory infiltration in UC patients. In contrast, in CD subjects the positive expression of MMP-2 and TIMP-1 was in glandular tubes while mainly MMP-7 and TIMP-2 expression was in inflammatory infiltration. Metalloproteinases' expression was associated with the presence of erosions, architectural tissue changes, and inflammatory infiltration in the lamina propria of UC patients. The expression of metalloproteinase inhibitors correlated with the presence of eosinophils and neutrophils in UC and granulomas in CD patients. Our studies indicate that the overexpression of metalloproteinases and weaker expression of their inhibitors may determine the development of IBD. It appears that MMP-2, MMP-7, and MMP-9 may be a potential therapeutic target and the use of their inhibitors may significantly reduce UC progression.
Collapse
|
|
21
|
de Bruyn M, Arijs I, De Hertogh G, Ferrante M, Van Assche G, Rutgeerts P, Vermeire S, Opdenakker G. Serum Neutrophil Gelatinase B-associated Lipocalin and Matrix Metalloproteinase-9 Complex as a Surrogate Marker for Mucosal Healing in Patients with Crohn's Disease. J Crohns Colitis 2015; 9:1079-87. [PMID: 26351381 DOI: 10.1093/ecco-jcc/jjv148] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2015] [Accepted: 08/20/2015] [Indexed: 12/24/2022]
Abstract
BACKGROUND AND AIMS Although costly and uncomfortable for the patient, the current standard to assess mucosal healing in Crohn's disease [CD] patients is endoscopy. The aim of this study was to evaluate NGAL-MMP-9 as surrogate marker for mucosal healing in CD patients. METHODS Serum NGAL-MMP-9 levels were determined with sandwich enzyme-linked immunosorbent assay before and up to 5 years after first infliximab infusion in 108 active CD patients [median age at first infliximab 36 years, 57% female] and 43 healthy controls [HC, median age 27 years, 60% female]. Serum samples were matched to the time of endoscopy and complete endoscopic healing was defined as absence of ulcerations. Histological healing was defined as absence of epithelial damage [D'Haens score]. RESULTS At baseline, median [interquartile range] NGAL-MMP-9 levels were significantly higher in active CD patients vs HC (77.6 [36.9-141.0] vs 25.5 [17.8-42.8] ng/ml; p < 0.001). After treatment, NGAL-MMP-9 levels significantly decreased in completely healed CD patients [n = 38] (84.5 [36.7-138.4] to 23.4 [7.4-42.5] ng/ml; p < 0.001) and--to a lesser extent--in non-healed CD patients [n = 36] (100.9 [43.4-152.6] to 43.8 [27.0-96.8] ng/ml; p = 0.001). Receiver operating characteristic analysis defined a NGAL-MMP-9 cut-off level of 45 ng/ml corresponding to complete endoscopic healing (area under the curve [AUC] = 0.79, 82% sensitivity, 65% specificity) and histological healing [AUC = 0.72, 79% sensitivity, 53% specificity]. At baseline, C-reactive protein [CRP] was not elevated in 33% of active CD patients, whereas 53% of these patients did have elevated NGAL-MMP-9 levels. CONCLUSIONS In the search for surrogate markers to assess mucosal healing in inflammatory bowel disease, NGAL-MMP-9 supplements and outperforms CRP in both ulcerative colitis and CD patients.
Collapse
Affiliation(s)
- Magali de Bruyn
- Rega Institute for Medical Research, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium Translational Research Center for Gastrointestinal Disorders [TARGID], Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
| | - Ingrid Arijs
- Translational Research Center for Gastrointestinal Disorders [TARGID], Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
| | - Gert De Hertogh
- Translational Cell and Tissue Research, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium
| | - Marc Ferrante
- Translational Research Center for Gastrointestinal Disorders [TARGID], Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
| | - Gert Van Assche
- Translational Research Center for Gastrointestinal Disorders [TARGID], Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
| | - Paul Rutgeerts
- Translational Research Center for Gastrointestinal Disorders [TARGID], Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
| | - Séverine Vermeire
- Translational Research Center for Gastrointestinal Disorders [TARGID], Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
| | - Ghislain Opdenakker
- Rega Institute for Medical Research, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium
| |
Collapse
|
|
22
|
Alutis ME, Grundmann U, Fischer A, Hagen U, Kühl AA, Göbel UB, Bereswill S, Heimesaat MM. The Role of Gelatinases in Campylobacter Jejuni Infection of Gnotobiotic Mice. Eur J Microbiol Immunol (Bp) 2015; 5:256-67. [PMID: 26716014 PMCID: PMC4681353 DOI: 10.1556/1886.2015.00033] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Accepted: 09/17/2015] [Indexed: 01/22/2023] Open
Abstract
Matrix metalloproteinases (MMP)-2 and -9 (also referred to gelatinases-A and -B, respectively) are upregulated in the inflamed gut of mice and men. We recently demonstrated that synthetic gelatinase blockage reduced large intestinal pro-inflammatory immune responses and apoptosis following murine Campylobacter (C.) jejuni infection. In order to address which gelatinase mediates C. jejuni-induced immune responses, gnotobiotic MMP-2(-/-), MMP-9(-/-), and wildtype (WT) mice were generated by broadspectrum antibiotic treatment and perorally infected with C. jejuni strain 81-176. The pathogen stably colonized the murine intestinal tract irrespective of the genotype but did not translocate to extra-intestinal compartments. At days 8 and 14 postinfection (p.i.), less pronounced colonic histopathological changes were observed in infected MMP-2(-/-) mice, less distinct epithelial apoptosis, but more epithelial proliferation in both MMP-2(-/-) and MMP-9(-/-) mice, as compared to WT controls. Reduced immune responses in gelatinase-deficient mice were characterized by lower numbers of effector as well as innate and adaptive immune cells within the colonic mucosa and lamina propria. The expression of IL-22, IL-18, IL-17A, and IL-1β mRNA was higher in the colon of MMP-2(-/-) as compared to WT mice. In conclusion, both MMP-2 and MMP-9 are differentially involved in mediating C. jejuni-induced intestinal immunopathology.
Collapse
Affiliation(s)
- Marie E Alutis
- Department of Microbiology and Hygiene, Charité - University Medicine Berlin , Berlin, Germany
| | - Ursula Grundmann
- Department of Microbiology and Hygiene, Charité - University Medicine Berlin , Berlin, Germany
| | - André Fischer
- Department of Microbiology and Hygiene, Charité - University Medicine Berlin , Berlin, Germany
| | - Ulrike Hagen
- Department of Microbiology and Hygiene, Charité - University Medicine Berlin , Berlin, Germany
| | - Anja A Kühl
- Department of Medicine I for Gastroenterology, Infectious Disease and Rheumatology/Research Center ImmunoSciences (RCIS), Charité - University Medicine Berlin , Berlin, Germany
| | - Ulf B Göbel
- Department of Microbiology and Hygiene, Charité - University Medicine Berlin , Berlin, Germany
| | - Stefan Bereswill
- Department of Microbiology and Hygiene, Charité - University Medicine Berlin , Berlin, Germany
| | - Markus M Heimesaat
- Department of Microbiology and Hygiene, Charité - University Medicine Berlin , Berlin, Germany
| |
Collapse
|
|
23
|
Alutis ME, Grundmann U, Hagen U, Fischer A, Kühl AA, Göbel UB, Bereswill S, Heimesaat MM. Matrix Metalloproteinase-2 Mediates Intestinal Immunopathogenesis in Campylobacter Jejuni-Infected Infant Mice. Eur J Microbiol Immunol (Bp) 2015; 5:188-98. [PMID: 26495129 PMCID: PMC4598886 DOI: 10.1556/1886.2015.00020] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Accepted: 07/27/2015] [Indexed: 12/20/2022] Open
Abstract
Increased levels of the matrix metalloproteinases (MMPs)-2 and -9 (also referred to gelatinase-A and -B, respectively) can be detected in the inflamed gut. We have recently shown that synthetic gelatinase blockage reduces colonic apoptosis and pro-inflammatory immune responses following murine Campylobacter (C.) jejuni infection. In order to dissect whether MMP-2 and/or MMP-9 is involved in mediating C. jejuni-induced immune responses, infant MMP-2(-/-), MMP-9(-/-), and wildtype (WT) mice were perorally infected with the C. jejuni strain B2 immediately after weaning. Whereas, at day 2 postinfection (p.i.), fecal C. jejuni B2 loads were comparable in mice of either genotype, mice expelled the pathogen from the intestinal tract until day 4 p.i. Six days p.i., colonic MMP-2 but not MMP-9 mRNA was upregulated in WT mice. Remarkably, infected MMP-2(-/-) mice exhibited less frequent abundance of blood in feces, less distinct colonic histopathology and apoptosis, lower numbers of effector as well as innate and adaptive immune cells within the colonic mucosa, and higher colonic IL-22 mRNA levels as compared to infected WT mice. In conclusion, these results point towards an important role of MMP-2 in mediating C. jejuni-induced intestinal immunopathogenesis.
Collapse
Affiliation(s)
- Marie E Alutis
- Department of Microbiology and Hygiene, Charité - University Medicine Berlin , Berlin, Germany
| | - Ursula Grundmann
- Department of Microbiology and Hygiene, Charité - University Medicine Berlin , Berlin, Germany
| | - Ulrike Hagen
- Department of Microbiology and Hygiene, Charité - University Medicine Berlin , Berlin, Germany
| | - André Fischer
- Department of Microbiology and Hygiene, Charité - University Medicine Berlin , Berlin, Germany
| | - Anja A Kühl
- Department of Medicine I for Gastroenterology, Infectious Disease and Rheumatology/Research Center ImmunoSciences (RCIS), Charité - University Medicine Berlin , Berlin, Germany
| | - Ulf B Göbel
- Department of Microbiology and Hygiene, Charité - University Medicine Berlin , Berlin, Germany
| | - Stefan Bereswill
- Department of Microbiology and Hygiene, Charité - University Medicine Berlin , Berlin, Germany
| | - Markus M Heimesaat
- Department of Microbiology and Hygiene, Charité - University Medicine Berlin , Berlin, Germany
| |
Collapse
|
|
24
|
Kim SJ, Goldstein J, Dorso K, Merad M, Mayer L, Crawford JM, Gregersen PK, Diamond B. Expression of Blimp-1 in dendritic cells modulates the innate inflammatory response in dextran sodium sulfate-induced colitis. Mol Med 2015; 20:707-19. [PMID: 25826676 DOI: 10.2119/molmed.2014.00231] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Accepted: 12/17/2014] [Indexed: 12/18/2022] Open
Abstract
A single nucleotide polymorphism of PRDM1, the gene encoding Blimp-1, is strongly associated with inflammatory bowel disease. Here, we demonstrate that Blimp-1 in CD103(+) dendritic cells (DCs) critically contributes to the regulation of macrophage homeostasis in the colon. Dextran sodium sulfate (DSS)-exposed Blimp-1(cko) mice with a deletion of Blimp-1 in CD103(+) DCs and CD11c(hi) macrophages exhibited severe inflammatory symptoms, pronounced weight loss, high mortality, robust infiltration of neutrophils in epithelial regions of the colon, an increased expression of proinflammatory cytokines and a significant decrease in CD103(+) DCs in the colon compared with DSS exposed wild-type (WT) mice. Purified colonic macrophages from Blimp-1(cko) mice expressed increased levels of matrix metalloproteinase 8, 9 and 12 mRNA. WT macrophages cocultured with colonic DCs but not bone marrow-derived DCs from Blimp-1(cko) produced increased matrix metalloproteinases in an interleukin (IL)-1β- and IL-6-dependent manner. Treatment of Blimp-1(cko) mice with anti-IL-1β and anti-IL-6 abrogated the exaggerated clinical response. Overall, these data demonstrate that Blimp-1 expression in DCs can alter an innate inflammatory response by modulating the activation of myeloid cells. This is a novel mechanism of contribution of Blimp-1 for the pathogenesis of inflammatory bowel diseases, implicating another therapeutic target for the development of inflammatory bowel disease.
Collapse
Affiliation(s)
- Sun Jung Kim
- The Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.,Department of Molecular Medicine, School of Medicine, Hofstra University, Hempstead, New York, United States of America
| | - Jordan Goldstein
- The Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America
| | - Kimberly Dorso
- The Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America
| | - Miriam Merad
- The Human Immunology Center, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Lloyd Mayer
- The Immunology Institute, Icahn School of Medicine at Mount Sinai (deceased), New York, New York, United States of America
| | - James M Crawford
- Department of Pathology and Laboratory Medicine, Hofstra North Shore-LIJ School of Medicine, Hempstead, New York, United States of America
| | - Peter K Gregersen
- Department of Molecular Medicine, School of Medicine, Hofstra University, Hempstead, New York, United States of America.,Center for Genomics and Human Genetics, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America
| | - Betty Diamond
- The Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.,Department of Molecular Medicine, School of Medicine, Hofstra University, Hempstead, New York, United States of America
| |
Collapse
|
|
25
|
Shimshoni E, Yablecovitch D, Baram L, Dotan I, Sagi I. ECM remodelling in IBD: innocent bystander or partner in crime? The emerging role of extracellular molecular events in sustaining intestinal inflammation. Gut 2015; 64:367-72. [PMID: 25416065 PMCID: PMC4345769 DOI: 10.1136/gutjnl-2014-308048] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Elee Shimshoni
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | - Doron Yablecovitch
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel,Department of Gastroenterology, Chaim Sheba Medical Center, Tel HaShomer, Israel
| | - Liran Baram
- IBD Center, Department of Gastroenterology and Liver Diseases, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Iris Dotan
- IBD Center, Department of Gastroenterology and Liver Diseases, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Irit Sagi
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| |
Collapse
|
|
26
|
Alutis ME, Grundmann U, Fischer A, Kühl AA, Bereswill S, Heimesaat MM. Selective gelatinase inhibition reduces apoptosis and pro-inflammatory immune cell responses in Campylobacter jejuni-infected gnotobiotic IL-10 deficient mice. Eur J Microbiol Immunol (Bp) 2014; 4:213-22. [PMID: 25544894 DOI: 10.1556/eujmi-d-14-00031] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2014] [Accepted: 11/06/2014] [Indexed: 11/19/2022] Open
Abstract
Increased levels of the matrix metalloproteinases-2 and -9 (also referred to gelatinase-A and -B, respectively) can be detected in intestinal inflammation. We have recently shown that selective gelatinase blockage by the synthetic compound RO28-2653 ameliorates acute murine ileitis and colitis. We here investigated whether RO28-2653 exerts anti-inflammatory effects in acute Campylobacter jejuni-induced enterocolitis of gnotobiotic IL-10(-/-) mice generated following antibiotic treatment. Mice were perorally infected with C. jejuni (day 0) and either treated with RO28-2653 (75 mg/kg body weight/day) or placebo from day 1 until day 6 post infection (p.i.) by gavage. Irrespective of the treatment, infected mice displayed comparable pathogen loads within the gastrointestinal tract. Following RO28-2653 administration, however, infected mice exhibited less severe symptoms such as bloody diarrhea as compared to placebo controls. Furthermore, less distinct apoptosis but higher numbers of proliferating cells could be detected in the colon of RO28-2653-treated as compared to placebo-treated mice at day 7 p.i. Remarkably, gelatinase blockage resulted in lower numbers of T- and B-lymphocytes as well as macrophages and monocytes in the colonic mucosa of C. jejuni-infected gnotobiotic IL-10(-/-) mice. Taken together, synthetic gelatinase inhibition exerts anti-inflammatory effects in experimental campylobacteriosis.
Collapse
|
|
27
|
Multi-faceted integrated omics analysis revealed parsley (Petroselinum crispum) as a novel dietary intervention in dextran sodium sulphate induced colitic mice. J Funct Foods 2014. [DOI: 10.1016/j.jff.2014.09.018] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
|
|
28
|
Heimesaat MM, Fischer A, Alutis M, Grundmann U, Boehm M, Tegtmeyer N, Göbel UB, Kühl AA, Bereswill S, Backert S. The impact of serine protease HtrA in apoptosis, intestinal immune responses and extra-intestinal histopathology during Campylobacter jejuni infection of infant mice. Gut Pathog 2014; 6:16. [PMID: 24883112 PMCID: PMC4040118 DOI: 10.1186/1757-4749-6-16] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2014] [Accepted: 05/19/2014] [Indexed: 12/19/2022] Open
Abstract
Background Campylobacter jejuni has emerged as a leading cause of bacterial enterocolitis. The serine protease HtrA has been shown to be a pivotal, novel C. jejuni virulence factor involved in cell invasion and transmigration across polarised epithelial cells in vitro. However, the functional relevance of the htrA gene for the interaction of C. jejuni with the host immune system in the infant mouse infection model has not been investigated so far. Results Here we studied the role of C. jejuni htrA during infection of 3-weeks-old infant mice. Immediately after weaning, conventional wild-type mice were perorally infected with the NCTC11168∆htrA mutant (∆htrA) or the parental wild-type strain. Approximately one third of infected infant mice suffered from bloody diarrhea until day 7 post infection (p.i.), whereas colonic histopathological changes were rather moderate but comparable between the two strains. Interestingly, parental, but not ∆htrA mutant infected mice, displayed a multifold increase of apoptotic cells in the colonic mucosa at day 7 p.i., which was paralleled by higher colonic levels of pro-inflammatory cytokines such as TNF-α and IFN-γ and the matrix-degrading enzyme matrixmetalloproteinase-2 (MMP-2). Furthermore, higher numbers of proliferating cells could be observed in the colon of ∆htrA infected mice as compared to the parental wild-type strain. Remarkably, as early as 7 days p.i. infant mice also exhibited inflammatory changes in extra-intestinal compartments such as liver, kidneys and lungs, which were less distinct in kidneys and lungs following ∆htrA versus parental strain infection. However, live C. jejuni bacteria could not be found in these organs, suggesting the induction of systemic effects during intestinal infection. Conclusion Upon C. jejuni ∆htrA strain infection of infant mice, intestinal and extra-intestinal pro-inflammatory immune responses were ameliorated in the infant mouse model system. Future studies will shed further light onto the molecular mechanisms of host-pathogen interactions.
Collapse
Affiliation(s)
- Markus M Heimesaat
- Department of Microbiology and Hygiene, Charité - University Medicine Berlin, Campus Benjamin Franklin, Hindenburgdamm 27, D-12203 Berlin, Germany
| | - André Fischer
- Department of Microbiology and Hygiene, Charité - University Medicine Berlin, Campus Benjamin Franklin, Hindenburgdamm 27, D-12203 Berlin, Germany
| | - Marie Alutis
- Department of Microbiology and Hygiene, Charité - University Medicine Berlin, Campus Benjamin Franklin, Hindenburgdamm 27, D-12203 Berlin, Germany
| | - Ursula Grundmann
- Department of Microbiology and Hygiene, Charité - University Medicine Berlin, Campus Benjamin Franklin, Hindenburgdamm 27, D-12203 Berlin, Germany
| | - Manja Boehm
- Department of Biology, Division of Microbiology, Friedrich Alexander University Erlangen, Nuremberg, Germany
| | - Nicole Tegtmeyer
- Department of Biology, Division of Microbiology, Friedrich Alexander University Erlangen, Nuremberg, Germany
| | - Ulf B Göbel
- Department of Microbiology and Hygiene, Charité - University Medicine Berlin, Campus Benjamin Franklin, Hindenburgdamm 27, D-12203 Berlin, Germany
| | - Anja A Kühl
- Department of Medicine I for Gastroenterology, Infectious Disease and Rheumatology / Research Center ImmunoSciences (RCIS), Charité - University Medicine Berlin, Berlin, Germany
| | - Stefan Bereswill
- Department of Microbiology and Hygiene, Charité - University Medicine Berlin, Campus Benjamin Franklin, Hindenburgdamm 27, D-12203 Berlin, Germany
| | - Steffen Backert
- Department of Biology, Division of Microbiology, Friedrich Alexander University Erlangen, Nuremberg, Germany
| |
Collapse
|
|
29
|
Tursi A, Elisei W, Giorgetti GM, Inchingolo CD, Nenna R, Picchio M, Giorgio F, Ierardi E, Brandimarte G. Expression of basic fibroblastic growth factor, syndecan 1 and tumour necrosis factor α in resected acute colonic diverticulitis. Colorectal Dis 2014; 16:O98-O103. [PMID: 24283919 DOI: 10.1111/codi.12504] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2013] [Accepted: 09/23/2013] [Indexed: 02/08/2023]
Abstract
AIM Inflammation and fibrosis are present in both colonic diverticulitis and Crohn's disease (CD). The molecular pattern of basic fibroblastic growth factor (bFGF) and syndecan 1 (SD1) expression is altered in stenosing CD, but their expression in resected complicated colonic diverticulitis (ACD) is unknown. METHOD The expression of bFGF, SD1 and tumour necrosis factor α (TNF-α) in 20 patients after resection of ACD was compared with 15 patients having a resection for CD. Analysis was conducted using real-time reverse transcriptase polymerase chain reaction in biopsy samples. RESULTS Lymphocytic and neutrophil inflammation scores were similar in both groups (P = 0.771 and P = 0.562). TNF-α and bFGF expression was significantly higher in ACD than in CD (P < 0.0001 and P = 0.009). SD1 expression was similar in both groups (P = 0.841). CONCLUSION TNF-α and bFGF are significantly overexpressed in ACD with respect to CD, whilst SD1 levels do not differ. The findings confirm that inflammation and its association with altered molecular patterns of mucosal healing may play an important role in the phenotype of the diseases.
Collapse
Affiliation(s)
- A Tursi
- Gastroenterology Service, ASL BAT, Andria, BT, Italy
| | | | | | | | | | | | | | | | | |
Collapse
|
|
30
|
Claudin-2 regulates colorectal inflammation via myosin light chain kinase-dependent signaling. Dig Dis Sci 2013; 58:1546-59. [PMID: 23306855 DOI: 10.1007/s10620-012-2535-3] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2012] [Accepted: 12/20/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND Claudins have been demonstrated to be associated with inflammatory bowel disease (IBD), but the specific role of claudin-2 in colorectal inflammation remains undefined. AIMS We aimed to determine the role of claudin-2 in TNFα-induced colorectal inflammation. METHODS We used claudin-2 (-/-) mice to assess the role of claudin-2 in colon. The mice were intraperitoneally injected with 3 μg of recombinant murine TNFα, and the NF-κB signaling and mRNA expression levels of proinflammatory cytokines and myosin light chain kinase (MLCK) were evaluated. Moreover, in claudin-2 (-/-) mice, colitis was induced by the administration of dextran sodium sulfate (DSS). The involvement of claudin-2 in colorectal inflammation was also investigated using the Caco-2 human colon adenocarcinoma cell line, and the expression of claudin-2 was downregulated using claudin-2 siRNA. RESULTS TNFα-induced colorectal inflammation via NF-κB signaling activation was enhanced in claudin-2 (-/-) mice compared with that in claudin-2 (+/+) mice. MLCK expression level in the colon tissue of claudin-2 (-/-) mice treated with TNFα was enhanced in comparison to that of the claudin-2 (+/+) mice. DSS-induced colitis was more severe in the claudin-2 (-/-) mice than in the claudin-2 (+/-) mice. In in vitro experiments, the decreased expression of claudin-2 enhanced the expressions of IL-6, IL-1β and MLCK. CONCLUSIONS Our findings concerning the role of claudin-2 in epithelial inflammatory responses enrich our collective understanding of mucosal homeostasis and intestinal diseases such as IBD. Furthermore, the results of this study indicate that claudin-2 and MLCK are potential therapeutic targets for treatments against intestinal disease.
Collapse
|
|
31
|
Liu H, Patel NR, Walter L, Ingersoll S, Sitaraman SV, Garg P. Constitutive expression of MMP9 in intestinal epithelium worsens murine acute colitis and is associated with increased levels of proinflammatory cytokine Kc. Am J Physiol Gastrointest Liver Physiol 2013; 304:G793-803. [PMID: 23471340 DOI: 10.1152/ajpgi.00249.2012] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease, is a chronic inflammatory disease associated with an increased risk for colon cancer. Matrix metalloproteinases (MMPs) are the predominant proteinases expressed in the gut mucosa during active IBD. Our laboratory has previously demonstrated that epithelial-derived MMP9 is absent in normal colonic tissue but is upregulated during IBD. In this study MMP9 transgenic mice (Tg-villin-MMP9) are generated specifically to overexpress MMP9 in intestinal epithelium to examine the role and underlying mechanism by which it modulates the pathogenesis of acute colitis. Dextran sodium sulfate (3% DSS)- and Salmonella typhimurium (S.T.)-induced colitis models were used to study gut inflammation in Tg-villin-MMP9 and wild-type littermates (WT). Colonic tissue was analyzed via Western blot, histology, myeloperoxidase (MPO) assay, and quantitative PCR. Tg-villin-MMP9 mice expressed significantly increased MMP9 mRNA and protein expression at basal level. There was a significant decrease in the goblet cells, but a significant increase in proliferation and apoptosis were observed among Tg-villin-MMP9 mice compared with WT mice. There was also a significant increase in the proinflammatory chemokine Kc among Tg-villin-MMP9 compared with WT mice. Tg-villin-MMP9 exhibited a severe inflammatory response than WT mice in both DSS- and S.T.-induced colitis models as evident by greater weight loss and higher clinical score, histological score, and MPO activity, which correlated with relative levels of Kc mRNA. MMP9 expressed by intestinal epithelial cells mediates inflammation in colitis with simultaneous increase in proinflammatory cytokine Kc.
Collapse
Affiliation(s)
- Hongchun Liu
- Center for Diagnostics and Therapeutics, Department of Biology, Georgia State University, Atlanta, GA 30303, USA
| | | | | | | | | | | |
Collapse
|
|
32
|
Drygiannakis I, Valatas V, Sfakianaki O, Bourikas L, Manousou P, Kambas K, Ritis K, Kolios G, Kouroumalis E. Proinflammatory cytokines induce crosstalk between colonic epithelial cells and subepithelial myofibroblasts: implication in intestinal fibrosis. J Crohns Colitis 2013; 7:286-300. [PMID: 22578910 DOI: 10.1016/j.crohns.2012.04.008] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2012] [Revised: 04/10/2012] [Accepted: 04/11/2012] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Colonic epithelial cells and adjacent subepithelial myofibroblasts are important counterparts in the pathogenesis of intestinal inflammation and fibrosis. We investigated the possible crosstalk between them, whilst focusing on the mucosal inflammation pathways that potentially trigger intestinal fibrosis. METHODS We studied the effects of proinflammatory cytokines (IL-1α, TNF-α, IFN-γ) on human colonic epithelial cell lines and the effects of epithelial cell-conditioned media on primary human colonic subepithelial myofibroblasts isolated from normal controls or patients with inflammatory Crohn's disease along with the corresponding 18CO cell line. Readouts included production of TGF-β and TIMP-1, total collagen synthesis, matrix metalloproteinases MMP-2 and MMP-9 and myofibroblast migration/mobility. RESULTS Proinflammatory cytokines upregulated TGF-β and TIMP-1 in colonic epithelial cells. Conditioned medium from these epithelial cell cultures induced production of MMP-9 and collagen and inhibited the migration/mobility of subepithelial myofibroblasts. MMP-9 production depended on endothelin receptor A signalling on responding myofibroblasts. Collagen up-regulation was independent of TGF-β, CTGF, TF and endothelin. Subepithelial myofibroblasts isolated from Crohn's disease patients had similar responses to those isolated from normal controls, with the exception of higher basal collagen production. CONCLUSIONS Our study indicates that colonic epithelial cells may respond to an inflammatory milieu by inducing myofibroblast functions similar to those observed during intestinal fibrosis.
Collapse
|
|
33
|
Al-Azri AR, Gibson RJ, Keefe DMK, Logan RM. Matrix metalloproteinases: do they play a role in mucosal pathology of the oral cavity? Oral Dis 2012; 19:347-59. [DOI: 10.1111/odi.12023] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2012] [Revised: 08/16/2012] [Accepted: 09/04/2012] [Indexed: 12/19/2022]
Affiliation(s)
| | - RJ Gibson
- School of Medical Sciences; University of Adelaide; Adelaide; SA; Australia
| | - DMK Keefe
- Department of Medical Oncology, Royal Adelaide Hospital Cancer Centre; Adelaide; SA; Australia
| | - RM Logan
- School of Dentistry; University of Adelaide; Adelaide; SA; Australia
| |
Collapse
|
|
34
|
Heimesaat MM, Heilmann K, Kühl AA, Erben U, Rühl M, Fischer A, Farndale RW, Bereswill S, Göbel UB, Zeitz M, Somasundaram R, Freise C. The synthetic hydroxyproline-containing collagen analogue (Gly-Pro-Hyp)10 ameliorates acute DSS colitis. Eur J Microbiol Immunol (Bp) 2012; 2:192-200. [PMID: 24688765 DOI: 10.1556/eujmi.2.2012.3.4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2012] [Accepted: 06/17/2012] [Indexed: 01/13/2023] Open
Abstract
In experimental models of and humans with intestinal inflammation, increased levels of the matrix-degrading gelatinases MMP-2 and -9 in inflamed tissues can be detected. The synthetic collagen analogue (Gly-Pro-Hyp)10, (GPO)10, has been identified as a relevant binding structure for proMMP-2/-9 and promotes enzymatic activity of proMMP-2. Since targeted MMP strategies might offer promising anti-inflammatory treatment options, we for the first time studied in vivo actions exerted by (GPO)10 applying an acute dextrane sulfate sodium (DSS) induced colitis model. Seven-day intraperitoneal (GPO)10 treatment ameliorated clinical symptoms and histopathological colonic changes as compared to placebo controls with severe colitis. (GPO)10-treated mice displayed a diminished influx of neutrophils, and T- and B-lymphocytes into their colonic mucosa whereas numbers of regulatory T-cells and regenerative cells were higher as compared to placebo controls. Furthermore, IL-6 secretion was down-regulated in ex vivo colonic biopsies derived from (GPO)10-treated mice whereas higher concentrations of the anti-inflammatory cytokine IL-10 in extra-intestinal compartments such as MLN and spleen could be detected. Strikingly, influx of inflammatory cells into lungs was abolished following (GPO)10 application. We therefore propose (GPO)10 as a promising effective and safe treatment option of intestinal and extra-intestinal inflammatory conditions in humans.
Collapse
|
|
35
|
Chang J, Wehner S, Schäfer N, Sioutis M, Bortscher S, Hirner A, Kalff JC, Bauer AJ, Overhaus M. Iatrogenic extracellular matrix disruption as a local trigger for postoperative ileus. J Surg Res 2012; 178:632-9. [PMID: 23079570 DOI: 10.1016/j.jss.2012.05.044] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2012] [Revised: 04/23/2012] [Accepted: 05/10/2012] [Indexed: 01/28/2023]
Abstract
BACKGROUND Active matrix metallopeptidase 9 (MMP-9) disruption of the extracellular matrix (ECM) plays an important role in inflammatory disorders. In this study, we investigated the inflammatory role of MMP-9 and the ECM breakdown product hyaluronan as a trigger for the postoperative intestinal inflammatory response of postoperative ileus. METHODS We performed a standardized intestinal surgical manipulation on rats to produce ileus assessed by the oral non-digestible fluorescein isothiocyanate-dextran transit assay. We studied isolated intestinal muscularis extracts for mRNA expressions of interleukin 6 (IL-6), MMP-9 and CD44. We quantified peritoneal MMP-9 activity using zymography, and quantified peritoneal fluid and serum for hyaluronan and tissue inhibitor of metalloproteinase 1 levels by enzyme-linked immunosorbent assay (ELISA). We cultured peritoneal macrophages and exposed them to peritoneal fluid or synthetic hyaluronan for ELISA analysis of IL-6 and macrophage inflammatory protein-1α. RESULTS Transit was significantly delayed after surgical manipulation, and extracts of the isolated jejunal and colonic muscularis demonstrated a significant induction of IL-6, MMP-9, and CD44 mRNAs compared with controls. Zymography confirmed significant MMP-9 activity in peritoneal fluid compared with controls. Enzyme-linked immunosorbent assay measurements showed a significant up-regulation in hyaluronan and tissue inhibitor of metalloproteinase 1 in the peritoneal fluid and serum. In addition, ELISA and reverse transcriptase-polymerase chain reaction measurements of peritoneal macrophages stimulated with postsurgical peritoneal fluid and synthetic hyaluronan resulted in higher expressions of IL-6 and macrophage inflammatory protein-1α in the macrophage supernatant. CONCLUSIONS Our results confirm that MMP-9 disruption in the ECM with hyaluronan release and muscularis CD44 receptor induction has the potential to trigger muscularis proinflammatory cascades that cause postoperative ileus. Matrix metallopeptidase 9 inhibition may be a novel therapeutic approach to limit postoperative ileus.
Collapse
Affiliation(s)
- Johannes Chang
- Department of General, Visceral, Thoracic, and Vascular Surgery, University of Bonn, Bonn, Germany
| | | | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Kawamura Y, Sugata K, Nakai H, Asano Y, Ohashi M, Kato T, Nishimura N, Ozaki T, Yui A, Taniguchi K, Yoshikawa T. Correlation between serum matrix metalloproteinase and antigenemia levels in patients infected with rotavirus. J Med Virol 2012; 84:986-91. [DOI: 10.1002/jmv.23296] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
|
|
37
|
Lakatos G, Sipos F, Miheller P, Hritz I, Varga MZ, Juhász M, Molnár B, Tulassay Z, Herszényi L. The behavior of matrix metalloproteinase-9 in lymphocytic colitis, collagenous colitis and ulcerative colitis. Pathol Oncol Res 2012; 18:85-91. [PMID: 21678108 DOI: 10.1007/s12253-011-9420-9] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2010] [Accepted: 05/26/2011] [Indexed: 02/05/2023]
Abstract
Matrix metalloproteinases play an important role in extracellular matrix remodelling. It has been proposed that matrix metalloproteinase-9 (MMP-9) is involved in epithelial damage in ulcerative colitis (UC). However, to our knowledge, no data are available in terms of MMP-9 expression in microscopic colitis. Determination of mucosal protein expression levels of MMP-9 in lymphocytic colitis (LC), collagenous colitis (CC) and UC. MMP-9 immunohistochemical expressions were analyzed in paraffin-embedded tissue samples by immunohistochemistry including patients with LC, CC, UC, active diverticulitis, inactive diverticular disease and healthy control subjects. UC was also subgrouped according to the severity of inflammation. Immunostaining was determined semiquantitatively. Independent colonic biopsies from healthy and severe UC cases were used for gene expression analyses. For further comparison MMP-9 serum antigen levels were also determined in patients with UC and control patients without macroscopic or microscopic changes during colonoscopy. MMP-9 mucosal expression was significantly higher in UC (26.7 ± 19.5%) compared to LC (6.6 ± 9.3%), CC (6.4 ± 7.6%), active diverticulitis (5.33 ± 2.4%), inactive diverticular disease (5.0 ± 2.2%) and controls (6.3 ± 2.6%) (P < 0.001). The immunohistochemical expression of MMP-9 in LC and CC was similar as compared to controls. MMP-9 expression was significantly higher in each inflammatory group of UC compared to controls (mild: 11.0 ± 2.8%, moderate: 23.9 ± 3.7%, severe UC: 52.6 ± 3.9% and 6.3 ± 2.6%, respectively, P < 0.005). The gene expression microarray data and RT-PCR results demonstrated a significantly higher expression of MMP-9 in severely active UC compared to healthy controls (P < 0.001). Significantly higher MMP-9 serum antigen concentrations were observed in UC patients compared with the control group (P < 0.05). MMP-9 seems to play no role in the inflammatory process of LC and CC. In contrast, the mucosal up-regulation of MMP-9 correlated with the severity of inflammation in UC. The increased MMP-9 expression could contribute to the severity of mucosal damage in active UC.
Collapse
Affiliation(s)
- Gábor Lakatos
- 2nd Department of Medicine, Semmelweis University, Budapest, Hungary
| | | | | | | | | | | | | | | | | |
Collapse
|
|
38
|
Altadill A, Eiró N, González LO, Junquera S, González-Quintana JM, Sánchez MR, Andicoechea A, Saro C, Rodrigo L, Vizoso FJ. Comparative analysis of the expression of metalloproteases and their inhibitors in resected crohn's disease and complicated diverticular disease. Inflamm Bowel Dis 2012; 18:120-30. [PMID: 21438097 DOI: 10.1002/ibd.21682] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2011] [Accepted: 01/14/2011] [Indexed: 01/29/2023]
Abstract
BACKGROUND Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs), are expressed in the gastrointestinal tract by different cellular types. Nevertheless, the imbalance between MMPs and TIMPs plays an important role in the physiopathology of diverse intestinal inflammatory processes. METHODS An immunohistochemical study was performed using tissue arrays and specific antibodies against MMPs -1, -2, -7, -9, -11, -13, -14, and TIMPs -1, -2 and -3. Immunohistochemical staining of intestinal samples from surgical interventions from 30 patients with complicated Crohn's disease (CD) and 25 patients with diverticulitis were performed at the inflamed mucosa and in adjacent noninflamed mucosa. A reverse-transcription polymerase chain reaction (RT-PCR) analysis was performed to confirm the results obtained by immunohistochemistry. In addition, western blot experiments were carried out. RESULTS CD inflamed mucosa showed higher global expression of MMP-2, MMP-9, and MMP-13 than diverticulitis inflamed mucosa. However, inflamed and noninflamed diverticulitis mucosal samples showed higher global expression of MMP-1, TIMP-1, and 3 than the CD samples. Epithelial cells of inflamed mucosa showed higher expression of MMP-2, 9, and 13 in CD than diverticulitis. However, the latter showed higher expression of TIMP-1. Similar differences for fibroblast-like cells and mononuclear inflammatory cells were found. CD samples presented an increased expression of MMPs and a decreased expression of TIMPs compared to diverticulitis. CONCLUSIONS These results indicate a differential pattern of expression of MMPs and TIMPs in CD and diverticulitis and the necessity to study the potential role of MMP inhibitors as new protective agents in both diseases.
Collapse
Affiliation(s)
- Antonio Altadill
- Unidad de Investigación, Fundación Hospital de Jove, Gijón, Spain
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
39
|
Heimesaat MM, Dunay IR, Fuchs D, Trautmann D, Fischer A, Kühl AA, Loddenkemper C, Siegmund B, Batra A, Bereswill S, Liesenfeld O. The distinct roles of MMP-2 and MMP-9 in acute DSS colitis. Eur J Microbiol Immunol (Bp) 2011; 1:302-10. [PMID: 24516737 DOI: 10.1556/eujmi.1.2011.4.6] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2011] [Accepted: 10/11/2011] [Indexed: 01/01/2023] Open
Abstract
Expression of gelatinases A and B, also referred to matrixmetalloproteinases (MMP)-2 and -9, respectively, is increased in inflamed tissues of experimental intestinal inflammation and humans with inflammatory bowel disease (IBDs). Given that we recently reported that treatment with the selective gelatinase inhibitor RO28-2653 ameliorates acute dextrane sulfate sodium (DSS) colitis, we asked whether gelatinase A or B expression is pivotal in mediating large intestinal inflammation. Results from our study reveal that symptoms of acute DSS colitis as well as histopathological colonic changes were ameliorated in MMP-2-, but not MMP-9-deficient mice, and were paralleled by a diminished influx of immune cells. In MMP-2-deficient mice, we observed lower expression of pro-inflammatory cytokines including interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and IL-6 in colonic biopsies and less overgrowth of the colonic lumen by potentially pro-inflammatory enterobacteria from the commensal gut microbiota. We conclude that rather MMP-2 than MMP-9 is causative for the establishment of DSS colitis in mice. The discrepancy of these data to prior reports might be due to substantial differences in the intestinal microbiota composition of the mice bred at different animal facilities impacting susceptibility to inflammatory stimuli. Consequently, a detailed survey of the gut microbiota should be implemented in immunological/inflammatory studies in the future in order to allow comparison of data from different facilities.
Collapse
|
|
40
|
Madisch A, Hellmig S, Schreiber S, Bethke B, Stolte M, Miehlke S. Allelic variation of the matrix metalloproteinase-9 gene is associated with collagenous colitis. Inflamm Bowel Dis 2011; 17:2295-8. [PMID: 21305678 DOI: 10.1002/ibd.21640] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2010] [Accepted: 01/03/2011] [Indexed: 12/17/2022]
Abstract
BACKGROUND Collagenous colitis is a chronic inflammatory bowel disease of unknown origin characterized by a thickened subepithelial collagen layer. Differential expression of matrix-metalloproteinases (MMPs) have been implicated in the pathogenesis of collagenous colitis. The aim was to assess genetic polymorphisms of MMP-1, -7, and -9 in a case-control setting for susceptibility to collagenous colitis. METHODS Seventy-five patients with symptomatic collagenous colitis and 334 healthy blood donors were genotyped for single nucleotide polymorphisms (SNPs) in MMP-1-1607, MMP-7-153, MMP-7-181, and MMP-9 exon 6 using TaqMan technology. Susceptibility to collagenous colitis was tested by comparison of the carrier status of the rare allele. RESULTS The carrier frequency of the allele GG of the coding SNP MMP-9 in exon 6 was 24% in patients with collagenous colitis and 14.3% in healthy blood donors (P = 0.039). The carriage of the allele GG significantly increased the risk for collagenous colitis with an odds ratio of 1.9 (95% confidence interval: 1.0-3.5). None of the other SNPs of MMP-1, MMP-7-153, and MMP-7-181 were associated with collagenous colitis. CONCLUSIONS Allelic variation in the MMP-9 gene may be part of a complex genetic risk profile for collagenous colitis. Further studies are needed to confirm this observation and to explore the functional role of this gene polymorphism in collagenous colitis.
Collapse
Affiliation(s)
- Ahmed Madisch
- Medical Department I, Academic Teaching Hospital Siloah, Hannover, Germany.
| | | | | | | | | | | |
Collapse
|
|
41
|
Heimesaat MM, Dunay IR, Fuchs D, Trautmann D, Fischer A, Kühl AA, Loddenkemper C, Batra A, Siegmund B, Krell HW, Bereswill S, Liesenfeld O. Selective gelatinase blockage ameliorates acute DSS colitis. Eur J Microbiol Immunol (Bp) 2011; 1:228-36. [PMID: 24516729 DOI: 10.1556/eujmi.1.2011.3.7] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2011] [Accepted: 07/06/2011] [Indexed: 12/11/2022] Open
Abstract
In the experimental models of intestinal inflammation and humans with inflammatory bowel diseases (IBD), increased levels of the matrix metalloproteinases (MMPs), MMP-2 and -9 (also referred to as gelatinase A and B, respectively), in inflamed tissue sites can be detected. In the presented study, we investigated potential beneficial effects exerted by doxycycline nonselectively blocking MMPs and the selective gelatinase inhibitor RO28-2653 in acute DSS colitis. Treatment with either compound for 8 days ameliorated clinical colitis pathology with a superior outcome in RO28-2653-treated animals. As compared to placebo controls, histopathological changes in the colon were less distinct following MMP blockage and IL-6 secretion in ex vivo biopsies was downregulated, paralleled by a diminished influx of pro-inflammatory immune cells and lack of overgrowth of the colonic lumen by potentially pro-inflammatory Escherichia coli of the commensal colon flora. We conclude that selective gelatinase inhibition not only exerts beneficial effects by disrupting the vicious cycle of positive feedback between immune cell stimulation and MMP induction but also prevents overgrowth of the colonic lumen by pro-inflammatory E. coli despite a lack of direct anti-bacterial properties, thus unaffecting the commensal gut microbiota. These findings put RO28-2653 into a center stage for development of intervention strategies in human IBD.
Collapse
|
|
42
|
Lakatos G, Sipos F, Miheller P, Hritz I, Varga MZ, Juhász M, Molnár B, Tulassay Z, Herszényi L. The behavior of matrix metalloproteinase-9 in lymphocytic colitis, collagenous colitis and ulcerative colitis. Pathol Oncol Res 2011. [PMID: 21678108 DOI: 10.1007/s12253-011-9420-9.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Matrix metalloproteinases play an important role in extracellular matrix remodelling. It has been proposed that matrix metalloproteinase-9 (MMP-9) is involved in epithelial damage in ulcerative colitis (UC). However, to our knowledge, no data are available in terms of MMP-9 expression in microscopic colitis. Determination of mucosal protein expression levels of MMP-9 in lymphocytic colitis (LC), collagenous colitis (CC) and UC. MMP-9 immunohistochemical expressions were analyzed in paraffin-embedded tissue samples by immunohistochemistry including patients with LC, CC, UC, active diverticulitis, inactive diverticular disease and healthy control subjects. UC was also subgrouped according to the severity of inflammation. Immunostaining was determined semiquantitatively. Independent colonic biopsies from healthy and severe UC cases were used for gene expression analyses. For further comparison MMP-9 serum antigen levels were also determined in patients with UC and control patients without macroscopic or microscopic changes during colonoscopy. MMP-9 mucosal expression was significantly higher in UC (26.7 ± 19.5%) compared to LC (6.6 ± 9.3%), CC (6.4 ± 7.6%), active diverticulitis (5.33 ± 2.4%), inactive diverticular disease (5.0 ± 2.2%) and controls (6.3 ± 2.6%) (P < 0.001). The immunohistochemical expression of MMP-9 in LC and CC was similar as compared to controls. MMP-9 expression was significantly higher in each inflammatory group of UC compared to controls (mild: 11.0 ± 2.8%, moderate: 23.9 ± 3.7%, severe UC: 52.6 ± 3.9% and 6.3 ± 2.6%, respectively, P < 0.005). The gene expression microarray data and RT-PCR results demonstrated a significantly higher expression of MMP-9 in severely active UC compared to healthy controls (P < 0.001). Significantly higher MMP-9 serum antigen concentrations were observed in UC patients compared with the control group (P < 0.05). MMP-9 seems to play no role in the inflammatory process of LC and CC. In contrast, the mucosal up-regulation of MMP-9 correlated with the severity of inflammation in UC. The increased MMP-9 expression could contribute to the severity of mucosal damage in active UC.
Collapse
Affiliation(s)
- Gábor Lakatos
- 2nd Department of Medicine, Semmelweis University, Budapest, Hungary
| | | | | | | | | | | | | | | | | |
Collapse
|
|
43
|
Mäkitalo L, Kolho KL, Karikoski R, Anthoni H, Saarialho-Kere U. Expression profiles of matrix metalloproteinases and their inhibitors in colonic inflammation related to pediatric inflammatory bowel disease. Scand J Gastroenterol 2010; 45:862-71. [PMID: 20367198 DOI: 10.3109/00365520903583863] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE The differential diagnosis of chronic colitis in inflammatory bowel disease (IBD) is challenging and a distinction between Crohn's disease (CD) and ulcerative colitis (UC) is not always possible. Matrix metalloproteinases (MMPs) cleave components of the extracellular matrix and their dysregulation leads to damage to the mucosa. They are involved in inflammation in IBD, as well as in eventual tissue repair. We aimed to examine putative differences in the profiles of MMPs and their tissue inhibitors [tissue inhibitors of metalloproteinase (TIMPs)] in pediatric IBD to find better tools for differential diagnosis of various IBD subgroups at the tissue level in the colon. MATERIAL AND METHODS Expression of MMPs -1, -7, -8, -9, -10, -12 and -26 and TIMPs -1 and -3 was studied by immunohistochemistry in colonic tissue samples of 32 pediatric patients with IBD and 11 non-IBD cases. RESULTS In the colon, expression of MMP-7 in epithelium was greater in CD samples compared to UC samples (1.09 versus 0.33; P = 0.010). Furthermore, epithelial MMP-10 expression was elevated in CD and UC samples compared to non-IBD samples (1.55 versus 1.00; P = 0.041 and 1.58 versus 1.00; P = 0.025, respectively). TIMP-3 expression in the stroma was higher in both the CD and UC groups when compared to non-IBD samples (2.18 versus 1.36; P = 0.026 and 2.50 versus 1.36; P = 0.002, respectively), but differences between UC and CD could not be observed. CONCLUSIONS Increased expression of epithelial MMP-10 and stromal TIMP-3 could serve as histological indicators of IBD etiology. Epithelial MMP-7 expression, on the other hand, could help to differentiate between CD-related colitis and UC.
Collapse
Affiliation(s)
- Laura Mäkitalo
- Department of Dermatology, Helsinki University Central Hospital and Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
| | | | | | | | | |
Collapse
|
|
44
|
Mäkitalo L, Sipponen T, Kärkkäinen P, Kolho KL, Saarialho-Kere U. Changes in matrix metalloproteinase (MMP) and tissue inhibitors of metalloproteinases (TIMP) expression profile in Crohn's disease after immunosuppressive treatment correlate with histological score and calprotectin values. Int J Colorectal Dis 2009; 24:1157-67. [PMID: 19652986 DOI: 10.1007/s00384-009-0756-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/23/2009] [Indexed: 02/04/2023]
Abstract
BACKGROUND Matrix metalloproteinases (MMPs) constitute a family of enzymes capable of degrading various extracellular matrices (ECM) and basement membrane components playing a role in ECM turnover. They activate and degrade signaling molecules, such as cytokines and chemokines. MMPs are involved in inflammation and have been implicated in tissue degradation and repair occurring in inflammatory bowel disease. The aim of this study was to investigate the MMP profile of intestinal Crohn's disease (CD) patients before and after immunosuppressive treatment (anti-TNF-alpha agents or corticosteroids and conventional immunosuppressants azathioprine or methotrexate) to learn more about the therapeutic pathways for immunosuppressive agents. METHODS Expression of MMP-1, MMP-7, MMP-9, MMP-10, and MMP-26 and tissue inhibitors of metalloproteinases (TIMP)-1 and TIMP-3 was studied by immunohistochemistry in pretreatment and post-treatment tissue samples. Semiquantitative immunohistochemical scores were tested for correlations with fecal and serum inflammation markers as well as endoscopic and clinical disease activity scores. RESULTS Neutrophil MMP-9 (p = 0.039) and MMP-26 (p = 0.030) and stromal TIMP-1 (p = 0.041) and TIMP-3 (p = 0.029) decreased along with treatment. However, expression of TIMP-3 by enterocytes tended to increase. Total histological score demonstrated positive correlation with neutrophil MMP-9 (p = 0.000), MMP-26 (p = 0.014), and macrophage TIMP-1 (p = 0.001). Calprotectin followed a similar pattern with stromal MMP-26 (p = 0.011), TIMP-1 (p = 0.000), and TIMP-3 (p = 0.001). Crohn's disease endoscopic index of severity (CDEIS) value correlated positively with macrophage TIMP-1 (p = 0.007) and stromal TIMP-3 (p = 0.005). Epithelial TIMP-3 presented with negative correlations with CDEIS (p = 0.006) and C-reactive protein values (p = 0.004). CONCLUSIONS Our results suggest that immunosuppressive drugs modulate disease activity in CD by downregulation of MMP-9 and MMP-26 positive neutrophils and stromal TIMP-1 and TIMP-3.
Collapse
Affiliation(s)
- Laura Mäkitalo
- Department of Dermatology, Helsinki University Central Hospital and Biomedicum Helsinki, University of Helsinki, Meilahdentie 2, 00250, Helsinki, Finland
| | | | | | | | | |
Collapse
|
|
45
|
Zemans RL, Colgan SP, Downey GP. Transepithelial migration of neutrophils: mechanisms and implications for acute lung injury. Am J Respir Cell Mol Biol 2009; 40:519-35. [PMID: 18978300 PMCID: PMC2677434 DOI: 10.1165/rcmb.2008-0348tr] [Citation(s) in RCA: 262] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2008] [Indexed: 12/20/2022] Open
Abstract
The primary function of neutrophils in host defense is to contain and eradicate invading microbial pathogens. This is achieved through a series of swift and highly coordinated responses culminating in ingestion (phagocytosis) and killing of invading microbes. While these tasks are usually performed without injury to host tissues, in pathologic circumstances such as sepsis, potent antimicrobial compounds can be released extracellularly, inducing a spectrum of responses in host cells ranging from activation to injury and death. In the lung, such inflammatory damage is believed to contribute to the pathogenesis of diverse lung diseases, including acute lung injury and the acute respiratory distress syndrome, chronic obstructive lung disease, and cystic fibrosis. In these disorders, epithelial cells are targets of leukocyte-derived antimicrobial products, including proteinases and oxidants. Herein, we review the mechanisms involved in the physiologic process of neutrophil transepithelial migration, including the role of specific adhesion molecules on the leukocyte and epithelial cells. We examine the responses of the epithelial cells to the itinerant leukocytes and their cytotoxic products and the consequences of this for lung injury and repair. This paradigm has important clinical implications because of the potential for selective blockade of these pathways to prevent or attenuate lung injury.
Collapse
Affiliation(s)
- Rachel L Zemans
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, National Jewish Health, Denver, CO 80206, USA
| | | | | |
Collapse
|
|
46
|
Garg P, Vijay-Kumar M, Wang L, Gewirtz AT, Merlin D, Sitaraman SV. Matrix metalloproteinase-9-mediated tissue injury overrides the protective effect of matrix metalloproteinase-2 during colitis. Am J Physiol Gastrointest Liver Physiol 2009; 296:G175-84. [PMID: 19171847 PMCID: PMC2643910 DOI: 10.1152/ajpgi.90454.2008] [Citation(s) in RCA: 125] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Matrix metalloproteinases (MMP) play an important role in pathogenesis of inflammatory bowel disease (IBD). Two known gelatinases, MMP-2 and MMP-9, are upregulated during IBD. Epithelial-derived MMP-9 is an important mediator of tissue injury in colitis, whereas MMP-2 protects against tissue damage and maintains gut barrier function. It has been suggested that developing strategies to block MMP-9 activity in the gut might be of benefit to IBD. However, given that MMP-2 and MMP-9 are structurally similar, such approaches would also likely inhibit MMP-2. Thus, to gain insight into outcome of inhibiting both MMP-2 and MMP-9, MMP-2(-/-)/MMP-9(-/-) double knockout mice (dKO) lacking both MMP-2 and MMP-9 were used in this study. Three models of murine colitis were used: dextran sodium sulfate (DSS), Salmonella typhimurium (S.T.), and trinitrobenzene sulfonic acid (TNBS). Our data demonstrate that MMP-2 and MMP-9 activities were highly upregulated in wild-type (WT) mice treated with DSS, S.T., or TNBS whereas dKO mice were resistant to the development of colitis. WT mice had extensive inflammation and tissue damage compared with dKO mice as suggested by histological assessment and myeloperoxidase activity. In conclusion, these results suggest an overriding role of MMP-9 in mediating tissue injury compared with the protective role of MMP-2 in development of colitis. Thus inhibition of MMP-9 may be beneficial in treatment of colitis even if resulting in inhibition of MMP-2.
Collapse
Affiliation(s)
- Pallavi Garg
- Division of Digestive Diseases, Department of Pathology, Emory University, Atlanta, Georgia
| | - Matam Vijay-Kumar
- Division of Digestive Diseases, Department of Pathology, Emory University, Atlanta, Georgia
| | - Lixin Wang
- Division of Digestive Diseases, Department of Pathology, Emory University, Atlanta, Georgia
| | - Andrew T. Gewirtz
- Division of Digestive Diseases, Department of Pathology, Emory University, Atlanta, Georgia
| | - Didier Merlin
- Division of Digestive Diseases, Department of Pathology, Emory University, Atlanta, Georgia
| | - Shanthi V. Sitaraman
- Division of Digestive Diseases, Department of Pathology, Emory University, Atlanta, Georgia
| |
Collapse
|
|
47
|
Manfredi MA, Zurakowski D, Rufo PA, Walker TR, Fox VL, Moses MA. Increased incidence of urinary matrix metalloproteinases as predictors of disease in pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis 2008; 14:1091-6. [PMID: 18338781 DOI: 10.1002/ibd.20419] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Matrix metalloproteinases (MMPs) are a family of metal-dependent enzymes responsible for the degradation and remodeling of extracellular matrix and basement membrane proteins that occurs during both normal physiologic activity and disease. It has been suggested that MMPs may also play a role in the pathogenesis of inflammatory bowel disease (IBD) by mediating mucosal breakdown in response to an enhanced inflammatory cascade. We previously demonstrated that elevated urinary MMP levels are independent predictors of disease status in cancer patients. Here we demonstrate that elevated urinary MMP levels may be biomarkers of disease activity in patients with IBD. METHODS We analyzed 95 urine samples prospectively collected from 55 children and young adults with known or suspected IBD who presented for evaluation to the Gastrointestinal Procedure Unit at Children's Hospital Boston. Urinary MMPs were analyzed in patients by zymography and compared to 40 age- and sex-matched controls. RESULTS Urinary MMP levels were significantly elevated (P < 0.0001) in patients with IBD, as well as in each subgroup (Crohn's disease or ulcerative colitis), relative to controls. Multiple logistic regression revealed that urinary MMP-2 and MMP-9 NGAL levels were independent predictors of Crohn's disease and ulcerative colitis (P < 0.0001). CONCLUSIONS These data are the first to demonstrate that urinary MMPs may represent novel noninvasive biomarkers for use in the evaluation of patients with IBD.
Collapse
Affiliation(s)
- Michael A Manfredi
- Center for Inflammatory Bowel Disease, Children's Hospital, Boston, Massachusetts, USA
| | | | | | | | | | | |
Collapse
|
|
48
|
Solberg A, Holmdahl L, Falk P, Palmgren I, Ivarsson ML. A local imbalance between MMP and TIMP may have an implication on the severity and course of appendicitis. Int J Colorectal Dis 2008; 23:611-8. [PMID: 18347803 DOI: 10.1007/s00384-008-0452-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/23/2008] [Indexed: 02/04/2023]
Abstract
BACKGROUND Matrix metalloproteinases (MMPs) and the tissue inhibitors of MMPs (TIMPs) have been demonstrated to be involved in inflammatory conditions in the intestine. The purpose of this study was to investigate whether the alterations of the MMP/TIMP balance might reflect the course of the inflammatory process in acute appendicitis and if the expression and localisation of MMPs and TIMP is variable in the various clinical manifestations of appendicitis. MATERIALS AND METHODS The study comprises 40 patients (26 men and 14 women) having emergency appendectomy and a control group constituting of 10 patients (5 men and 5 women) having a hemicolectomy for other reasons. MMP and TIMP expressions were assessed and compared in tissue specimens from phlegmonous (n = 15), gangrenous (n = 7), perforated appendicitis (n = 11) and controls with noninflamed appendices (n = 10) by means of enzyme-linked immunosorbent assay technique. Localisation of the enzymes was performed by immunohistochemistry. RESULTS MMP-1 was significantly higher in gangrenous and perforated appendicitis compared with phlegmonous appendicitis and controls (p < 0.05) while MMP-2 was significantly lower in gangrenous appendicitis compared with phlegmonous appendicitis and controls. MMP-2 was also lower in perforated appendicitis when compared with controls (p < 0.01). Elevated expression of MMP-9 was demonstrated in all groups of appendicitis compared with the controls (p < 0.001). CONCLUSIONS MMP-9 is the most abundantly expressed MMP of those investigated in inflamed appendix. We postulate that a local imbalance between MMP-9 and TIMP-1 may trigger a perforation. These results suggest that MMPs might be useful as biomarkers of appendices prone to perforation.
Collapse
Affiliation(s)
- Anna Solberg
- Department of Surgery, Colorectal Unit, Sahlgrenska University Hospital/Ostra, Gothenburg University, Gothenburg, Sweden.
| | | | | | | | | |
Collapse
|
|
49
|
Miao YL, Duan LP, Huang HL. Therapeutic effect of phenanthroline on trinitrobenzene sulfonic acid-induced colitis in rats. Shijie Huaren Xiaohua Zazhi 2008; 16:1499-1506. [DOI: 10.11569/wcjd.v16.i14.1499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the effect of a matrix metalloproteinase (MMP) inhibitor, phenan-throline, on colonic inflammation in experi-mental colitis induced by trinitrobenzene sulfonic acid (TNBS) in rats.
METHODS: A rat model of experimental colitis was induced by administration of TNBS. Animals were divided into 3 groups, treated with 1, 10-phenanthroline (20 mg/kg per day), sulphasalazine, and double distilled water (1 mL, control group), respectively. All the animals were killed after 7 days. Myeloperoxidase (MPO) activity was assessed; the mRNA expression of MMP-1, MMP-2, MMP-3 and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in colon tissues were detected by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). Meanwhile, MMP-3 and TIMP-1 proteins expression were analyzed by immunohistochemistry.
RESULTS: The absorbency value of MPO in the SASP group or phenanthroline group was significantly lower than that in the control group (0.25 ± 0.15, 0.16 ± 0.09 vs 0.48 ± 0.34, P = 0.025, 0.004). The expression levels of MMP-1, MMP-2 and MMP-3 mRNA had no markedly difference between the SASP group (0.19 ± 0.11, 0.35 ± 0.21, 0.25 ± 0.16) and phenanthroline group (0.33 ± 0.19, 0.29 ± 0.16, 0.22 ± 0.17); however, they were lower than those in the control group (0.45 ± 0.23, 0.53 ± 0.17, 0.62 ± 0.15; P = 0.002, 0.020, 0.000). There was no significant difference in TIMP-1 mRNA and protein among the three groups. However, the expression of MMP-3 protein in the SASP group or phenanthroline group was lower than that in the control group (2971.3 ± 1036.5, 2507.7 ± 1101.0 vs 7812.8 ± 4761.6, P = 0.000).
CONCLUSION: Phenanthroline may treat TNBS-induced colitis in rats by down-regulating MPO activity and MMP-1, MMP-2 and MMP-3 expression, but it has no effect on TIMP-1 expression.
Collapse
|
|
50
|
Armaka M, Apostolaki M, Jacques P, Kontoyiannis DL, Elewaut D, Kollias G. Mesenchymal cell targeting by TNF as a common pathogenic principle in chronic inflammatory joint and intestinal diseases. ACTA ACUST UNITED AC 2008; 205:331-7. [PMID: 18250193 PMCID: PMC2271010 DOI: 10.1084/jem.20070906] [Citation(s) in RCA: 252] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Tumor necrosis factor (TNF) is key to the pathogenesis of various arthritic diseases and inflammatory bowel disease (IBD). Anti-TNF therapies have proved successful in the clinical treatment of these diseases, but a mechanistic understanding of TNF function is still lacking. We have investigated early cellular mechanisms of TNF function in these diseases using an established TNF transgenic model, which develops a spondyloarthritis-like disease characterized by peripheral joint arthritis, sacroiliitis, enthesitis, and Crohn's-like IBD. Bone marrow grafting experiments demonstrated that development of arthritis requires TNF receptor I (TNFRI) expression in the radiation-resistant compartment, which is also known to be a sufficient target of TNF in the development of Crohn's-like IBD in the same model. Early activation of synovial fibroblasts and intestinal myofibroblasts could also be demonstrated by perturbed expression of matrix metalloproteases and their inhibitors. Notably, selective Cre/loxP-mediated TNFRI expression in mesenchymal cells resulted in a fully arthritic–spondyloarthritic and intestinal phenotype, indicating that mesenchymal cells are primary and sufficient targets of TNF in these pathologies. Our results offer a novel mechanistic perspective for TNF function in gut and joint pathologies and indicate early common cellular pathways that may also explain the often observed synovial–gut axis in human disease.
Collapse
Affiliation(s)
- Maria Armaka
- Institute of Immunology, Biomedical Sciences Research Center (BSRC) Alexander Fleming, Vari 16672, Greece
| | | | | | | | | | | |
Collapse
|