Connective Tissue Response in IBD

Similar documents
Tissue repair. (3&4 of 4)

Supplemental Table 1. Primer sequences for transcript analysis

Supplemental Table 1. Primers used for RT-PCR analysis of inflammatory cytokines Gene Primer Sequence

European Respiratory Society Annual Congress. Presented at: of new drugs for respiratory diseases. Barcelona, Spain, September 7-11, 2013 Page 1

Supplementary Material

Molecular mechanisms of Fibrosis: Targets of Therapy. John P Iredale University of Edinburgh, UK

Healing & Repair. Tissue Regeneration

Understanding Root Cause: Pathogenesis of Hepatic Fibrosis

Tissue renewal and Repair. Nisamanee Charoenchon, PhD Department of Pathobiology, Faculty of Science

Healing and Repair. Dr. Nabila Hamdi MD, PhD

Innate immune regulation of T-helper (Th) cell homeostasis in the intestine

Laura Smart 9/22/2011

CELL BIOLOGY - CLUTCH CH CELL JUNCTIONS AND TISSUES.

Mechanisms of hepatic fibrogenesis in chronic liver disease

SUPPLEMENTARY INFORMATION

DICHIARAZIONE Relatore: NADIA PASINETTI

Neoplasia 18 lecture 8. Dr Heyam Awad MD, FRCPath

As outlined under External contributions (see appendix 7.1), the group of Prof. Gröne at the

Murine Models of. Inflammatory Bowel Disease. Outline. Laura P. Hale, M.D. Ph.D. Professor of Pathology Duke University Medical Center

Scleroderma. Chronic multisystemic disease characterized by vasculopathy, variable degree of inflammation, and fibrosis

Abnormally differentiating keratinocytes in the epidermis of systemic sclerosis patients show enhanced secretion of CCN2 and S100A9

Supplementary Figure 1. ETBF activate Stat3 in B6 and Min mice colons

Regenerative Tissue Matrix in Treatment of Wounds

High Fat Diets Induce Colonic Epithelial Cell Stress and Inflammation that is Reversed by IL-22

Jesse K. McKenney, MD

Serum mirna signature diagnoses and discriminates murine colitis subtypes and predicts ulcerative colitis in humans

IL-12 family members in experimental colitis. Markus F. Neurath I. Medical Clinic Johannes Gutenberg-University Mainz, Germany

Postn MCM Smad2 fl/fl Postn MCM Smad3 fl/fl Postn MCM Smad2/3 fl/fl. Postn MCM. Tgfbr1/2 fl/fl TAC

Supplementary table I. Real-time primers used in the study. The fold change was obtained by

Inflammation in heart failure: biomarker, bystander or mediator

Bile Acids and Liver Fibrosis Causative Agent and Therapeutic Tool

Small Molecule Inhibitor of the Wnt Pathway (SM04755) as a Potential Topical Scleroderma Treatment

Topically Applicable Stromal Cell Growth Factors - Encapsulated Cosmeceuticals

Neutrophils contribute to fracture healing by synthesizing fibronectin+ extracellular matrix rapidly after injury

Uncovering the mechanisms of wound healing and fibrosis

1.The metastatic cascade. 2.Pathologic features of metastasis. 3.Therapeutic ramifications

THE ROLES OF SECRETED PROTEIN ACIDIC AND RICH IN CYSTIENE (SPARC) IN INTESTINAL INFLAMMATION, HEALING AND FIBROSIS. Yoke Leng NG

THE BIOLOGY OF PLATELET-GEL THERAPY

Topical nanocrystalline silver cream inhibits expression of matrix metalloproteinase-9 in animal models of allergic contact dermatitis.

Targeting the cgmp Pathway to Treat Colorectal Cancer

Effect of a nutrient mixture on the localization of extracellular matrix proteins in HeLa human cervical cancer xenografts in female nude mice

GeneralDiscussion and Summary

?Who binds to it. ? Who binds these inflammatory proteins RAGE SUGAR-FREE GLYCOBIOLOGY INFLAMMATION. BASIC SCIENCE?sugar chain structure

17 th International Conference of the Inflammation Research Association: Wednesday AM (Day 4) September 9-13, 2012

Dr Nadine Gravett School of Anatomical Sciences Room 2B10B

Key Role for Matrix Metalloproteinases-19 and -28 in Maintenance of Intestinal Homeostasis

number Done by Corrected by Doctor Maha Shomaf

General Features. Originates mostly from mesoderm. Composed of cells, fibres and extracellular matrix. Highly vascular. Variable regenerative power.

Supplementary Figure 1. Repression of hepcidin expression in the liver of mice treated with

Supplementary Figure 1. Lkb1-deficient lung ADC progressively transdifferentiates into SCC. (a) A scheme showing the progression pattern of atypical

Immunological Lung Diseases

Increased Expression of Matrix Metalloproteinase-1 and 3 in Remission Patients of Steroid-Dependent Ulcerative Colitis

Supplementary Figure 1. Characterization of NMuMG-ErbB2 and NIC breast cancer cells expressing shrnas targeting LPP. NMuMG-ErbB2 cells (a) and NIC

RSM. Indications For Use

Inflammation-Induced Endothelial-to-Mesenchymal Transition

Supplementary Figure 1

D2 inhibits TLR2- initiated 12p40 transcription (-) TLR2 PGN MDP. MyD88 IRAK ECSIT TRAF6 NIK. Smallest unit of PGN muramyl dipeptide IKK.

EARLY INFLAMMATORY RESPONSES TO VASCULAR DEVICES

Innate immunity as a therapeutic target in IBD. Elke Cario Division of Gastroenterology & Hepatology University Hospital of Essen Essen, Germany

AMPK Activation by Metformin Suppresses Abnormal Extracellular Matrix Remodeling in Adipose Tissue and Ameliorates Insulin Resistance in Obesity

Mitosis. Single Nano Micro Milli Macro. Primary. PCNA expression

HISTOLOGY. GIT Block 432 Histology Team. Lecture 1: Alimentary Canal (1) (Esophagus & Stomach) Done by: Ethar Alqarni Reviewed by: Ibrahim Alfuraih

Four Types of Vertebrate Tissue

Title: Smooth muscle cell-specific Tgfbr1 deficiency promotes aortic aneurysm formation by stimulating multiple signaling events

Anatomy of the liver and pancreas

1. The metastatic cascade. 3. Pathologic features of metastasis. 4. Therapeutic ramifications. Which malignant cells will metastasize?

Construction of Nephron by Fusion of Adult Glomeruli to Ureteric Buds with Type V Collagen. Yusuke Murasawa, Pi-chao Wang

Fibrosis and Remodeling in EoE

Matrix metalloproteinases

University of Groningen

EXTRACELLULAR MATRIX (pp 9-17)

Supplemental Digital Content 1. Endoscopic and histolological findings in INR and FR study subjects

After this presentation and discussion, the participants should be able to:

Obstructive nephropathy: Insights from genetically engineered animals

Pathophysiology of heart failure with preserved ejection fraction. Extracellular matrix

Contents 1 Introduction Structure and function of the skin Wound definition and implications 2 Phases and processes during healing Inflammatory phase

Figure S1 Generation of γ-gt DTR transgenic mice. (A) Schematic construct of the transgene. (B)

Myofibroblasts. II. Intestinal subepithelial myofibroblasts

SUPPLEMENTARY INFORMATION

Tumor development in murine ulcerative colitis depends on MyD88 signaling of colonic F4/80 + CD11b high Gr1 low macrophages

Stromal and immune cells in gut fibrosis: the myofibroblast and the scarface

Nature Immunology: doi: /ni Supplementary Figure 1

Supplementary Figure 1. HOPX is hypermethylated in NPC. (a) Methylation levels of HOPX in Normal (n = 24) and NPC (n = 24) tissues from the

Supplementary fig. 1. Crystals induce necroptosis does not involve caspases, TNF receptor or NLRP3. A. Mouse tubular epithelial cells were pretreated

Recovery of Myocardial Infarction via Unique Modulation of the Cardiac Microenvironment

ulcer healing role 118 Bicarbonate, prostaglandins in duodenal cytoprotection 235, 236

Connective Tissue Part-2. Dr. Heba Kalbouneh Assistant Professor of Anatomy and Histology

HISTOLOGY Lecture TWO DR. ASHRAF SAID

Vitreo-retinal interface pathologies and fibrinolytic treatment approaches

Histopathology: gastritis and peptic ulceration

Supplementary Figure 1. H-PGDS deficiency does not affect GI tract functions and anaphylactic reaction. (a) Representative pictures of H&E-stained

Immunology of Wound Healing

Treatment of murine Th1- and Th2-mediated inflammatory bowel disease with NF-κB decoy oligonucleotides

NEUTROPHIL-PLATELET INTERACTION

Combining an epithelial repair factor and antifibrotic with a corticosteroid offers optimal treatment for allergic airways disease

SCFA in gut health. Kristin Verbeke. On behalf of the Prebiotic Task Force of ILSI Europe

Supplementary Figure 1:

Supplemental Figure 1: Lrig1-Apple expression in small intestine. Lrig1-Apple is observed at the crypt base and in insterstial cells of Cajal, but is

Balancing intestinal and systemic inflammation through cell type-specific expression of

Transcription:

Connective Tissue Response in IBD Dr I C Lawrance MB BS, PhD FRACP School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital

Intestinal response to Chronic Inflammation Control UC CD Trichrome Staining of Collagen

Balancing ECM deposition and degradation Collagens Elastin Fibronectin Laminin TIMPs PAI Proteoglycans Plasmin/PA MMPs Collagenases Gelatinases Stromeolysins Deposition Degradation

Balancing ECM deposition and degradation Collagens Elastin Fibronectin Laminin TIMPs PAI Proteoglycans Plasmin/PA MMPs Collagenases Gelatinases Stromeolysins Deposition Degradation

Balancing ECM deposition and degradation Collagens Elastin Fibronectin Laminin TIMPs PAI Proteoglycans Plasmin/PA MMPs Collagenases Gelatinases Stromeolysins Deposition Degradation

Balancing ECM deposition and degradation Collagens Elastin Fibronectin Laminin TIMPs PAI Proteoglycans Plasmin/PA MMPs Collagenases Gelatinases Stromeolysins Deposition Degradation

Balancing ECM deposition and degradation Collagens Elastin Fibronectin Laminin TIMPs PAI Proteoglycans Plasmin/PA MMPs Collagenases Gelatinases Stromeolysins Degradation Deposition

Balancing ECM deposition and degradation Collagens Elastin Fibronectin Laminin TIMPs PAI Proteoglycans Plasmin/PA MMPs Collagenases Gelatinases Stromeolysins Degradation Deposition

Balancing ECM deposition and degradation Collagens Elastin Fibronectin Laminin TIMPs PAI Proteoglycans Plasmin/PA MMPs Collagenases Gelatinases Stromeolysins Degradation Deposition

Balancing ECM deposition and degradation Collagens Elastin Fibronectin Laminin TIMPs PAI Proteoglycans Plasmin/PA MMPs Collagenases Gelatinases Stromeolysins Deposition Degradation

Balancing ECM deposition and degradation Collagens Elastin Fibronectin Laminin TIMPs PAI Proteoglycans Plasmin/PA MMPs Collagenases Gelatinases Stromeolysins Deposition Degradation

Balancing ECM deposition and degradation Collagens Elastin Fibronectin Laminin TIMPs PAI Proteoglycans Plasmin/PA MMPs Collagenases Gelatinases Stromeolysins Deposition Degradation

Balancing ECM deposition and degradation Collagens Elastin Fibronectin Laminin TIMPs PAI Proteoglycans Plasmin/PA MMPs Collagenases Gelatinases Stromeolysins Deposition Degradation

Balancing ECM deposition and degradation Collagens Elastin Fibronectin Laminin TIMPs PAI Proteoglycans Plasmin/PA MMPs Collagenases Gelatinases Stromeolysins Deposition Degradation

Balancing ECM deposition and degradation Collagens Elastin Fibronectin Laminin TIMPs PAI Proteoglycans Plasmin/PA MMPs Collagenases Gelatinases Stromeolysins Deposition Degradation

Balancing ECM deposition and degradation Collagens Elastin Fibronectin Laminin TIMPs PAI Proteoglycans Plasmin/PA MMPs Collagenases Gelatinases Stromeolysins Deposition Degradation

Balancing ECM deposition and degradation Collagens Elastin Fibronectin Laminin TIMPs PAI Proteoglycans Plasmin/PA MMPs Collagenases Gelatinases Stromeolysins Deposition Degradation

Immunohistochemisrty Collagen III and I 1.50 1.25 LP Lamina Propria Control 1.00 0.75 0.50 0.25 SM Submucosa ME Muscularis Externa Inflamed UC Ratio Collagen type III:I 0.00 1.50 1.25 1.00 0.75 0.50 0.25 0.00 1.50 LP SM * SM ME A A Adverntia Fibrosed CD 1.25 1.00 0.75 ** 0.50 0.25 Collagen III Collagen I 0.00 LP SM ME A Lawrance et.al. IBD 2001

Isolated IBD Intestinal Fibroblasts-like like cells Phase contrast light microscopy Electron microscopy Rough endoplasmic reticulum (thick arrows) Collagen fibrils (thin arrows). Lawrance et.al. IBD 2001

Intestinal Fibroblasts 200 bfgf 10 ng/ml 150 Scintillation CPM x10 3 /μgdna 100 50 0 75 50 Doubling times in days 3.5 3.0 2.5 2.0 IGF-1 10 ng/ml 1.5 1.0 Control Bowel Fibrosed CD Inflamed CD Inflamed UC 25 0 Unstim Stim Unstim Stim Unstim Stim Control CD UC Lawrance et.al. IBD 2001

Fibroblast TGF-β1 IGF-1 bfgf Myofibroblast Smooth Muscle Cell

Regulators of ECM - TGF-β1 Plasmin - + PAI-1 PA + + + + TGF-β1 + + - + + COL I TIMP-1 - IGF-1 + - MMP-1 MMP-3 MMP-9 PDGF Recruitment Macrophages Leukocytes Recruitment Fibroblasts Myofibroblasts

150 TGF-β1 1 and IGF-1 1 expression in IBD TGF- β1 In situ hybridisation TGF- β1 Immunohistochemistry 125 100 No. Positive cells per HPF 75 50 25 0 150 125 100 75 50 LP SM ME A IGF-1 Insitu hybridisation LP SM ME A IGF-1 Immunohistochemistry Control Inflamed UC Fibrosed CD LP - Lamina Propria SM - Submucosa ME - Muscularis Externa A- Adverntia 25 0 LP SM ME A LP SM ME A Lawrance et.al. IBD 2001

Regulators of ECM - SPARC SPARC (Secreted Protein Acidic and Rich in Cysteine) Transiently secreted in actively inflamed tissue Plasmin - PAI-1 + + PDGF - + + Retinoic acid TGF-β1 SPARC + + + COX-2 - Indomethacin COX-2 2 inhibitors COL I TIMP-1 - PGE2? + Blocks TGF-β1 1 effects Fibroblast MMP-1 MMP-3 MMP-9 Macrophage MMP-1 MMP-3

Microarray analysis of ECM-related genes UC & CD compared to Control UC 24 genes 5 genes CD 15 genes 0 genes 7 genes in common Inflamed UC Fibrosed CD Mucin Trefoil factor 1 Mucin 4 MMP-12 MMP-9 MMP-1 MMP-3 Elafin Cystatin A Fibronectin 1 COL4A2 COL3A1 COL1A2 COL1A1 COL6A3 COL6A2 Proteoglycan 1 Epican Amelogenin Vimentin a2-sma g2-sma PMP22 vwf APM2 TGFbI OSF-2 SPARC Hevin Adducin 2 Zygin 2 Trichohyalin Actin-related Cytokeratin 20 Paralemmin Caldesmon 1 Tropomyosin 4 20 15 10 5 0 Lawrance et.al. Human Mol Genetics 2001 Fold Change c/w Control

SPARC Immunohistochemistry Control Intestine Neural bundles Fibroblast-like like cells Lawrance et.al. Gastro 126 (4): Suppl. 2 2004

SPARC Immunohistochemistry Inflamed UC Inflamed Ischaemic Colitis Neo-endothlial endothlial cells Inflammatory cells

SPARC Immunohistochemistry Fibrosed CD Fibrosed Diverticular Disease Neo-endothlial endothlial cells Fibroblasts-like like cells Inflammatory cells

Methods TNBS murine model of Chronic Inflammation-induced induced intestinal fibrosis 12 week old female CD-1 1 and BALB/c mice sensitised to TNBS. Weekly enemas for 6-88 weeks Colons removed cleaned & weighed Lawrance, Wu et.al. Gastroenterology 2003

Histology H & E Trichrome Water control TNBS & ETOH 2/52 TNBS & ETOH 8/52 Lawrance, Wu et.al. Gastroenterology 2003

Methods TNBS murine model ± Indomethacin or Retinoic Acid 12 week old female CD-1 mice sensitised to TNBS. Retinoic Acid 50ug/day or Indomethacin 0.2mg/kg/day Weekly enemas for 6 weeks Colons removed cleaned & weighed Lawrance et.al. Gastroenterology 126 (4): Suppl. 2 2004

Histology at 2 weeks TNBS alone or with 0.2mg/kg/day indomethacin or 50ug RA/day TNBS TNBS + Indo TNBS + RA Nil Mild Mod Severe Inflammation Nil Mild Mod/Severe Fibrosis

SPARC mrna at 2 weeks Ratio to control mice SPARC/ βactin 8 6 4 2 0 Control p=0.047 TNBS High Fibrosis p=0.0090 p=0.016 TNBS Low Fibrosis p=0.005 p=0.016 p=0.047 RA/TNBS Indo/TNBS

SPARC Immunohistochemistry Trichrome SPARC

SPARC +ve+ Cells per High Power Field 150 p=0.007 p=0.005 Cell count 100 50 p=0.01 0 Water Control n=10 RA Control n=5 Indo Control n=5 TNBS High n=6 TNBS Low n=6 RA n=6 Indo n=10

Regulators of ECM - SPARC Indomethacin SPARC - + + COX-2 - PGE2 PGE2? + Fibroblast MMP-1 MMP-3 MMP-9 Macrophage MMP-1 MMP-3

SPARC-null and WT mice TNBS murine model Weekly enemas for 2 weeks and 6 weeks Indomethacin 0.2mg/kg/day.. SPARC-null 11 week female C57bl6 x 129SV mice SPARC WT ± Indomethacin 11 week female C57bl6 x 129SV mice Lawrance et.al. Gastroenterology 128 (4): Suppl. 2 Apr 2005

SPARC-null and WT mice at 2 weeks SPARC +/+ mice TNBS ± with 0.2mg/kg/day indomethacin SPARC -/- mice TNBS alone Wild type TNBS alone Wild type TNBS + Indo SPARC -/- TNBS alone Nil Mild Mod Severe Inflammation Nil Mild Mod/Severe Fibrosis

IGF-1 SPARC TGF-β1 Myofibroblast Epithelial cells SPARC IGF-1 Fibroblast TGF-β1 SPARC Smooth Muscle Cells Macrophage Collagen III IGF-1 Collagen I TGF-β1 Extracellular Matrix (ECM)

2024 © healthdocbox.com Privacy Policy | Terms of Service | Feedback