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Tumor Necrosis Factor Alpha Converting Enzyme Inhibition During Acute Colitis in Mice: a Regional Analysis

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Tumor Necrosis Factor Alpha Converting Enzyme Inhibition During Acute Colitis in Mice: a Regional Analysis BearWorks MSU Graduate Theses Summer 2015 Tumor Necrosis Factor Alpha Converting Enzyme Inhibition during Acute Colitis in Mice: A Regional Analysis Brian Maddox As with any intellectual project, the content and views expressed in this thesis may be considered objectionable by some readers. However, this student-scholar’s work has been judged to have academic value by the student’s thesis committee members trained in the discipline. The content and views expressed in this thesis are those of the student-scholar and are not endorsed by Missouri State University, its Graduate College, or its employees. Follow this and additional works at: https://bearworks.missouristate.edu/theses Part of the Medical Molecular Biology Commons Recommended Citation Maddox, Brian, "Tumor Necrosis Factor Alpha Converting Enzyme Inhibition during Acute Colitis in Mice: A Regional Analysis" (2015). MSU Graduate Theses. 2866. https://bearworks.missouristate.edu/theses/2866 This article or document was made available through BearWorks, the institutional repository of Missouri State University. The work contained in it may be protected by copyright and require permission of the copyright holder for reuse or redistribution. For more information, please contact [email protected]. TUMOR NECROSIS FACTOR ALPHA CONVERTING ENZYME INHIBITION DURING ACUTE COLITIS IN MICE: A REGIONAL ANALYSIS A Masters Thesis Presented to The Graduate College of Missouri State University In Partial Fulfillment Of the Requirements for the Degree Master of Science, Cell and Molecular Biology By Brian Maddox July 2015 TUMOR NECROSIS FACTOR ALPHA CONVERTING ENZYME INHIBITION DURING ACUTE COLITIS IN MICE: A REGIONAL ANALYSIS Biomedical Sciences Missouri State University, July 2015 Master of Science Brian Maddox ABSTRACT Tumor Necrosis Factor-α Converting Enzyme (TACE) induces active TNFα and may contribute to the development of colitis in humans. I hypothesized that pharmacological blockade of TNFα production would improve colitis scoring through decreased expression of inflammatory biomarkers. Acute colitis was induced in wild type BALB/c mice using 5% dextran sulfate sodium (DSS) in drinking water for 7 days. TACE inhibition was accomplished through twice daily intraperitoneal injection of DPC- 333 (10mg/kg; BSM Inc.) To determine the effects of TACE blockade during colitis, the following experimental groups (n=6-7/group) were tested: 1) vehicle; 2) DPC-333; 3) 5% DSS and vehicle; and 4) 5% DSS and DPC-333. Twice daily TACE inhibition did not significantly improve overall colitis scoring index as determined by the presence of diarrhea, rectal bleeding, and percent weight loss. TNFα, IL-6, Il-1β, IL-10, and MPO in regional colon tissue were not reduced following DPC-333 in this model (p<0.05). Thus, TACE inhibition does not appear to reduce colitis scoring, TNFα production, or other regional biomarkers of inflammation in this model of experimental colitis. Future studies may ascertain the role of TACE during systemic inflammatory diseases. KEYWORDS: TNFα converting enzyme, colitis, inflammation This abstract is approved as to form and content _______________________________ Tyler Morris Chairperson, Advisory Committee Missouri State University ii TUMOR NECROSIS FACTOR ALPHA CONVERTING ENZYME INHIBITION DURING ACUTE COLITIS IN MICE: A REGIONAL ANALYSIS By Brian Maddox A Masters Thesis Submitted to the Graduate College Of Missouri State University In Partial Fulfillment of the Requirements For the Degree of Master of Science, Cell and Molecular Biology July 2015 Approved: _______________________________________ Tyler Morris, PhD _______________________________________ Paul Durham, PhD _______________________________________ Jianjie Wang, MD, PhD _______________________________________ Julie Masterson, PhD: Dean, Graduate College iii ACKNOWLEDGEMENTS I would like to thank my mentor, Dr. Morris, for insight, encouragement, and understanding throughout completion of this project and writing of this thesis. I would also like to thank my committee members, Dr. Paul Durham and Dr. Jainjie Wang for their expert advice and input on the project and thesis. In addition, I would like to thank my project collaborator Tricia Haynes. Our laboratory undergraduates Zach Harter, James Norris, and Kate Sanders have been an indispensable addition to the project, making an overwhelming workload manageable. This project was made possible through funding from Missouri State University, by a Faculty Research Grant and thesis research funding from the Graduate College. Finally, I would like to thank my friends and family; their personal support has truly made this work possible. iv TABLE OF CONTENTS Introduction ..........................................................................................................................1 Clinical Inflammatory Bowel Disease .....................................................................1 Tumor Necrosis Factor-α and Inflammatory Signaling ...........................................8 Tumor Necrosis Factor-α Converting Enzyme ......................................................18 Neutrophil Recruitment and Myeloperoxidase ......................................................24 A Colitis Mouse Model with Dextran Sulfate Sodium ..........................................25 Hypotheses and Rationale ......................................................................................27 Materials and Methods .......................................................................................................27 Animals and Induction of Colitis ...........................................................................29 Dosing of DPC-333................................................................................................29 Study Design ..........................................................................................................30 Disease Activity Index (DAI) Methodology and Scoring .....................................31 Blood and Tissue Sample Collection .....................................................................32 Tissue Homogenization .........................................................................................33 Pierce Bicinchonicic Acid Assay ...........................................................................34 Cytokine Quantification .........................................................................................35 MPO Quantification ...............................................................................................38 Statistics .................................................................................................................39 Results ...............................................................................................................................41 Clinical Presentation of 5% DSS Colitis ...............................................................41 Plasma Cytokine Levels .........................................................................................45 Colon Cytokine Levels ..........................................................................................46 Overview of Colon Cytokine Levels during DSS Colitis and TACE Inhibition ...50 Colon Tissue Myeloperoxidase Levels ..................................................................53 Discussion ..........................................................................................................................55 Clinical Evaluation of DSS Colitis and Effect of TACE Inhibition ......................55 Effect of DSS on Inflammatory Cytokines ............................................................55 Effect of TACE Inhibition on Inflammatory Cytokine Concentrations ................59 Overview of Colon Cytokine Concentrations ........................................................60 Effect of DSS on Colon Neutrophil Recruitment as Determined by MPO Levels ......................................................................................................61 Effect of TACE Inhibition on Colon MPO Levels during Development of Colitis.................................................................................................................62 Conclusions ............................................................................................................62 Limitations of Data ................................................................................................66 Future Study ...........................................................................................................68 References ..........................................................................................................................71 v LIST OF TABLES Table 1. Clinical Scoring Parameters and Scoring Guide of Disease Activity Index ........32 Table 2. Statistical Analysis of Clinical Parameters in Colitis Development ....................46 Table 3. TACE Inhibition and Percent Difference in TNFα Levels ..................................50 Table 4. Effect of 5% DSS and TACE Inhibition on Colon MPO Concentrations ...........54 Table 5. ANOVA and Post Hoc Results of Colon IL-1β and IL-6 Concentrations in the Colon ........................................................................................................................57 vi LIST OF FIGURES Figure 1. Methods of Medical Rescue Therapy for Severe Acute Ulcerative Colitis .........7 Figure 2. Activation and Inhibition of Tumor Necrosis Factor (TNF) and TNF receptor (TNFR) .................................................................................................................................9
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