Subject Index Actin cellular forms 48, 49 epidermal growth factor, cytoskeletal change induction in mucosal repair 22, 23 wound repair 64, 65 polyamine effects on cytoskeleton 49 51 S-Adenosylmethionine decarboxylase inhibitors 45, 46, 48, 49 polyamine biosynthesis 44, 45 Angiogenesis alcohol injury response and growth factors 104, 105 angiogenic factors angiopoietins 110 112 basic fibroblast growth factor 110 gene therapy 217 223 peptide therapy basic fibroblast growth factor 212 215 overview 210 212 platelet-derived growth factor 215, 216 216, 217 platelet-derived growth factor 110 prostaglandins 112 110 granulation tissue and ulcer healing 109 heparin modulation 182, 183 hyperemic response to injury 101, 102 nonsteroidal anti-inflammatory drug inhibition 112, 113 platelet factor modulation endostatin 121 123 thrombospondin 123, 124 signal transduction 111, 112 submucosal vessels 101, 210 vascular damage in mucosal injury 103, 104, 210 response 105 107, 109 112 AP-1, protooncogene product interactions 84 Apoptosis Helicobacter pylori induction in epithelial cells 147, 148 ischemia/reperfusion injury response in intestinal mucosa 137, 138 Aspirin, see also Nonsteroidal anti-inflammatory drugs challenge protection by diacylglycerol/protein kinase C pathway 71, 72 gastric damage mechanisms 158, 159 Basic fibroblast growth factor angiogenesis promotion 110 peptide therapy chronic duodenal ulcer 212, 213 chronic gastric ulcer 213 chronic gastritis 213, 214 inflammatory bowel disease 214, 215 244
ulcer healing role 118 Bicarbonate, prostaglandins in duodenal cytoprotection 235, 236 Calcium signaling, epithelial restitution cell mobility modulation 30, 32 34 diacylglycerol/protein kinase C pathway, see Diacylglycerol/protein kinase C pathway homeostasis regulation membrane potential and calcium driving force 34 36, 39 transient receptor potential channels 36 voltage-gated calcium channels 34, 35 in vitro studies 31 34 in vivo studies 30, 31 intracellular sources 29 polyamine signaling interactions 49, 50 prospects for study 40 targets overview 36 Rho 37, 38 effectors 39 Capsaicin, gastroprotection 230, 231 -Catenin, cell-cell interaction alterations in mucosal repair 24 Cornea, protooncogene role in healing 88, 89 Cyclooxygenase COX-1 inhibition gastric mucosa effects 167, 168 gastroprotective agent interactions 172, 173 mucosal defense effects 168, 169 mucosal repair and healing effects 174, 175 COX-2 inhibition comparison with NO-NSAIDs 162, 163 gastric mucosa effects 168 gastroprotective agent interactions 172, 173 mucosal defense effects 168, 169 mucosal repair and healing effects 173 175 rationale for specific inhibition 167 gastric mucosal damage minimization and inhibition effects 169 171, 175, 176 Helicobacter pylori induction of COX-2 172 inhibitor specificity 166, 167 intestinal immune response and inflammation role of COX-2 171, 172 isoforms 162, 163, 166 Cytokines, see also specific cytokines cell-cell interaction alterations in mucosal repair 23, 24 cell-matrix interaction alterations in mucosal repair 24 26 cell migration stimulation in mucosal restitution 17 21 cytoskeletal change induction in mucosal repair 22, 23 mucosal repair regulation 21, 22 receptor signaling 17 secretion at mucosal injury site 15, 17 Cytoskeleton, see Actin, Myosin Diacylglycerol/protein kinase C pathway aspirin challenge gastric protection studies 71, 72 intestinal injury protection Caco-2 cell studies 72 74 colonic mucosal sample studies 75 experimental colitis model 75 IEC-18 studies 75, 76 modeling of gastrointestinal injury and protection 78, 79 OAG protection against cellular injury 70, 74 prostaglandin cytoprotection modulation 70 protein kinase C isoforms and families gastric cytoprotection 72 injury vs protection roles 76 78 intestinal cytoprotection 74 76 overview 70 Endostatin, angiogenesis modulation 121 123 EP receptors, see Prostaglandins Subject Index 245
Epidermal growth factor actin cytoskeletal change induction in mucosal repair 22, 23 cell-cell interaction alterations in mucosal repair 24 cell-matrix interaction alterations in mucosal repair 25, 26 enterocyte migration role 5, 6 receptor signaling 23 recombinant protein therapy 149 ulcer healing role 118, 119 Epithelium barrier function, restoration phases 14 intestinal, see Intestinal epithelium restitution, see Wound healing ERM proteins, cytoskeletal regulation 39 Ethanol, cytoskeletal effects in gastric wound repair 6 Extracellular matrix components 24, 25 cytokines, cell-matrix interaction alterations in mucosal repair 24 26 intestinal epithelium healing effects 4, 5 wound repair 65 67 protease functions 26 Extracellular-regulated kinase integrin receptor signaling 6, 7 myosin light chain kinase as target 7 Fibroblast, cytokine secretion 15, 17 Fish oil, ischemia/reperfusion injury protection of intestinal mucosa 138, 139 Focal adhesion kinase integrin receptor signaling 6, 7 wound repair 65, 66 polyamine modulation 51, 52 c-fos, see Protooncogenes Gene therapy definition 217 platelet-derived growth factor chronic duodenal ulcer 218, 219 inflammatory bowel disease 219 221 prospects 223 chronic duodenal ulcer 221, 222 chronic gastric ulcer 222 inflammatory bowel disease 222, 223 vectors 217, 218 Helicobacter pylori COX-2 induction 172 eradication regimens 153, 154 gastroduodenal mucosa injury acid secretion induction 146, 147 apoptosis of epithelial cells 147, 148 inflammation and immune response 146, 209 virulence factors alcohol dehydrogenase 145 CagA 145 lipopolysaccharide 145 phospholipases 145 proteases 145 urease 144 VacA 144, 145 healing inhibition cell proliferation effects 150 growth factor interference 148 150 mucosal healing 150, 151 inducible nitric oxide synthase gene induction 199, 200 nonsteroidal anti-inflammatory drug interactions mucosal adaptation to aspirin 152 mucosal healing 152 ulceration and bleeding incidence 151, 152 use effects on infection incidence 151 prevalence of infection 143 Heme oxygenase-1 inducible nitric oxide interactions 202, 203 inflammation role 202 Heparin angiogenesis modulation 182, 183 anticoagulation 182 cell proliferation effects 183 Helicobacter pylori binding 149 inflammation inhibition 183, 184 structure 182 Subject Index 246
Hepatocyte growth factor, ulcer healing role 118, 120, 121 Histamine, ischemia/reperfusion injury response in intestinal mucosa 134 136 Hypoxia-inducible factor-1, vascular endothelial growth factor gene activation 107, 108 Inflammatory bowel disease gene therapy platelet-derived growth factor 219 221 222, 223 growth factor therapy, see specific factors inducible nitric oxide synthase detection animal models 191, 192 human studies 192 Insulin-like growth factor, ulcer healing role 118 Integrins cell migration and wound closure role in intestine 5, 6 cell-matrix interaction alterations in mucosal repair 25 wound repair 65, 66 polyamine role in signaling 51 receptor signal transduction 6, 7 Interferon-, epithelial cell restitution role 18 Interleukin-1, epithelial cell restitution role interleukin-1 19, 20 interleukin-1 18 Interleukin-2 epithelial cell restitution role 17, 18 sources 17 Interleukin-4, endothelial activation 89 Interleukin-8, epithelial cell restitution role 20 Intestinal epithelium cell lines 3 functions 1 injury, see also Ischemia/reperfusion injury, intestinal mucosa actomyosin contraction in cell movement 7 10 epithelial cell phenotypic shift 2 extracellular matrix, direct and independent effects in healing 4, 5 fence assay of healing 4 integrins cell migration role 5, 6 receptor signal transduction 6, 7 mucosal sheet model 3 prospects for study 10, 11 wound healing overview 1, 2 mechanical strain effects 63 polyamines in restitution, see Polyamines, intestinal epithelium restitution Ischemia/reperfusion injury, intestinal mucosa apoptosis of enterocytes 137, 138 assessment 129 fish oil protection 138, 139 lipid absorption mechanisms of impairment 132, 133 monitoring of injury 130, 139, 140 rat studies 130 132 phases 129 repair and restoration 134 137 ITF cell-cell interaction alterations in mucosal repair 23, 24 epithelial cell restitution role 21 c-jun, see Protooncogenes Keratinocyte growth factor, epithelial cell restitution role 20 Macrophage, cytokine secretion 15 Mechanical strain airway epithelium effects 62, 63 gastric forces 57 gastric wound repair clinical implications 67 Flexercell Strain Unit stretching of cells 59, 61, 62 mechanisms of inhibition cytoskeletal system 64, 65 extracellular matrix adhesion 65 67 Subject Index 247
Mechanical strain (continued) gastric wound repair (continued) RGM-1 cell model 58, 59, 61, 62 smooth muscle effects 62 growth factor induction 57 intestinal epithelium effects 63 Mesenchymal cell, cytokine secretion 15 Mitogen-activated protein kinase, see also Extracellular-regulated kinase wound repair 65, 66 Ras pathway in vascular endothelial growth factor activation 106, 107 signaling 110, 111 Mucin, prostaglandin regulation of secretion 238, 239 Mucosal restitution, see Wound healing c-myc, see Protooncogenes Myosin intestinal epithelial cell contraction and migration 7, 8 myosin light chain kinase role in movement 8 10 phosphorylation 7, 8 polyamine effects on cytoskeleton 49, 50, 52 Nitric oxide cytoprotective vs cytotoxic effects 194, 195, 238 donors 159, 160 immune response 191 mucosal homeostasis role 159, 160 mucosal injury response 102 nonsteroidal anti-inflammatory drug conjugates aspirin conjugates 161 cyclooxygenase-2 inhibitor comparisons 162, 163 mechanisms of action 161, 162 rationale for use 160, 163, 164 peroxynitrite cytotoxic effects 195, 196, 201 superoxide interactions 201, 202 synthases, see Nitric oxide synthase Nitric oxide synthase cell distribution 190 inducible enzyme cytoprotective vs cytotoxic effects 194, 195 detection in inflammatory bowel diseases animal models 191, 192 human studies 192 endothelial and epithelial injury role 192 194 heme oxygenase-1 interactions 202, 203 induction of gene expression Helicobacter pylori 199, 200 lipopolysaccharide 200, 201 inhibition rationale 203 inhibitor studies 196 198 knockout consequences 198 peroxynitrite cytotoxic effects 195, 196 isoforms 102, 103, 190 Nonsteroidal anti-inflammatory drugs, see also Aspirin angiogenesis inhibition 112, 113 gastric damage mechanisms 158, 159 Helicobacter pylori interactions mucosal adaptation to aspirin 152 mucosal healing 152 ulceration and bleeding incidence 151, 152 use effects on infection incidence 151 nitric oxide conjugates aspirin conjugates 161 cyclooxygenase-2 inhibitor comparisons 162, 163 mechanisms of action 161, 162 rationale for use 160, 163, 164 prostaglandin protection against damage, see Prostaglandins Nuclear factor- B, gastric ulcer healing role 87 Ornithine decarboxylase Dong Quai induction 185, 186 inhibitors 45, 90, 91 ischemia/reperfusion injury response in intestinal mucosa 134, 137 Subject Index 248
polyamine biosynthesis 44, 45 stress effects on expression 91 Peroxynitrite, cytotoxic effects 195, 196, 201 Phosphatidylinositol 3 -kinase, angiogenesis signaling 111, 112 Platelet angiogenesis modulation endostatin 121 123 thrombospondin 123, 124 granules 118 ulcer healing role accumulation at injury site 125, 126 clinical manipulation 126, 127 growth factors 118 121 overview 124, 125 Platelet-derived growth factor angiogenesis promotion 110 gene therapy chronic duodenal ulcer 218, 219 inflammatory bowel disease 219 221 peptide therapy chronic duodenal ulcer 215 chronic gastric ulcer 215, 216 chronic gastritis 216 inflammatory bowel disease 216 ulcer healing role 118, 120 Polyamines, intestinal epithelium restitution biosynthesis 44, 45 calcium signaling interactions 49, 50 cell migration and proliferation effects 43 cytoskeletal modulation 49 52 deficiency 46, 47 discovery 43 in vitro models 47, 48 inhibitor studies 46, 48, 49 integrin signaling role 51 model 52 nucleic acid interactions 90, 95 protooncogene expression regulation inhibitor studies 91, 93, 94 posttranscriptional regulation 95 97 spermidine response 93, 94 transcriptional regulation mechanisms 95 RhoA interactions 50 toxicity 45, 46 transport 46 Polysaccharides, gastrointestinal protection Dong Quai polysaccharides 185, 186 ginseng polysaccharides 185, 186 heparin, see Heparin mushroom polysaccharides 184, 185 seaweed polysaccharides 184, 185 sources and pharmacological actions, overview 180, 181 ulcer formation and healing, polysaccharide mechanisms 187 Prostaglandins cyclooxygenase inhibition effects, see Cyclooxygenase diacylglycerol/ protein kinase C signaling, see Diacylglycerol/protein kinase C pathway inhibition in mucosal damage 158, 159 metabolism 166 PGE 2 angiogenesis promotion 112 calcium modulation of effects 32, 33 duodenal cytoprotection 235, 236 EP receptor subtypes and agonists 227, 228, 231, 232, 239, 240 gastric cytoprotection acid secretion inhibition 231 EP receptor knockout effects 229 231, 240 hydrochloric acid/ethanol-induced gastric damage 228 231 indomethacin-induced gastric damage 231 motility effects 232 234 neutrophil inhibition 234 overview 69, 70 intestinal cytoprotection functional alterations in protection 238, 239 indomethacin-induced damage 236, 237 synthesis 167, 227 therapeutic prospects 240 Protein kinase C, see Diacylglycerol/ protein kinase C pathway Subject Index 249
Protooncogenes cell cycle regulation 82, 83 corneal healing role 88, 89 endothelial cell expression in response to injury 89 heterodimerization of proteins 83, 84 polyamine regulation of expression posttranscriptional regulation 95 97 regulation inhibitor studies 91, 93, 94 spermidine response 93, 94 transcriptional regulation mechanisms 95 prospects for wound healing studies 97, 98 ulcer healing role cell renewal and ulceration 84, 85 cellular sources 87, 88 expression c-fos 85, 86 c-jun 87 c-myc 85 87 wounding response and activation of expression 83, 84 Putrescine, see Polyamines, intestinal epithelium restitution Rebamipide, cyclooxygenase interactions 172, 173 Rho activation 37 calcium regulation 37, 38 effectors 39 wound repair 65, 66 RhoA cell migration role during wound healing 37, 40 polyamine interactions 50 Spermidine, see Polyamines, intestinal epithelium restitution Spermine, see Polyamines, intestinal epithelium restitution Stress, see Mechanical strain Superoxide dismutase, nitric oxide cytotoxicity protection 201, 204 Thrombospondin, angiogenesis modulation 123, 124 Transforming growth factor-, ulcer healing role 118 120 Transforming growth factor- cell-matrix interaction alterations in mucosal repair 25, 26 epithelial cell restitution role 18, 19, 22 ulcer healing role 118 Tumor necrosis factor-, epithelial cell restitution role 19, 20 Ulcer healing, see Wound healing Vascular endothelial growth factor angiogenesis promotion and signaling 110 112 antibody inhibition studies of angiogenesis 105, 106 ethanol triggering of overexpression 105 gene activation hypoxia 107, 108 Ras pathway 106, 107 gene therapy chronic duodenal ulcer 221, 222 chronic gastric ulcer 222 inflammatory bowel disease 222, 223 mechanical strain induction 57 peptide therapy chronic duodenal ulcer 216, 217 inflammatory bowel disease 217 structure 118 ulcer healing role 118, 119 Wound healing angiogenesis, see Angiogenesis calcium signaling, see Calcium signaling, epithelial restitution cyclooxygenase role, see Cyclooxygenase cytokine role, see Cytokines diacylglycerol/protein kinase C pathway, see Diacylglycerol/protein kinase C pathway Subject Index 250
early primary response genes, see Protooncogenes epithelial barrier function, restoration phases 14 gene therapy, see Gene therapy growth factor therapy, see specific factors Helicobacter pylori effects, see Helicobacter pylori intestinal epithelium, see Intestinal epithelium polyamines in restitution, see Polyamines, intestinal epithelium restitution stress effects, see Mechanical strain Subject Index 251