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Andrea M Stringer - One of the best experts on this subject based on the ideXlab platform.
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Dark Agouti Rat model of chemotherapy induced mucositis establishment and current state of the art
Experimental Biology and Medicine, 2015Co-Authors: Barbara Vanhoecke, Emma Bateman, Bronwen Mayo, Eline Vanlancker, Andrea M Stringer, Daniel Thorpe, Dorothy M K KeefeAbstract:Mucositis is a major oncological problem. The entire gastrointestinal and genitourinary tract and also other mucosal surfaces can be affected in recipients of radiotherapy, and/or chemotherapy. Major progress has been made in recent years in understanding the mechanisms of oral and small intestinal mucositis, which appears to be more prominent than colonic damage. This progress is largely due to the development of representative laboRatory animal models of mucositis. This review focuses on the development and establishment of the Dark Agouti Rat mammary adenocarcinoma model by the Mucositis Research Group of the University of Adelaide over the past 20 years to characterize the mechanisms underlying methotrexate-, 5-fluorouracil-, and irinotecan-induced mucositis. It also aims to summarize the results from studies using different animal model systems to identify new molecular and cellular markers of mucositis.
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irinotecan induced alteRations in intestinal cell kinetics and extracellular matrix component expression in the Dark Agouti Rat
International Journal of Experimental Pathology, 2011Co-Authors: Andrea M Stringer, Richard M Logan, Joanne M Bowen, Rachel J Gibson, Noor AldasooqiAbstract:Chemotherapy-induced mucositis is characterized by damage of mucous membranes throughout the alimentary tract (AT). Extracellular matrix (ECM) components play a vital role in maintaining mucosal barrier integrity by regulating cellular apoptosis, prolifeRation and differentiation of overlying epithelial cells. The aims of this study were to characterize the changes in epithelial cell kinetics and to investigate the expression of the ECM components in the gastrointestinal tract following irinotecan administRation. Female Dark Agouti Rats were treated with single 200 mg/kg dose irinotecan and killed at various time points (1, 6, 24, 48, 72, 96 and 14 h) after treatment. Ki67 immunostaining and TUNEL were used to assess prolifeRation and apoptosis, respectively, in the jejunum and colon. Masson trichrome staining and picro-sirius red staining were used to determine the level of collagen, and immunohistochemistry was used to further assess collagen IV, fibronectin and laminin 1 and 2 expression in these tissues. Irinotecan halved cellular prolifeRation in the jejunum and colon at 48 and 24 h, respectively, while apoptosis peaked at 6 h (P < 0.05). There was a substantial increase in total collagen deposits around crypts from 24 h in both regions. However, collagen IV expression decreased significantly in the crypt region in a delayed fashion (P < 0.05). Fibronectin expression decreased significantly in jejunum and colon from 6 to 24 h following treatment (P < 0.05). Irinotecan induced a significant alteRation in epithelial cell kinetics in both the jejunum and colon, and this correlated with changes in ECM component expression. Changes in ECM expression may have a direct impact on the loss of mucosal layer integrity evident in chemotherapy-induced mucositis.
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matrix metalloproteinases are possible mediators for the development of alimentary tract mucositis in the Dark Agouti Rat
Experimental Biology and Medicine, 2010Co-Authors: Andrea M Stringer, Richard M Logan, Joanne M Bowen, Rachel J Gibson, Noor AldasooqiAbstract:Alimentary tract (AT) mucositis is a serious and debilitating side-effect of cancer therapy primarily characterized by damage of the mucous membranes throughout the AT. It is well established that this damage is a result of up-regulation of stress response genes and pro-inflammatory cytokines. Matrix metalloproteinases (MMPs) have been shown to function in several of the pathways known to be up-regulated in mucositis and play a key role in tissue injury and inflammation in many gastrointestinal disorders. This study aims to characterize the expression of multiple MMPs including MMP-1, -2, -3, -9 and -12 and their inhibitors, tissue inhibitor of metalloproteinase (TIMP)-1 and -2, in a Rat model of irinotecan-induced mucositis. Dark Agouti Rats were administered a single 200 mg/kg intraperitoneal dose of irinotecan and killed at 1, 6, 24, 48, 72, 96 and 144 h following treatment. Hematoxylin and eosin staining, immunohistochemistry and realtime polymerase chain reaction were used to assess histopathological damage and MMP expression in the jejunum and colon. Marked histopathological evidence of mucositis was observed in the jejunum and colon as early as six hours following irinotecan treatment. A significant alteRation in both gene expression and tissue levels of MMPs and TIMPs was noted following irinotecan. The increase in MMP-2, -3, -9 and -12 levels was associated with inflammatory infiltRate and maximum tissue damage. In contrast, MMP-1 expression correlated with tissue restitution. TIMP-1 and -2 levels were significantly altered in the jejunum following irinotecan. The augmentation in the expression profiles of MMPs and their inhibitors correlated with histopathological alteRations observed in the tissue following irinotecan. This prompts the consideRation of MMPs as possible mediators of chemotherapy-induced mucositis.
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is the pathobiology of chemotherapy induced alimentary tract mucositis influenced by the type of mucotoxic drug administered
Cancer Chemotherapy and Pharmacology, 2009Co-Authors: Richard M Logan, Andrea M Stringer, Dorothy M K Keefe, Joanne M Bowen, Rachel J Gibson, Stephen T SonisAbstract:Purpose Alimentary tract (AT) mucositis is a serious problem complicating cancer treatment, however, its pathobiology remains incompletely understood. Nuclear factor-κB (NF-κB) and pro-inflammatory cytokines are considered to have important roles in its development. This has been previously demonstRated in different sites of the AT following administRation of irinotecan in an animal model using the Dark Agouti Rat. The aim of the present study was to determine whether the changes that occur in the AT are affected by the type of mucotoxic drug.
Dorothy M K Keefe - One of the best experts on this subject based on the ideXlab platform.
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Dark Agouti Rat model of chemotherapy induced mucositis establishment and current state of the art
Experimental Biology and Medicine, 2015Co-Authors: Barbara Vanhoecke, Emma Bateman, Bronwen Mayo, Eline Vanlancker, Andrea M Stringer, Daniel Thorpe, Dorothy M K KeefeAbstract:Mucositis is a major oncological problem. The entire gastrointestinal and genitourinary tract and also other mucosal surfaces can be affected in recipients of radiotherapy, and/or chemotherapy. Major progress has been made in recent years in understanding the mechanisms of oral and small intestinal mucositis, which appears to be more prominent than colonic damage. This progress is largely due to the development of representative laboRatory animal models of mucositis. This review focuses on the development and establishment of the Dark Agouti Rat mammary adenocarcinoma model by the Mucositis Research Group of the University of Adelaide over the past 20 years to characterize the mechanisms underlying methotrexate-, 5-fluorouracil-, and irinotecan-induced mucositis. It also aims to summarize the results from studies using different animal model systems to identify new molecular and cellular markers of mucositis.
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is the pathobiology of chemotherapy induced alimentary tract mucositis influenced by the type of mucotoxic drug administered
Cancer Chemotherapy and Pharmacology, 2009Co-Authors: Richard M Logan, Andrea M Stringer, Dorothy M K Keefe, Joanne M Bowen, Rachel J Gibson, Stephen T SonisAbstract:Purpose Alimentary tract (AT) mucositis is a serious problem complicating cancer treatment, however, its pathobiology remains incompletely understood. Nuclear factor-κB (NF-κB) and pro-inflammatory cytokines are considered to have important roles in its development. This has been previously demonstRated in different sites of the AT following administRation of irinotecan in an animal model using the Dark Agouti Rat. The aim of the present study was to determine whether the changes that occur in the AT are affected by the type of mucotoxic drug.
Rachel J Gibson - One of the best experts on this subject based on the ideXlab platform.
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irinotecan induced alteRations in intestinal cell kinetics and extracellular matrix component expression in the Dark Agouti Rat
International Journal of Experimental Pathology, 2011Co-Authors: Andrea M Stringer, Richard M Logan, Joanne M Bowen, Rachel J Gibson, Noor AldasooqiAbstract:Chemotherapy-induced mucositis is characterized by damage of mucous membranes throughout the alimentary tract (AT). Extracellular matrix (ECM) components play a vital role in maintaining mucosal barrier integrity by regulating cellular apoptosis, prolifeRation and differentiation of overlying epithelial cells. The aims of this study were to characterize the changes in epithelial cell kinetics and to investigate the expression of the ECM components in the gastrointestinal tract following irinotecan administRation. Female Dark Agouti Rats were treated with single 200 mg/kg dose irinotecan and killed at various time points (1, 6, 24, 48, 72, 96 and 14 h) after treatment. Ki67 immunostaining and TUNEL were used to assess prolifeRation and apoptosis, respectively, in the jejunum and colon. Masson trichrome staining and picro-sirius red staining were used to determine the level of collagen, and immunohistochemistry was used to further assess collagen IV, fibronectin and laminin 1 and 2 expression in these tissues. Irinotecan halved cellular prolifeRation in the jejunum and colon at 48 and 24 h, respectively, while apoptosis peaked at 6 h (P < 0.05). There was a substantial increase in total collagen deposits around crypts from 24 h in both regions. However, collagen IV expression decreased significantly in the crypt region in a delayed fashion (P < 0.05). Fibronectin expression decreased significantly in jejunum and colon from 6 to 24 h following treatment (P < 0.05). Irinotecan induced a significant alteRation in epithelial cell kinetics in both the jejunum and colon, and this correlated with changes in ECM component expression. Changes in ECM expression may have a direct impact on the loss of mucosal layer integrity evident in chemotherapy-induced mucositis.
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matrix metalloproteinases are possible mediators for the development of alimentary tract mucositis in the Dark Agouti Rat
Experimental Biology and Medicine, 2010Co-Authors: Andrea M Stringer, Richard M Logan, Joanne M Bowen, Rachel J Gibson, Noor AldasooqiAbstract:Alimentary tract (AT) mucositis is a serious and debilitating side-effect of cancer therapy primarily characterized by damage of the mucous membranes throughout the AT. It is well established that this damage is a result of up-regulation of stress response genes and pro-inflammatory cytokines. Matrix metalloproteinases (MMPs) have been shown to function in several of the pathways known to be up-regulated in mucositis and play a key role in tissue injury and inflammation in many gastrointestinal disorders. This study aims to characterize the expression of multiple MMPs including MMP-1, -2, -3, -9 and -12 and their inhibitors, tissue inhibitor of metalloproteinase (TIMP)-1 and -2, in a Rat model of irinotecan-induced mucositis. Dark Agouti Rats were administered a single 200 mg/kg intraperitoneal dose of irinotecan and killed at 1, 6, 24, 48, 72, 96 and 144 h following treatment. Hematoxylin and eosin staining, immunohistochemistry and realtime polymerase chain reaction were used to assess histopathological damage and MMP expression in the jejunum and colon. Marked histopathological evidence of mucositis was observed in the jejunum and colon as early as six hours following irinotecan treatment. A significant alteRation in both gene expression and tissue levels of MMPs and TIMPs was noted following irinotecan. The increase in MMP-2, -3, -9 and -12 levels was associated with inflammatory infiltRate and maximum tissue damage. In contrast, MMP-1 expression correlated with tissue restitution. TIMP-1 and -2 levels were significantly altered in the jejunum following irinotecan. The augmentation in the expression profiles of MMPs and their inhibitors correlated with histopathological alteRations observed in the tissue following irinotecan. This prompts the consideRation of MMPs as possible mediators of chemotherapy-induced mucositis.
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is the pathobiology of chemotherapy induced alimentary tract mucositis influenced by the type of mucotoxic drug administered
Cancer Chemotherapy and Pharmacology, 2009Co-Authors: Richard M Logan, Andrea M Stringer, Dorothy M K Keefe, Joanne M Bowen, Rachel J Gibson, Stephen T SonisAbstract:Purpose Alimentary tract (AT) mucositis is a serious problem complicating cancer treatment, however, its pathobiology remains incompletely understood. Nuclear factor-κB (NF-κB) and pro-inflammatory cytokines are considered to have important roles in its development. This has been previously demonstRated in different sites of the AT following administRation of irinotecan in an animal model using the Dark Agouti Rat. The aim of the present study was to determine whether the changes that occur in the AT are affected by the type of mucotoxic drug.
Joanne M Bowen - One of the best experts on this subject based on the ideXlab platform.
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irinotecan induced alteRations in intestinal cell kinetics and extracellular matrix component expression in the Dark Agouti Rat
International Journal of Experimental Pathology, 2011Co-Authors: Andrea M Stringer, Richard M Logan, Joanne M Bowen, Rachel J Gibson, Noor AldasooqiAbstract:Chemotherapy-induced mucositis is characterized by damage of mucous membranes throughout the alimentary tract (AT). Extracellular matrix (ECM) components play a vital role in maintaining mucosal barrier integrity by regulating cellular apoptosis, prolifeRation and differentiation of overlying epithelial cells. The aims of this study were to characterize the changes in epithelial cell kinetics and to investigate the expression of the ECM components in the gastrointestinal tract following irinotecan administRation. Female Dark Agouti Rats were treated with single 200 mg/kg dose irinotecan and killed at various time points (1, 6, 24, 48, 72, 96 and 14 h) after treatment. Ki67 immunostaining and TUNEL were used to assess prolifeRation and apoptosis, respectively, in the jejunum and colon. Masson trichrome staining and picro-sirius red staining were used to determine the level of collagen, and immunohistochemistry was used to further assess collagen IV, fibronectin and laminin 1 and 2 expression in these tissues. Irinotecan halved cellular prolifeRation in the jejunum and colon at 48 and 24 h, respectively, while apoptosis peaked at 6 h (P < 0.05). There was a substantial increase in total collagen deposits around crypts from 24 h in both regions. However, collagen IV expression decreased significantly in the crypt region in a delayed fashion (P < 0.05). Fibronectin expression decreased significantly in jejunum and colon from 6 to 24 h following treatment (P < 0.05). Irinotecan induced a significant alteRation in epithelial cell kinetics in both the jejunum and colon, and this correlated with changes in ECM component expression. Changes in ECM expression may have a direct impact on the loss of mucosal layer integrity evident in chemotherapy-induced mucositis.
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matrix metalloproteinases are possible mediators for the development of alimentary tract mucositis in the Dark Agouti Rat
Experimental Biology and Medicine, 2010Co-Authors: Andrea M Stringer, Richard M Logan, Joanne M Bowen, Rachel J Gibson, Noor AldasooqiAbstract:Alimentary tract (AT) mucositis is a serious and debilitating side-effect of cancer therapy primarily characterized by damage of the mucous membranes throughout the AT. It is well established that this damage is a result of up-regulation of stress response genes and pro-inflammatory cytokines. Matrix metalloproteinases (MMPs) have been shown to function in several of the pathways known to be up-regulated in mucositis and play a key role in tissue injury and inflammation in many gastrointestinal disorders. This study aims to characterize the expression of multiple MMPs including MMP-1, -2, -3, -9 and -12 and their inhibitors, tissue inhibitor of metalloproteinase (TIMP)-1 and -2, in a Rat model of irinotecan-induced mucositis. Dark Agouti Rats were administered a single 200 mg/kg intraperitoneal dose of irinotecan and killed at 1, 6, 24, 48, 72, 96 and 144 h following treatment. Hematoxylin and eosin staining, immunohistochemistry and realtime polymerase chain reaction were used to assess histopathological damage and MMP expression in the jejunum and colon. Marked histopathological evidence of mucositis was observed in the jejunum and colon as early as six hours following irinotecan treatment. A significant alteRation in both gene expression and tissue levels of MMPs and TIMPs was noted following irinotecan. The increase in MMP-2, -3, -9 and -12 levels was associated with inflammatory infiltRate and maximum tissue damage. In contrast, MMP-1 expression correlated with tissue restitution. TIMP-1 and -2 levels were significantly altered in the jejunum following irinotecan. The augmentation in the expression profiles of MMPs and their inhibitors correlated with histopathological alteRations observed in the tissue following irinotecan. This prompts the consideRation of MMPs as possible mediators of chemotherapy-induced mucositis.
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is the pathobiology of chemotherapy induced alimentary tract mucositis influenced by the type of mucotoxic drug administered
Cancer Chemotherapy and Pharmacology, 2009Co-Authors: Richard M Logan, Andrea M Stringer, Dorothy M K Keefe, Joanne M Bowen, Rachel J Gibson, Stephen T SonisAbstract:Purpose Alimentary tract (AT) mucositis is a serious problem complicating cancer treatment, however, its pathobiology remains incompletely understood. Nuclear factor-κB (NF-κB) and pro-inflammatory cytokines are considered to have important roles in its development. This has been previously demonstRated in different sites of the AT following administRation of irinotecan in an animal model using the Dark Agouti Rat. The aim of the present study was to determine whether the changes that occur in the AT are affected by the type of mucotoxic drug.
Céline Demougeot - One of the best experts on this subject based on the ideXlab platform.
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pristane induced arthritis in Dark Agouti Rat is a relevant model for mimicking vascular dysfunction and lipid paradox in rheumatoid arthritis
Joint Bone Spine, 2019Co-Authors: Mickaël Chouk, Romain Bordy, Johnny Moretto, Perle Totoson, Daniel Wendling, Céline DemougeotAbstract:OBJECTIVES To understand the pathophysiology of cardiovascular (CV) dysfunction in rheumatoid arthritis (RA) is crucial, but limited by the paucity of animal models able to mimic CV impairments. We wanted to determine if the Rat model of Pristane-Induced Arthritis (PIA) reproduced cardiometabolic impairments of RA. METHODS Dark Agouti Rats received an injection of pristane or saline (controls) at day 0. Reactivity to vasoconstrictors and vasodilators was studied in aortic rings and mesenteric arteries at day 28 (acute) and day 120 post-induction (chronic phase). Circulating markers of inflammation, lipid and glucose levels, arthritis and radiographic scores were assessed. RESULTS In aortic rings, PIA induced a reduced vasoconstriction to phenylephrine and serotonin in both phases of the model. The relaxant effect of acetylcholine was decreased in PIA in acute (P < 0.05) but not in chronic phase. In mesenteric arteries, only the acetylcholine-induced vasorelaxation was impaired in PIA Rats in the chronic phase (P < 0.001). Serum interleukin-6 levels were higher, total cholesterol and triglycerides levels were lower in PIA in both phases (P < 0.001) whereas myeloperoxidase activity and blood glucose were unchanged. Adiponectine levels were lower in PIA in acute (P < 0.001) but not in chronic phase. Endothelial function correlated with interleukin-6, total cholesterol levels and arthritis score in aorta but not in mesenteric arteries. CONCLUSIONS As new information, PIA induces endothelial dysfunction in micro-/macro-vascular beds and low lipid levels, like in RA. This model of chronic arthritis might be useful to study CV pathophysiology and to screen new therapeutic options for reducing CV risk in RA.
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SAT0102 Pristane-induced arthritis in Dark Agouti Rat: a new animal model to study cardiovascular dysfunction in rheumatoid arthritis
Annals of the Rheumatic Diseases, 2018Co-Authors: Mickaël Chouk, Romain Bordy, Johnny Moretto, Perle Totoson, Maude Tournier-nappey, Clement Prati, Daniel Wendling, Céline DemougeotAbstract:Background Rheumatoid arthritis (RA) is characterised by an increased cardiovascular (CV) mortality. Animal models provide the opportunity to study CV features in RA, however, most used animal models develop a “monophasic” arthritis, making those models inappropriate for long-term studies on CV impairments. Objectives The aim of this study was to characterise vascular function and cardio-metabolic parameters in the “chronic” model of pristane-induced arthritis (PIA) in Dark Agouti (DA) Rats. Methods 80 Rats DA received an intradermal injection of 150 µL of pristane (PIA) or of saline solution (controls) at day 0. Arthritis score was daily followed. Acetylcholine (Ach) and sodium nitroprusside (SNP) -induced vasorelaxation were studied in macrovascular (aortic rings pre-contracted with serotonin) and in microvascular levels (mesenteric artery segments pre-contracted with phenylephrine) at day 28 (acute phase) and day 120 (chronic phase). Radiographic score, circulating markers of inflammation, lipid and glucose levels were also measured. Results PIA Rats developed an acute arthritis phase from day 13 to day 50 followed by a remission phase, then by a chronic arthritis phase from day 70 to day 120. Radiographic score was higher in chronic than in acute phase in PIA (p Conclusions PIA model shares several features of the CV alteRations in RA: an endothelial dysfunction at the micro- and macrovascular level with independency of course among these vascular beds, a link between inflammation and macrovascular endothelial dysfunction, associated with low lipid levels. These data suggest that this model would be very useful for long-term pharmacological studies as well for deciphering the complex pathophysiology of increased CV risk in RA. Disclosure of Interest None declared
