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Hans-christoph Pape - One of the best experts on this subject based on the ideXlab platform.
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monotrauma is associated with enhanced Remote inflammatory response and Organ damage while polytrauma intensifies both in porcine trauma model
European Journal of Trauma and Emergency Surgery, 2020Co-Authors: Philipp Stormann, Roman Pfeifer, Hans-christoph Pape, Nils Wagner, Kernt Kohler, Birgit Auner, Timp Simon, Klemens Horst, Frank Hildebrand, Sebastian WutzlerAbstract:Aim Severely injured patients experience substantial immunological stress upon traumatic insult. Next to the direct local tissue injury also other Organs, which are not directly injured such as liver and lung, are frequently affected by a so-called Remote Organ damage (ROD) after trauma. Thus, we studied the inflammatory response of lung and liver either after isolated femur fracture as example for ROD, or after multiple trauma in a porcine polytrauma model.
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Cumulative Effects of Bone and Soft Tissue Injury on Systemic Inflammation: A Pilot Study
Clinical Orthopaedics and Related Research®, 2013Co-Authors: Roman Pfeifer, Sophie Darwiche, Lauryn Kohut, Timothy R. Billiar, Hans-christoph PapeAbstract:Background In multiply injured patients, bilateral femur fractures invoke a substantial systemic inflammatory impact and Remote Organ dysfunction. However, it is unclear whether isolated bone or soft tissue injury contributes to the systemic inflammatory response and Organ injury after fracture. Questions/purposes We therefore asked whether the systemic inflammatory response and Remote Organ dysfunction are attributable to the bone fragment injection, adjacent soft tissue injury, or both. Methods Male C57/BL6 mice (8–10 weeks old, 20–30 g) were assigned to four groups: bone fragment injection (BF, n = 9) group; soft tissue injury (STI, n = 9) group; BF + STI (n = 9) group, in which both insults were applied; and control group, in which neither insult was applied. Animals were sacrificed at 6 hours. As surrogates for systemic inflammation, we measured serum IL-6, IL-10, osteopontin, and alanine aminotransferase (ALT) and nuclear factor (NF)-κB and myeloperoxidase (MPO) in the lung. Results The systemic inflammatory response (mean IL-6 level) was similar in the BF (61.8 pg/mL) and STI (67.9 pg/mL) groups. The combination (BF + STI) of both traumatic insults induced an increase in mean levels of inflammatory parameters (IL-6: 189.1 pg/mL) but not in MPO levels (1.21 ng/mL) as compared with the BF (0.82 ng/mL) and STI (1.26 ng/mL) groups. The model produced little evidence of Remote Organ inflammation. Conclusions Our findings suggest both bone and soft tissue injury are required to induce systemic changes. The absence of Remote Organ inflammation suggests further fracture-associated factors, such as hemorrhage and fat liberation, may be more critical for induction of Remote Organ damage. Clinical Relevance Both bone and soft tissue injuries contribute to the systemic inflammatory response.
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cumulative effects of bone and soft tissue injury on systemic inflammation a pilot study
Clinical Orthopaedics and Related Research, 2013Co-Authors: Roman Pfeifer, Sophie Darwiche, Lauryn Kohut, Timothy R. Billiar, Hans-christoph PapeAbstract:Background In multiply injured patients, bilateral femur fractures invoke a substantial systemic inflammatory impact and Remote Organ dysfunction. However, it is unclear whether isolated bone or soft tissue injury contributes to the systemic inflammatory response and Organ injury after fracture.
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the degree of fracture associated soft tissue injury modifies systemic inflammation and Remote Organ dysfunction following bilateral femur fracture
Orthopaedic Proceedings, 2011Co-Authors: Philipp Kobbe, Roman Pfeifer, Philipp Lichte, Hans-christoph PapeAbstract:Patients with bilateral femur fractures are known to be at a high risk for the Systemic Inflammatory Response Syndrome; however the impact of fracture-associated soft tissue injury in the induction of systemic inflammation following bilateral femur fracture is poorly understood. To address this, the systemic inflammatory response and Remote Organ dysfunction following bilateral femur fracture with various degrees of soft tissue injuries were investigated in this study. 6–8 weeks old male C57/BL6 mice (n = 4–8 animals per group) were grouped as follows: Control-group (no anaesthesia, no femoral catheterisation); Sham-group (6 hour anaesthesia, femoral catheterisation); Fx-group (6 hour anaesthesia, femoral catheterisation, bilateral femur fracture with minor soft tissue injury); Fx+STI-group (6 hour anaesthesia, femoral catheterisation, bilateral femur fracture with severe soft tissue injury). Six hours after bilateral femur fracture serum levels of IL-2, IL-4, IL-6, IL-10, IL-12, TNF-α, KC and MCP-1 were measured. Furthermore, IL-6 levels of homogenized liver tissue were assessed. Neutrophil accumulation in liver and lung was determined with a myeloperoxidase (MPO) assay. Changes in liver permeability were assessed by measuring the wet-dry-ratio. The Fx+STI-group showed significantly increased serum cytokine levels as compared to the Fx- or Sham-group. The homogenized liver tissue of the Fx+STI-group showed significantly increased IL-6 levels as compared to the Sham-group. The MPO activity in lung and liver in the Fx+STI-group was significantly increased in comparison to the Fx- or Sham-group and in the Fx-group in comparison to the Sham-group. The wet-dry-ratio of the liver was significantly increased in the Fx+STI-group as compared to the Sham-group. The degree of fracture-associated soft tissue injury appears to modify systemic inflammation following bilateral femur fracture and is able to induce Remote Organ dysfunction. These results may have implications that have been underestimated, thus warranting clinical follow-up studies.
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Role of hemorrhage in the induction of systemic inflammation and Remote Organ damage: analysis of combined pseudo-fracture and hemorrhagic shock.
Journal of orthopaedic research : official publication of the Orthopaedic Research Society, 2010Co-Authors: Roman Pfeifer, Sophie Darwiche, Timothy R. Billiar, Philipp Kobbe, Hans-christoph PapeAbstract:This study was performed to analyze the role of hemorrhage-induced hypotension in the induction of systemic inflammation and Remote Organ dysfunction. Male C57/BL6 mice (6- to 10-week old and 20–30 g) were used. Animals were either subjected to pseudo-fracture [PF; standardized soft-tissue injury and injection of crushed bone, PF group: n = 9], or PF combined with hemorrhagic shock (HS + PF group: n = 6). Endpoint was 6 h. Systemic inflammation was assessed by IL-6 and IL-10 levels. Myeloperoxidase (MPO) and NF-κB activity in the lung and liver tissue were obtained to assess Remote Organ damage. The increases of systemic cytokines are similar for animals subjected to PF and PF + HS (IL-6: 189 pg/ml ± 32.5 vs. 160 pg/ml ± 5.3; IL-10: 60.3 pg/ml ± 15.8 vs. 88 pg/ml ± 32.4). Furthermore, the features (ALT; NF-κB) of liver injury are equally elevated in mice subjected to PF (76.9 U/L ± 4.5) and HS + PF (80 U/L ± 5.5). Lung injury, addressed by MPO activity was more severe in group HS + PF (2.95 ng/ml ± 0.32) than in group PF (1.21 ng/ml ± 0.2). Both PF and additional HS cause a systemic inflammatory response. In addition, hemorrhage seems to be associated with Remote affects on the lung. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:270–274, 2011
Paul G. Hellewell - One of the best experts on this subject based on the ideXlab platform.
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p selectin deficiency is protective against Remote Organ injury in a model of ruptured abdominal aortic aneurysm
British Journal of Surgery, 2001Co-Authors: J. B. Stewart, K. E. Norman, A. E. John, P Chan, Paul G. HellewellAbstract:Background: Multisystem Organ failure (MSOF) accounts for 50–60 per cent of postoperative deaths following repair of ruptured abdominal aortic aneurysm (AAA). A murine model is described in which the combined insults of hypotension and aortic clamping reproduce the physiological changes during repair of ruptured AAA. The resulting Remote Organ injury (the hallmark of MSOF) is prevented in the absence of the adhesion molecule P-selectin, which mediates neutrophil–endothelial interaction. Methods: C57BL6 wild-type mice (n = 4) and mice constitutively unable to express P-selectin (P–/–) (n = 4) were subjected to 60 min of controlled hypotension followed by cross-clamping of the infrarenal aorta for 60 min, reinfusion of shed blood and then 60 min of reperfusion. Controls (n = 16) were sham-operated, had hypotension only or clamp/reperfusion only. Lungs and kidneys were harvested and assayed for the neutrophil-specific marker myeloperoxidase (MPO), which indicates inflammatory infiltrate in the tissue. Results: MPO levels in the Organs of C57BL6 mice subjected to hypotension and aortic clamping were 50 times greater than those in sham-operated mice. MPO levels in sham-operated P–/– animals were similar to those in sham-operated C57BL6 mice. MPO levels in the lungs and kidneys of P–/– mice subjected to hypotension and aortic clamping were unchanged from those in sham-operated P–/– mice. Conclusion: The combined effects of hypotension and infrarenal aortic clamping, followed by reperfusion, are synergistic. This gives rise to a profound early inflammatory reaction in tissues Remote from the site of ischaemia–reperfusion, which is likely to contribute towards clinical MSOF after ruptured AAA repair. Absence of the adhesion molecule P-selectin protects against this Remote Organ injury. © 2001 British Journal of Surgery Society Ltd
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P‐selectin deficiency is protective against Remote Organ injury in a model of ruptured abdominal aortic aneurysm
British Journal of Surgery, 2001Co-Authors: J. B. Stewart, K. E. Norman, A. E. John, Philip Wing Keung Chan, Paul G. HellewellAbstract:Background: Multisystem Organ failure (MSOF) accounts for 50–60 per cent of postoperative deaths following repair of ruptured abdominal aortic aneurysm (AAA). A murine model is described in which the combined insults of hypotension and aortic clamping reproduce the physiological changes during repair of ruptured AAA. The resulting Remote Organ injury (the hallmark of MSOF) is prevented in the absence of the adhesion molecule P-selectin, which mediates neutrophil–endothelial interaction. Methods: C57BL6 wild-type mice (n = 4) and mice constitutively unable to express P-selectin (P–/–) (n = 4) were subjected to 60 min of controlled hypotension followed by cross-clamping of the infrarenal aorta for 60 min, reinfusion of shed blood and then 60 min of reperfusion. Controls (n = 16) were sham-operated, had hypotension only or clamp/reperfusion only. Lungs and kidneys were harvested and assayed for the neutrophil-specific marker myeloperoxidase (MPO), which indicates inflammatory infiltrate in the tissue. Results: MPO levels in the Organs of C57BL6 mice subjected to hypotension and aortic clamping were 50 times greater than those in sham-operated mice. MPO levels in sham-operated P–/– animals were similar to those in sham-operated C57BL6 mice. MPO levels in the lungs and kidneys of P–/– mice subjected to hypotension and aortic clamping were unchanged from those in sham-operated P–/– mice. Conclusion: The combined effects of hypotension and infrarenal aortic clamping, followed by reperfusion, are synergistic. This gives rise to a profound early inflammatory reaction in tissues Remote from the site of ischaemia–reperfusion, which is likely to contribute towards clinical MSOF after ruptured AAA repair. Absence of the adhesion molecule P-selectin protects against this Remote Organ injury. © 2001 British Journal of Surgery Society Ltd
Roman Pfeifer - One of the best experts on this subject based on the ideXlab platform.
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monotrauma is associated with enhanced Remote inflammatory response and Organ damage while polytrauma intensifies both in porcine trauma model
European Journal of Trauma and Emergency Surgery, 2020Co-Authors: Philipp Stormann, Roman Pfeifer, Hans-christoph Pape, Nils Wagner, Kernt Kohler, Birgit Auner, Timp Simon, Klemens Horst, Frank Hildebrand, Sebastian WutzlerAbstract:Aim Severely injured patients experience substantial immunological stress upon traumatic insult. Next to the direct local tissue injury also other Organs, which are not directly injured such as liver and lung, are frequently affected by a so-called Remote Organ damage (ROD) after trauma. Thus, we studied the inflammatory response of lung and liver either after isolated femur fracture as example for ROD, or after multiple trauma in a porcine polytrauma model.
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Cumulative Effects of Bone and Soft Tissue Injury on Systemic Inflammation: A Pilot Study
Clinical Orthopaedics and Related Research®, 2013Co-Authors: Roman Pfeifer, Sophie Darwiche, Lauryn Kohut, Timothy R. Billiar, Hans-christoph PapeAbstract:Background In multiply injured patients, bilateral femur fractures invoke a substantial systemic inflammatory impact and Remote Organ dysfunction. However, it is unclear whether isolated bone or soft tissue injury contributes to the systemic inflammatory response and Organ injury after fracture. Questions/purposes We therefore asked whether the systemic inflammatory response and Remote Organ dysfunction are attributable to the bone fragment injection, adjacent soft tissue injury, or both. Methods Male C57/BL6 mice (8–10 weeks old, 20–30 g) were assigned to four groups: bone fragment injection (BF, n = 9) group; soft tissue injury (STI, n = 9) group; BF + STI (n = 9) group, in which both insults were applied; and control group, in which neither insult was applied. Animals were sacrificed at 6 hours. As surrogates for systemic inflammation, we measured serum IL-6, IL-10, osteopontin, and alanine aminotransferase (ALT) and nuclear factor (NF)-κB and myeloperoxidase (MPO) in the lung. Results The systemic inflammatory response (mean IL-6 level) was similar in the BF (61.8 pg/mL) and STI (67.9 pg/mL) groups. The combination (BF + STI) of both traumatic insults induced an increase in mean levels of inflammatory parameters (IL-6: 189.1 pg/mL) but not in MPO levels (1.21 ng/mL) as compared with the BF (0.82 ng/mL) and STI (1.26 ng/mL) groups. The model produced little evidence of Remote Organ inflammation. Conclusions Our findings suggest both bone and soft tissue injury are required to induce systemic changes. The absence of Remote Organ inflammation suggests further fracture-associated factors, such as hemorrhage and fat liberation, may be more critical for induction of Remote Organ damage. Clinical Relevance Both bone and soft tissue injuries contribute to the systemic inflammatory response.
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cumulative effects of bone and soft tissue injury on systemic inflammation a pilot study
Clinical Orthopaedics and Related Research, 2013Co-Authors: Roman Pfeifer, Sophie Darwiche, Lauryn Kohut, Timothy R. Billiar, Hans-christoph PapeAbstract:Background In multiply injured patients, bilateral femur fractures invoke a substantial systemic inflammatory impact and Remote Organ dysfunction. However, it is unclear whether isolated bone or soft tissue injury contributes to the systemic inflammatory response and Organ injury after fracture.
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the degree of fracture associated soft tissue injury modifies systemic inflammation and Remote Organ dysfunction following bilateral femur fracture
Orthopaedic Proceedings, 2011Co-Authors: Philipp Kobbe, Roman Pfeifer, Philipp Lichte, Hans-christoph PapeAbstract:Patients with bilateral femur fractures are known to be at a high risk for the Systemic Inflammatory Response Syndrome; however the impact of fracture-associated soft tissue injury in the induction of systemic inflammation following bilateral femur fracture is poorly understood. To address this, the systemic inflammatory response and Remote Organ dysfunction following bilateral femur fracture with various degrees of soft tissue injuries were investigated in this study. 6–8 weeks old male C57/BL6 mice (n = 4–8 animals per group) were grouped as follows: Control-group (no anaesthesia, no femoral catheterisation); Sham-group (6 hour anaesthesia, femoral catheterisation); Fx-group (6 hour anaesthesia, femoral catheterisation, bilateral femur fracture with minor soft tissue injury); Fx+STI-group (6 hour anaesthesia, femoral catheterisation, bilateral femur fracture with severe soft tissue injury). Six hours after bilateral femur fracture serum levels of IL-2, IL-4, IL-6, IL-10, IL-12, TNF-α, KC and MCP-1 were measured. Furthermore, IL-6 levels of homogenized liver tissue were assessed. Neutrophil accumulation in liver and lung was determined with a myeloperoxidase (MPO) assay. Changes in liver permeability were assessed by measuring the wet-dry-ratio. The Fx+STI-group showed significantly increased serum cytokine levels as compared to the Fx- or Sham-group. The homogenized liver tissue of the Fx+STI-group showed significantly increased IL-6 levels as compared to the Sham-group. The MPO activity in lung and liver in the Fx+STI-group was significantly increased in comparison to the Fx- or Sham-group and in the Fx-group in comparison to the Sham-group. The wet-dry-ratio of the liver was significantly increased in the Fx+STI-group as compared to the Sham-group. The degree of fracture-associated soft tissue injury appears to modify systemic inflammation following bilateral femur fracture and is able to induce Remote Organ dysfunction. These results may have implications that have been underestimated, thus warranting clinical follow-up studies.
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Role of hemorrhage in the induction of systemic inflammation and Remote Organ damage: analysis of combined pseudo-fracture and hemorrhagic shock.
Journal of orthopaedic research : official publication of the Orthopaedic Research Society, 2010Co-Authors: Roman Pfeifer, Sophie Darwiche, Timothy R. Billiar, Philipp Kobbe, Hans-christoph PapeAbstract:This study was performed to analyze the role of hemorrhage-induced hypotension in the induction of systemic inflammation and Remote Organ dysfunction. Male C57/BL6 mice (6- to 10-week old and 20–30 g) were used. Animals were either subjected to pseudo-fracture [PF; standardized soft-tissue injury and injection of crushed bone, PF group: n = 9], or PF combined with hemorrhagic shock (HS + PF group: n = 6). Endpoint was 6 h. Systemic inflammation was assessed by IL-6 and IL-10 levels. Myeloperoxidase (MPO) and NF-κB activity in the lung and liver tissue were obtained to assess Remote Organ damage. The increases of systemic cytokines are similar for animals subjected to PF and PF + HS (IL-6: 189 pg/ml ± 32.5 vs. 160 pg/ml ± 5.3; IL-10: 60.3 pg/ml ± 15.8 vs. 88 pg/ml ± 32.4). Furthermore, the features (ALT; NF-κB) of liver injury are equally elevated in mice subjected to PF (76.9 U/L ± 4.5) and HS + PF (80 U/L ± 5.5). Lung injury, addressed by MPO activity was more severe in group HS + PF (2.95 ng/ml ± 0.32) than in group PF (1.21 ng/ml ± 0.2). Both PF and additional HS cause a systemic inflammatory response. In addition, hemorrhage seems to be associated with Remote affects on the lung. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:270–274, 2011
J. B. Stewart - One of the best experts on this subject based on the ideXlab platform.
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p selectin deficiency is protective against Remote Organ injury in a model of ruptured abdominal aortic aneurysm
British Journal of Surgery, 2001Co-Authors: J. B. Stewart, K. E. Norman, A. E. John, P Chan, Paul G. HellewellAbstract:Background: Multisystem Organ failure (MSOF) accounts for 50–60 per cent of postoperative deaths following repair of ruptured abdominal aortic aneurysm (AAA). A murine model is described in which the combined insults of hypotension and aortic clamping reproduce the physiological changes during repair of ruptured AAA. The resulting Remote Organ injury (the hallmark of MSOF) is prevented in the absence of the adhesion molecule P-selectin, which mediates neutrophil–endothelial interaction. Methods: C57BL6 wild-type mice (n = 4) and mice constitutively unable to express P-selectin (P–/–) (n = 4) were subjected to 60 min of controlled hypotension followed by cross-clamping of the infrarenal aorta for 60 min, reinfusion of shed blood and then 60 min of reperfusion. Controls (n = 16) were sham-operated, had hypotension only or clamp/reperfusion only. Lungs and kidneys were harvested and assayed for the neutrophil-specific marker myeloperoxidase (MPO), which indicates inflammatory infiltrate in the tissue. Results: MPO levels in the Organs of C57BL6 mice subjected to hypotension and aortic clamping were 50 times greater than those in sham-operated mice. MPO levels in sham-operated P–/– animals were similar to those in sham-operated C57BL6 mice. MPO levels in the lungs and kidneys of P–/– mice subjected to hypotension and aortic clamping were unchanged from those in sham-operated P–/– mice. Conclusion: The combined effects of hypotension and infrarenal aortic clamping, followed by reperfusion, are synergistic. This gives rise to a profound early inflammatory reaction in tissues Remote from the site of ischaemia–reperfusion, which is likely to contribute towards clinical MSOF after ruptured AAA repair. Absence of the adhesion molecule P-selectin protects against this Remote Organ injury. © 2001 British Journal of Surgery Society Ltd
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P‐selectin deficiency is protective against Remote Organ injury in a model of ruptured abdominal aortic aneurysm
British Journal of Surgery, 2001Co-Authors: J. B. Stewart, K. E. Norman, A. E. John, Philip Wing Keung Chan, Paul G. HellewellAbstract:Background: Multisystem Organ failure (MSOF) accounts for 50–60 per cent of postoperative deaths following repair of ruptured abdominal aortic aneurysm (AAA). A murine model is described in which the combined insults of hypotension and aortic clamping reproduce the physiological changes during repair of ruptured AAA. The resulting Remote Organ injury (the hallmark of MSOF) is prevented in the absence of the adhesion molecule P-selectin, which mediates neutrophil–endothelial interaction. Methods: C57BL6 wild-type mice (n = 4) and mice constitutively unable to express P-selectin (P–/–) (n = 4) were subjected to 60 min of controlled hypotension followed by cross-clamping of the infrarenal aorta for 60 min, reinfusion of shed blood and then 60 min of reperfusion. Controls (n = 16) were sham-operated, had hypotension only or clamp/reperfusion only. Lungs and kidneys were harvested and assayed for the neutrophil-specific marker myeloperoxidase (MPO), which indicates inflammatory infiltrate in the tissue. Results: MPO levels in the Organs of C57BL6 mice subjected to hypotension and aortic clamping were 50 times greater than those in sham-operated mice. MPO levels in sham-operated P–/– animals were similar to those in sham-operated C57BL6 mice. MPO levels in the lungs and kidneys of P–/– mice subjected to hypotension and aortic clamping were unchanged from those in sham-operated P–/– mice. Conclusion: The combined effects of hypotension and infrarenal aortic clamping, followed by reperfusion, are synergistic. This gives rise to a profound early inflammatory reaction in tissues Remote from the site of ischaemia–reperfusion, which is likely to contribute towards clinical MSOF after ruptured AAA repair. Absence of the adhesion molecule P-selectin protects against this Remote Organ injury. © 2001 British Journal of Surgery Society Ltd
Leena Alhonen - One of the best experts on this subject based on the ideXlab platform.
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association between Remote Organ injury and tissue polyamine homeostasis in acute experimental pancreatitis treatment with a polyamine analogue bismethylspermine
Pharmacological Reports, 2011Co-Authors: Hai-tao Jin, Teemu Lämsä, Panu H. Nordback, Mervi T. Hyvönen, Nikolay Grigorenko, Alex R. Khomutov, Isto Nordback, Sari Räty, Ilkka Pörsti, Leena AlhonenAbstract:Abstract Experimental pancreatitis is associated with activation of polyamine catabolism. The polyamine analog bismethylspermine (Me 2 Spm) can ameliorate pancreatic injury. We investigated the roles of polyamine catabolism in Remote Organs during pancreatitis and explored the mechanism of polyamine catabolism by administering Me 2 Spm. Acute pancreatitis was induced by an infusion of 2 or 6% taurodeoxycholate before Me 2 Spm administration. Blood, urine and tissues were sampled at 24 and 72 h to assess multi-Organ injury and polyamine catabolism. The effect of Me 2 Spm on mortality in experimental pancreatitis was tested separately. Liver putrescine levels were elevated following liver injury. Me 2 Spm increased the activity of spermidine/spermine N 1 -acetyltransferase (SSAT) and depleted the spermidine, spermine or putrescine levels. Lung putrescine levels increased, and SSAT and spermine decreased following lung injury. Me 2 Spm enhanced the activity of SSAT and decreased the spermidine and spermine levels. Renal injury was manifested as an increase in creatinine or a decrease in urine output. Decreases in kidney SSAT, spermidine or spermine and an increase in putrescine were found during pancreatitis. In the 2% taurodeoxycholate model, Me 2 Spm decreased urine output and raised plasma creatinine levels. Me 2 Spm increased SSAT and decreased polyamines. Excessive Me 2 Spm accumulated in the kidney, and greater amounts were found in the 6% taurodeoxycholate model in which this mortality was not reduced by Me 2 Spm. In the 2% taurodeoxycholate model, Me 2 Spm dose-dependently induced mortality at 72 h. Like pancreatic injury, Remote Organ injury in pancreatitis is associated with increased putrescine levels. However, Me 2 Spm could not ameliorate multi-Organ injury. Me 2 Spm administration was associated with significant renal toxicity and induced mortality, suggesting that the current dose is too high and needs to be modified.
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Association between Remote Organ injury and tissue polyamine homeostasis in acute experimental pancreatitis – treatment with a polyamine analogue bismethylspermine
Pharmacological reports : PR, 2011Co-Authors: Hai-tao Jin, Teemu Lämsä, Panu H. Nordback, Mervi T. Hyvönen, Nikolay Grigorenko, Alex R. Khomutov, Isto Nordback, Sari Räty, Ilkka Pörsti, Leena AlhonenAbstract:Abstract Experimental pancreatitis is associated with activation of polyamine catabolism. The polyamine analog bismethylspermine (Me 2 Spm) can ameliorate pancreatic injury. We investigated the roles of polyamine catabolism in Remote Organs during pancreatitis and explored the mechanism of polyamine catabolism by administering Me 2 Spm. Acute pancreatitis was induced by an infusion of 2 or 6% taurodeoxycholate before Me 2 Spm administration. Blood, urine and tissues were sampled at 24 and 72 h to assess multi-Organ injury and polyamine catabolism. The effect of Me 2 Spm on mortality in experimental pancreatitis was tested separately. Liver putrescine levels were elevated following liver injury. Me 2 Spm increased the activity of spermidine/spermine N 1 -acetyltransferase (SSAT) and depleted the spermidine, spermine or putrescine levels. Lung putrescine levels increased, and SSAT and spermine decreased following lung injury. Me 2 Spm enhanced the activity of SSAT and decreased the spermidine and spermine levels. Renal injury was manifested as an increase in creatinine or a decrease in urine output. Decreases in kidney SSAT, spermidine or spermine and an increase in putrescine were found during pancreatitis. In the 2% taurodeoxycholate model, Me 2 Spm decreased urine output and raised plasma creatinine levels. Me 2 Spm increased SSAT and decreased polyamines. Excessive Me 2 Spm accumulated in the kidney, and greater amounts were found in the 6% taurodeoxycholate model in which this mortality was not reduced by Me 2 Spm. In the 2% taurodeoxycholate model, Me 2 Spm dose-dependently induced mortality at 72 h. Like pancreatic injury, Remote Organ injury in pancreatitis is associated with increased putrescine levels. However, Me 2 Spm could not ameliorate multi-Organ injury. Me 2 Spm administration was associated with significant renal toxicity and induced mortality, suggesting that the current dose is too high and needs to be modified.
