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| 2. |
- Changhui, Yu, et al.
(författare)
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Rac1 signaling regulates neutrophil-dependent tissue damage in experimental colitis.
- 2014
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 741:Jul 30, s. 90-96
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Tidskriftsartikel (refereegranskat)abstract
- Excessive neutrophil recruitment in the colon is a major feature in acute colitis although the signaling mechanisms behind colonic recruitment of neutrophils remain elusive. Herein, we hypothesized that Rac1 activity might play an important role in neutrophil infiltration in the inflamed colon. Female Balb/c mice were treated with the Rac1 inhibitor NSC23766 (0.5 and 5mg/kg) before and daily after administration of 5% dextran sodium sulfate (DSS). Colonic tissue was collected for quantification of neutrophil recruitment, interleukin-6 (IL-6) and CXC chemokine formation as well as histological damage score five days after challenge with DSS. Rac1 activity was determined by western blot and Mac-1 expression by flow cytometry in neutrophils. Administration of NSC23766 decreased DSS-induced neutrophil recruitment and tissue damage in the colon. Rac1 inhibition decreased colonic formation of IL-6 and CXC chemokines in experimental colitis. Chemokine challenge increased Rac1 activity in neutrophils and NSC23766 markedly reduced this neutrophil activity of Rac1. Inhibition of Rac1 abolished CXC chemokine-induced neutrophil chemotaxis and up-regulation of Mac-1 in vitro. Taken together, Rac1 signaling plays a significant role in controlling accumulation of neutrophils and tissue injury in experimental colitis. Thus, our novel results suggest that targeting Rac1 signaling might be a useful way to protect against neutrophil-mediated tissue injury in acute colitis.
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| 3. |
- Hwaiz, Rundk, et al.
(författare)
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Rac1 regulates platelet shedding of CD40L in abdominal sepsis.
- 2014
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Ingår i: Laboratory Investigation. - : Elsevier BV. - 1530-0307 .- 0023-6837. ; 94:9, s. 1054-1063
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Tidskriftsartikel (refereegranskat)abstract
- Matrix metalloproteinase-9 (MMP-9) regulates platelet shedding of CD40L in abdominal sepsis. However, the signaling mechanisms controlling sepsis-induced shedding of CD40L from activated platelets remain elusive. Rac1 has been reported to regulate diverse functions in platelets; we hypothesized herein that Rac1 might regulate platelet shedding of CD40L in sepsis. The specific Rac1 inhibitor NSC23766 (N6-[2-[[4-(diethylamino)-1-methylbutyl] amino]-6-methyl-4-pyrimidinyl]-2 methyl-4, 6-quinolinediamine trihydrochloride) was administered to mice undergoing cecal ligation and puncture (CLP). Levels of CD40L and MMP-9 in plasma, platelets, and neutrophils were determined by use of ELISA, western blot, and confocal microscopy. Platelet depletion abolished the CLP-induced increase in plasma levels of CD40L. Rac1 activity was significantly increased in platelets from septic animals. Administration of NSC23766 abolished the CLP-induced enhancement of soluble CD40L levels in the plasma. Moreover, Rac1 inhibition completely inhibited proteinase-activated receptor-4-induced surface mobilization and secretion of CD40L in isolated platelets. CLP significantly increased plasma levels of MMP-9 and Rac1 activity in neutrophils. Treatment with NSC23766 markedly attenuated MMP-9 levels in the plasma from septic mice. In addition, Rac1 inhibition abolished chemokine-induced secretion of MMP-9 from isolated neutrophils. Finally, platelet shedding of CD40L was significantly reduced in response to stimulation with supernatants from activated MMP-9-deficient neutrophils compared with supernatants from wild-type neutrophils, indicating a direct role of neutrophil-derived MMP-9 in regulating platelet shedding of CD40L. Our novel data suggest that sepsis-induced platelet shedding of CD40L is dependent on Rac1 signaling. Rac1 controls surface mobilization of CD40L on activated platelets and MMP-9 secretion from neutrophils. Thus, our findings indicate that targeting Rac1 signaling might be a useful way to control pathologic elevations of CD40L in the systemic circulation in abdominal sepsis.Laboratory Investigation advance online publication, 21 July 2014; doi:10.1038/labinvest.2014.92.
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| 4. |
- Luo, Lingtao, et al.
(författare)
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Pro-inflammatory role of neutrophil extracellular traps in abdominal sepsis.
- 2014
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Ingår i: American Journal of Physiology: Lung Cellular and Molecular Physiology. - : American Physiological Society. - 1522-1504 .- 1040-0605. ; 307:7, s. 586-596
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Tidskriftsartikel (refereegranskat)abstract
- Excessive neutrophil activation is a major component in septic lung injury. Neutrophil-derived DNA may form extracellular traps in response to bacterial invasions. The aim of the present study was to investigate the potential role of neutrophil extracellular traps (NETs) in septic lung injury. Male C57BL/6 mice were treated with rhDNAse (5 mg/kg) after cecal ligation and puncture (CLP). Extracellular DNA was stained by Sytox green and NET formation was quantified by confocal microscopy and cell-free DNA in plasma, peritoneal cavity and lung. Blood, peritoneal fluid and lung tissue were harvested for analysis of neutrophil infiltration, NET levels, tissue injury as well as CXC chemokine and cytokine formation. We observed that CLP caused increased formation of NETs in the plasma, peritoneal cavity and lung. Administration of rhDNAse not only eliminated NET formation in the plasma, peritoneal cavity and bronchoalveolar space but also reduced lung edema and tissue damage 24 h after CLP induction. Moreover, treatment with rhDNAse decreased CLP-induced formation of CXC chemokines, IL-6 and HMGB1 in the plasma as well as CXC chemokines and IL-6 in the lung. In vitro, we found that neutrophil-derived NETs had the capacity to stimulate secretion of CXCL2, TNF-α and HMGB1 from alveolar macrophages. Taken together, our findings show that NETs regulate pulmonary infiltration of neutrophils and tissue injury via formation of pro-inflammatory compounds in abdominal sepsis. Thus, we conclude that NETs exert a pro-inflammatory role in septic lung injury.
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| 6. |
- Merza, Mohammed, et al.
(författare)
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Human thrombin-derived host defense peptides inhibit neutrophil recruitment and tissue injury in severe acute pancreatitis.
- 2014
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Ingår i: American Journal of Physiology: Gastrointestinal and Liver Physiology. - : American Physiological Society. - 1522-1547 .- 0193-1857. ; 307:9, s. 914-921
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Tidskriftsartikel (refereegranskat)abstract
- Severe acute pancreatitis (AP) is characterized by leukocyte infiltration and tissue injury. Herein, we wanted to examine the potential effects of thrombin-derived host defense peptides (TDPs) in severe AP. Pancreatitis was provoked by infusion of taurocholate into the pancreatic duct or by intraperitoneal administration of L-arginine in C57BL/6 mice. Animals were treated with the TDPs GKY20 and GKY25 or a control peptide WFF25 30 min before induction of AP. TDPs reduced blood amylase levels, neutrophil infiltration, hemorrhage, necrosis and edema formation in the inflamed pancreas. Treatment with TDPs markedly attenuated the taurocholate-induced increase in plasma levels of CXCL2 and interleukin-6. Moreover, administration of TDPs decreased histone 3, histone 4 and MPO levels in the pancreas in response to taurocholate challenge. Interestingly, administration of TDPs abolished neutrophil expression of Mac-1 in mice with pancreatitis. In addition, TDPs inhibited CXCL2-induced chemotaxis of isolated neutrophils in vitro. Fluorescent-labeled TDP was found to directly bind to isolated neutrophils. Finally, a beneficial effect of TDPs was confirmed in L-arginine-induced pancreatitis. Our novel results demonstrate that TDPs exert protective effects against pathological inflammation and tissue damage in AP. These novel findings suggest that TDPs might be useful in the management of patients with severe AP.
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| 7. |
- Rahman, Milladur, et al.
(författare)
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Ticagrelor reduces neutrophil recruitment and lung damage in abdominal sepsis.
- 2014
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Ingår i: Platelets. - : Informa UK Limited. - 1369-1635 .- 0953-7104. ; 25:4, s. 257-263
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Platelets play an important role in abdominal sepsis and P2Y12 receptor antagonists have been reported to exert anti-inflammatory effects. Herein, we assessed the impact of platelet inhibition with the P2Y12 receptor antagonist ticagrelor on pulmonary neutrophil recruitment and tissue damage in a model of abdominal sepsis. Wild-type C57BL/6 mice were subjected to cecal ligation and puncture (CLP). Animals were treated with ticagrelor (100 mg/kg) or vehicle prior to CLP induction. Edema formation and bronchoalveolar neutrophils as well as lung damage were quantified. Flow cytometry was used to determine expression of platelet-neutrophil aggregates, neutrophil activation and CD40L expression on platelets. CLP-induced pulmonary infiltration of neutrophils at 24 hours was reduced by 50% in ticagrelor-treated animals. Moreover, ticagrelor abolished CLP-provoked lung edema and decreased lung damage score by 41%. Notably, ticagrelor completely inhibited formation of platelet-neutrophil aggregates and markedly reduced thrombocytopenia in CLP animals. In addition, ticagrelor reduced platelet shedding of CD40L in septic mice. Our data indicate that ticagrelor can reduce CLP-induced pulmonary neutrophil recruitment and lung damage suggesting a potential role for platelet antagonists, such as ticagrelor, in the management of patients with abdominal sepsis.
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| 8. |
- Thorlacius, Henrik, et al.
(författare)
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Cystic neuroendocrine tumor in the pancreas detected by endoscopic ultrasound and fine-needle aspiration: a case report.
- 2014
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Ingår i: BMC Research Notes. - : Springer Science and Business Media LLC. - 1756-0500. ; 7:Aug 9
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Tidskriftsartikel (refereegranskat)abstract
- Pancreatic neuroendocrine tumors are typically solid neoplasms but in very rare cases present as cystic lesions. The diagnosis of cystic tumors in the pancreas is extremely difficult and the use of endoscopic ultrasound and fine-needle aspiration might be helpful in the work-up of patients with cystic neuroendocrine tumors in the pancreas.
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| 9. |
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| 10. |
- Wang, Yongzhi, et al.
(författare)
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DYNAMIC CHANGES IN THROMBIN GENERATION IN ABDOMINAL SEPSIS IN MICE.
- 2014
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Ingår i: Shock. - 1540-0514. ; 42:4, s. 343-349
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT-Systemic inflammatory response syndrome and severe infections are associated with major derangements in the coagulation system. The purpose of this study was to examine the dynamic alterations in thrombin generation in abdominal sepsis. Abdominal sepsis was induced by cecal ligation and puncture (CLP) in C57/Bl6 mice. CLP caused a systemic inflammatory response with neutrophil recruitment and tissue damage in the lung as well as thrombocytopenia and leukocytopenia. Thrombin generation, coagulation factors, lung histology and myeloperoxidase (MPO) activity was determined 1h, 3h, 6h and 24h after induction of CLP. It was found that thrombin generation was increased 1h after CLP and that thrombin generation started to decrease at 3h and was markedly reduced 6h and 24h after CLP induction. Platelet poor plasma from healthy mice could completely reverse the inhibitory effect of CLP on thrombin generation, suggesting that sepsis caused a decrease in the levels of plasma factors regulating thrombin generation in septic animals. Indeed, it was found that CLP markedly decreased plasma levels of prothrombin, factor V and factor X at 6h and 24h. Moreover, we observed that CLP increased plasma levels of activated protein C at 6h, which returned to baseline levels 24h after CLP induction. Finally, pretreatment with imipenem/cilastatin attenuated the CLP-evoked decrease in thrombin generation and consumption of prothrombin 24h after CLP induction. Our novel findings suggest that thrombin generation is initially increased and later decreased in abdominal sepsis. Sepsis-induced reduction in thrombin generation is correlated to changes in the plasma levels of coagulation factors and activated protein C. These findings help explain the dynamic changes in global hemostasis in abdominal sepsis.
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