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| 2. |
- Abdulla, Aree, et al.
(författare)
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Role of platelets in experimental acute pancreatitis.
- 2011
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Ingår i: British Journal of Surgery. - : Oxford University Press (OUP). - 1365-2168 .- 0007-1323. ; 98, s. 93-103
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:: Platelets not only control thrombosis and haemostasis but may also regulate inflammatory processes. Acute pancreatitis (AP) is characterized by changes in both coagulation and proinflammatory activities. The role of platelets in AP is not yet known. METHODS:: AP was induced in C57BL/6 mice by repeated caerulein administration (50 µg/kg intraperitoneally). Mice received a platelet-depleting or control antibody before caerulein challenge. Neutrophil infiltration, myeloperoxidase (MPO) and macrophage inflammatory protein (MIP) 2 levels, acinar cell necrosis and haemorrhage in the pancreas, as well as serum amylase activity, were determined 24 h after caerulein injection. In an alternative model of pancreatitis, L-arginine (4 g/kg intraperitoneally) was given twice with an interval of 1 h and tissue samples were taken after 72 h [Correction added after online publication 29 September 2010: in the preceding sentence, 4 mg/kg was corrected to 4 g/kg]. RESULTS:: Caerulein administration increased acinar cell necrosis, neutrophil infiltration, focal haemorrhage and serum amylase levels. Platelet depletion reduced acinar cell necrosis, haemorrhage and serum amylase levels in AP. Depletion of platelets decreased caerulein-induced MPO levels and neutrophil recruitment in the pancreas. Platelet depletion abolished caerulein-induced MIP-2 generation in the pancreas and circulation. The effects of platelet depletion on necrosis, neutrophils and MPO levels were confirmed in L-arginine-induced pancreatitis. CONCLUSION:: Platelets play a crucial role in AP by regulating neutrophil infiltration, most likely mediated by MIP-2 production in the pancreas. Copyright © 2010 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.
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| 3. |
- Algaber, Anwar, et al.
(författare)
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MicroRNA-340-5p inhibits colon cancer cell migration via targeting of RhoA
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1, s. 16934-16934
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Tidskriftsartikel (refereegranskat)abstract
- Colon cancer is the third most common cancer and a significant cause of cancer-related deaths worldwide. Metastasis is the most insidious aspect of cancer progression. Convincing data suggest that microRNAs (miRs) play a key function in colon cancer biology. We examined the role of miR-340-5p in regulating RhoA expression as well as cell migration and invasion in colon cancer cells. Levels of miR-340-5p and RhoA mRNA varied inversely in serum-free and serum-grown HT-29 and AZ-97 colon cancer cells. It was found transfection with miR-340-5p not only decreased expression of RhoA mRNA and protein levels in HT-29 cells but also reduced colon cancer cell migration and invasion. Bioinformatics analysis predicted one putative binding sites at the 3'-UTR of RhoA mRNA. Targeting this binding site with a specific blocker reversed mimic miR-340-5p-induced inhibition of RhoA activation and colon cancer cell migration and invasion. These novel results suggest that miR-340-5p is an important regulator of colon cancer cell motility via targeting of RhoA and further experiments are warranted to evaluate the role of miR-340-5p in colon cancer metastasis.
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| 4. |
- Awla, Darbaz, et al.
(författare)
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Rho-kinase signalling regulates trypsinogen activation and tissue damage in severe acute pancreatitis.
- 2011
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Ingår i: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 162, s. 648-658
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose: Severe acute pancreatitis (SAP) is characterized by trypsinogen activation, infiltration of leucocytes and tissue necrosis but the intracellular signalling mechanisms regulating organ injury in the pancreas remain elusive. Rho-kinase is a potent regulator of specific cellular processes effecting several pro-inflammatory activities. Herein, we examined the role of Rho-kinase signalling in acute pancreatitis. Experimental approach: Pancreatitis was induced by infusion of taurocholate into the pancreatic duct in C57BL/6 mice. Animals were treated with a Rho-kinase inhibitor Y-27632 (0.5-5 mg kg(-1) ) before induction of pancreatitis. Key results: Taurocholate infusion caused a clear-cut increase in serum amylase, pancreatic neutrophil infiltration, acinar cell necrosis and oedema formation in the pancreas. Levels of pancreatic myeloperoxidase (MPO), macrophage inflammatory protein-2 (MIP-2), trypsinogen activation peptide (TAP) and lung MPO were significantly increased, indicating local and systemic disease. Inhibition of Rho-kinase activity dose-dependently protected against pancreatitis. For example, 5 mg kg(-1) Y-27632 reduced acinar cell necrosis, leucocyte infiltration and pancreatic oedema by 90%, 89% and 58% respectively as well as tissue levels of MPO by 75% and MIP-2 by 84%. Moreover, Rho-kinase inhibition decreased lung MPO by 75% and serum amylase by 83%. Pancreatitis-induced TAP levels were reduced by 61% in Y-27632-treated mice. Inhibition of Rho-kinase abolished secretagogue-induced activation of trypsinogen in pancreatic acinar cells in vitro. Conclusions and Implications: Our novel data suggest that Rho-kinase signalling plays an important role in acute pancreatitis by regulating trypsinogen activation and subsequent CXC chemokine formation, neutrophil infiltration and tissue injury. Thus, these results indicate that Rho-kinase may constitute a novel target in the management of SAP.
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| 5. |
- Chew, Michelle, et al.
(författare)
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Soluble CD40L (CD154) is increased in patients with shock.
- 2010
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Ingår i: Inflammation Research. - : Springer Science and Business Media LLC. - 1420-908X .- 1023-3830. ; 59, s. 979-982
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Recent data suggest that soluble CD40L (sCD40L) plays an important role in murine sepsis. The aim of the present study was to determine plasma levels of CD40L in critically ill patients with systemic inflammatory response syndrome (SIRS) and shock, with and without sepsis. DESIGN: A prospective observational one-centre cohort study in a mixed-bed ICU of an university hospital. Fifty-three consecutive patients fulfilling the criteria for SIRS with shock as well as seven age-matched controls were included. ELISA was used to determine sCD40L in the plasma. RESULTS: The level of sCD40L in plasma from healthy controls was 0.18 +/- 0.03 ng/ml. It was found that sCD40L levels were significantly higher in patients with non-septic shock (0.72 +/- 0.18 ng/ml) and septic shock (0.50 +/- 0.1 ng/ml). However, the levels of sCD40L were not different between these two groups of patients, or in those with low and high APACHE scores. CONCLUSION: Our data show that sCD40L is increased in patients with shock from septic and non-septic etiologies. However, further studies are needed to delineate the functional significance of sCD40L in the clinical outcome in shock patients.
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| 6. |
- Ding, Zhiyi, et al.
(författare)
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Actin-related protein 2/3 complex regulates neutrophil extracellular trap expulsion and lung damage in abdominal sepsis
- 2022
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Ingår i: American Journal of Physiology - Lung Cellular and Molecular Physiology. - 1040-0605. ; 322:5, s. 662-672
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophil extracellular trap (NET) formation is a key feature in sepsis. The aim of the present study was to examine the role of the actin cytoskeleton in regulating the expulsion of NETs. Actin-related protein 2/3 (Arp 2/3) complex is an important regulator of F-actin polymerization. Coincubation with CK666, a specific Arp 2/3 inhibitor, decreased 12-phorbol 13-myristate acetate-induced NET formation in vitro. CK666 not only abolished F-actin polymerization but also caused intracellular retention of NETs. Inhibition of Arp 2/3 reduced NET formation on circulating neutrophils and in the bronchoalveolar space in mice undergoing cecal ligation and puncture (CLP). Notably, treatment with CK666 attenuated CLP-induced neutrophil recruitment, edema formation, and tissue damage in the lungs. Moreover, Arp 2/3 inhibition decreased levels of C-X-C motif chemokine ligand 1 (CXCL-1) and interleukin-6 in the lung and plasma of septic animals. Taken together, this study shows that expulsion of NETs is regulated by the actin cytoskeleton and that inhibition of Arp 2/3-dependent F-actin polymerization not only decreases NET formation but also protects against pathological inflammation and tissue damage in septic lung injury. Thus, we suggest that targeting NET release is a novel and useful way to ameliorate lung damage in abdominal sepsis.
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| 7. |
- Ding, Zhiyi, et al.
(författare)
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Targeting s100a9 reduces neutrophil recruitment, inflammation and lung damage in abdominal sepsis
- 2021
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 22:23
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Tidskriftsartikel (refereegranskat)abstract
- S100A9, a pro-inflammatory alarmin, is up-regulated in inflamed tissues. However, the role of S100A9 in regulating neutrophil activation, inflammation and lung damage in sepsis is not known. Herein, we hypothesized that blocking S100A9 function may attenuate neutrophil recruitment in septic lung injury. Male C57BL/6 mice were pretreated with the S100A9 inhibitor ABR-238901 (10 mg/kg), prior to cercal ligation and puncture (CLP). Bronchoalveolar lavage fluid (BALF) and lung tissue were harvested for analysis of neutrophil infiltration as well as edema and CXC chemokine production. Blood was collected for analysis of membrane-activated complex-1 (Mac-1) expression on neutrophils as well as CXC chemokines and IL-6 in plasma. Induction of CLP mark-edly increased plasma levels of S100A9. ABR-238901 decreased CLP-induced neutrophil infiltration and edema formation in the lung. In addition, inhibition of S100A9 decreased the CLP-induced up-regulation of Mac-1 on neutrophils. Administration of ABR-238901 also inhibited the CLP-induced increase of CXCL-1, CXCL-2 and IL-6 in plasma and lungs. Our results suggest that S100A9 promotes neutrophil activation and pulmonary accumulation in sepsis. Targeting S100A9 function decreased formation of CXC chemokines in circulation and lungs and attenuated sepsis-induced lung damage. These novel findings suggest that S1000A9 plays an important pro-inflammatory role in sepsis and could be a useful target to protect against the excessive inflammation and lung damage associated with the disease.
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| 8. |
- Du, Feifei, et al.
(författare)
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E3 Ubiquitin Ligase Midline 1 Regulates Endothelial Cell ICAM-1 Expression and Neutrophil Adhesion in Abdominal Sepsis
- 2023
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- Septic lung damage is associated with endothelial cell and neutrophil activation. This study examines the role of the E3 ubiquitin ligase midline 1 (Mid1) in abdominal sepsis. Mid1 expression was increased in endothelial cells derived from post-capillary venules in septic mice and TNF-α challenge increased Mid1 levels in endothelial cells in vitro. The siRNA-mediated knockdown of Mid1 decreased TNF-α-induced upregulation of ICAM-1 and neutrophil adhesion to endothelial cells. Moreover, Mid1 silencing reduced leukocyte adhesion in post-capillary venules in septic lungs in vivo. The silencing of Mid1 not only decreased Mid1 expression but also attenuated expression of ICAM-1 in lungs from septic mice. Lastly, TNF-α stimulation decreased PP2Ac levels in endothelial cells in vitro, which was reversed in endothelial cells pretreated with siRNA directed against Mid1. Thus, our novel data show that Mid1 is an important regulator of ICAM-1 expression and neutrophil adhesion in vitro and septic lung injury in vivo. A possible target of Mid1 is PP2Ac in endothelial cells. Targeting the Mid1-PP2Ac axis may be a useful way to reduce pathological lung inflammation in abdominal sepsis.
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| 9. |
- Du, Feifei, et al.
(författare)
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S100A9 induces reactive oxygen species-dependent formation of neutrophil extracellular traps in abdominal sepsis
- 2022
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 1090-2422 .- 0014-4827. ; 421:2
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Tidskriftsartikel (refereegranskat)abstract
- Recent evidence suggests that targeting S100A9 reduces pathological inflammation in abdominal sepsis. Herein, we investigated the role of S100A9 in neutrophil extracellular trap (NET) formation in septic lung damage. NETs were detected by electron microscopy in the lung and by confocal microscopy in vitro. Stimulation of isolated mouse bone marrow-derived neutrophils with S100A9 triggered formation of NETs. Blocking TLR4 and RAGE reduced S100A9-induced generation of NETs and DNA-histone complexes. Moreover, S100A9 challenge increased generation of reactive oxygen species (ROS) in bone marrow neutrophils. Co-incubation with the NADPH oxidase inhibitor not only decreased ROS formation but also attenuated induction of DNA-histone complexes in S100A9-stimulated neutrophils. Abdominal sepsis was induced by cecal ligation and puncture (CLP) in male C57BL/6 mice. Administration of the S100A9 inhibitor ABR-238901 decreased CLP-induced formation of NETs in lungs and DNA-histone complexes in plasma. In addition, transmission electron microscopy revealed that S100A9 was abundantly expressed on NETs in the lungs in CLP mice. By use of intravital microscopy, we found that local injection of NETs increased leukocyte adhesion and migration in the mouse cremaster muscle microvasculature. Notably, treatment with ABR-238901 attenuated NET-induced leukocyte adhesion and extravasation in the cremaster muscle, suggesting that NET-associated S100A9 promotes leukocyte recruitment in vivo. Taken together, these novel findings suggest that S100A9 triggers ROS-dependent formation of NETs via TLR4 and RAGE signaling in neutrophils. Moreover, S100A9 regulates both formation of NETs and NET-induced leukocyte recruitment in vivo. Thus, targeting S100A9 might be useful to ameliorate lung damage in abdominal sepsis.
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| 10. |
- Hasan, Zirak, et al.
(författare)
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Geranylgeranyl transferase regulates CXC chemokine formation in alveolar macrophages and neutrophil recruitment in septic lung injury
- 2013
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Ingår i: American Journal of Physiology: Lung Cellular and Molecular Physiology. - : American Physiological Society. - 1522-1504 .- 1040-0605. ; 304:4, s. 221-229
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Tidskriftsartikel (refereegranskat)abstract
- Hasan Z, Rahman M, Palani K, Syk I, Jeppsson B, Thorlacius H. Geranylgeranyl transferase regulates CXC chemokine formation in alveolar macrophages and neutrophil recruitment in septic lung injury. Am J Physiol Lung Cell Mol Physiol 304: L221-L229, 2013. First published December 14, 2012; doi:10.1152/ajplung.00199.2012.-Overwhelming accumulation of neutrophils is a significant component in septic lung damage, although the signaling mechanisms behind neutrophil infiltration in the lung remain elusive. In the present study, we hypothesized that geranylgeranylation might regulate the inflammatory response in abdominal sepsis. Male C57BL/6 mice received the geranylgeranyl transferase inhibitor, GGTI-2133, before cecal ligation and puncture (CLP). Bronchoalveolar lavage fluid and lung tissue were harvested for analysis of neutrophil infiltration, as well as edema and CXC chemokine formation. Blood was collected for analysis of Mac-1 on neutrophils and CD40L on platelets. Gene expression of CXC chemokines, tumor necrosis factor-alpha (TNF-alpha), and CCL2 chemokine was determined by quantitative RT-PCR in isolated alveolar macrophages. Administration of GGTI-2133 markedly decreased CLP-induced infiltration of neutrophils, edema, and tissue injury in the lung. CLP triggered clear-cut upregulation of Mac-1 on neutrophils. Inhibition of geranylgeranyl transferase reduced CLP-evoked upregulation of Mac-1 on neutrophils in vivo but had no effect on chemokine-induced expression of Mac-1 on isolated neutrophils in vitro. Notably, GGTI-2133 abolished CLP-induced formation of CXC chemokines, TNF-alpha, and CCL2 in alveolar macrophages in the lung. Geranylgeranyl transferase inhibition had no effect on sepsis-induced platelet shedding of CD40L. In addition, inhibition of geranylgeranyl transferase markedly decreased CXC chemokine-triggered neutrophil chemotaxis in vitro. Taken together, our findings suggest that geranylgeranyl transferase is an important regulator of CXC chemokine production and neutrophil recruitment in the lung. We conclude that inhibition of geranylgeranyl transferase might be a potent way to attenuate acute lung injury in abdominal sepsis.
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