| 31. |
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| 32. |
- Merza, Mohammed, et al.
(author)
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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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In: American Journal of Physiology: Gastrointestinal and Liver Physiology. - : American Physiological Society. - 1522-1547 .- 0193-1857. ; 307:9, s. 914-921
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Journal article (peer-reviewed)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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| 33. |
- Merza, Mohammed, et al.
(author)
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Neutrophil Extracellular Traps Induce Trypsin Activation, Inflammation, and Tissue Damage in Mice with Severe Acute Pancreatitis.
- 2015
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In: Gastroenterology. - : Elsevier BV. - 1528-0012 .- 0016-5085. ; 149:7, s. 1920-1920
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Journal article (peer-reviewed)abstract
- Neutrophils are involved in development of acute pancreatitis (AP), but it is not clear how neutrophil-induced tissue damage is regulated. In addition to secreting antimicrobial compounds, activated neutrophils eliminate invading microorganisms by expelling nuclear DNA and histones to form extracellular web-like structures called neutrophil extracellular traps (NETs). However, NETs have been reported contribute to organ dysfunction in patients with infectious diseases. We investigated whether NETs contribute to development of AP in mice.
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| 34. |
- Muhammad, Asad, et al.
(author)
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P-selectin glycoprotein-ligand-1 regulates pulmonary recruitment of neutrophils in a platelet-independent manner in abdominal sepsis
- 2009
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In: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 156:2, s. 307-315
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Journal article (peer-reviewed)abstract
- Neutrophil-mediated lung injury is an insidious feature in sepsis although the mechanisms regulating pulmonary recruitment of neutrophils remain elusive. Here, we investigated the role of P-selectin glycoprotein-ligand-1 (PSGL-1) in sepsis-induced neutrophil recruitment and tissue injury in the lung. Bronchoalveolar infiltration of neutrophils, levels of myeloperoxidase, oedema formation and CXC chemokines were determined 24 h after caecal ligation and puncture (CLP) in mice. Animals were pretreated with a control antibody, monoclonal antibodies directed against PSGL-1 and P-selectin as well as a platelet-depleting antibody directed against GP1b alpha. CLP caused pulmonary damage characterized by oedema formation, neutrophil infiltration and increased levels of CXC chemokines in the lung. Immunoneutralization of PSGL-1 or P-selectin reduced CLP-induced neutrophil recruitment in the bronchoalveolar space by more than 56% and lung myeloperoxidase activity by 62%. Notably, the inhibitory effect of the anti-PSGL-1 antibody on sepsis-induced neutrophil infiltration was also observed in platelet-depleted mice. Moreover, inhibition of PSGL-1 and P-selectin abolished CLP-induced oedema formation and tissue damage in the lung. CLP-induced formation of CXC chemokines was not changed in mice pretreated with the anti-PSGL-1 and anti-P-selectin antibodies. These data demonstrate that PSGL-1 plays a key role in pulmonary infiltration of neutrophils as well as lung oedema associated with abdominal sepsis. Moreover, our findings suggest that PSGL-1-dependent neutrophil recruitment is independent of circulating platelets. Thus, these novel findings indicate that PSGL-1 may be a useful target to protect against sepsis-induced accumulation of neutrophils and tissue damage in the lung.
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| 35. |
- Muhammad, Asad, et al.
(author)
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Platelets support pulmonary recruitment of neutrophils in abdominal sepsis
- 2009
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In: Critical Care Medicine. - 1530-0293. ; 37:4, s. 1389-1396
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Journal article (peer-reviewed)abstract
- Objective. Recent findings Indicate that platelets not only regulate thrombosis and hemostasis but may also be involved in proinflammatory activities. Herein, we hypothesized that platelets may play a role in sepsis by activating and priming circulating neutrophils for subsequent recruitment Into the lung. Design: Prospective experimental study. Setting. University Hospital Research Unit. Subject. Male C57BL/6 mice. Interventions. Lung edema, bronchoalveolar infiltration of neutrophils, levels of myeloperoxidase, expression and function of membrane-activated complex-1 (Mac-1) on neutrophils and the CXC chemokines, macrophage inflammatory protein-2, and cytokine-induced neutrophil chemoattractant were determined after cecal ligation and puncture (CLP). Mice received a platelet-depleting antibody as well as antibodies directed against P-selectin glycoprotein-ligand-1 and Mac-1 before CLP induction. Measurements and Main Results. CLP caused significant pulmonary damage characterized by neutrophil infiltration, increased levels of CXC chemokines, and edema formation in the lung. Furthermore, CLP up-regulated Mac-1 expression on neutrophils and increased the number of neutrophils binding platelets in the circulation. Interestingly, depletion of platelets reduced CLP-induced edema and neutrophil recruitment in the bronchoalveolar space by >60%. Furthermore, depletion of platelets reduced Mac-1 expression on neutrophils. On the other hand, inhibition of P-selectin glycoprotein-ligand-1 abolished CLP-induced neutrophil-platelet aggregation but had no effect on neutrophil expression of Mac-1. Conclusions: These data demonstrate that platelets play a key role in regulating infiltration of neutrophils and edema formation in the lung via upregulation of Mac-1 in abdominal sepsis. (Crit Care Med 2009; 37:1389-1396)
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| 36. |
- Palani, Karzan, et al.
(author)
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Rho-kinase regulates adhesive and mechanical mechanisms of pulmonary recruitment of neutrophils in abdominal sepsis.
- 2012
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In: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 682:1-3, s. 181-187
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Journal article (peer-reviewed)abstract
- We hypothesized that Rho-kinase signaling plays a role in mechanical and adhesive mechanisms of neutrophil accumulation in lung. Male C57BL/6 mice were treated with the Rho-kinase inhibitor Y-27632 prior to cecal ligation and puncture (CLP). Lung levels of myeloperoxidase (MPO) and histological tissue damage were determined 6h and 24h after CLP. Expression of Mac-1 and F-actin formation in neutrophils were quantified by using flow cytometry 6h after CLP. Mac-1 expression and F-actin formation were also determined in isolated neutrophils up to 3h after stimulation with CXCL2. Labeled and activated neutrophils co-incubated with Y-27632, an anti-Mac-1 antibody and cytochalasin B were adoptively transferred to CLP mice. Y-27632 reduced the CLP-induced pulmonary injury and MPO activity as well as Mac-1 on neutrophils. Neutrophil F-actin formation peaked at 6h and returned to baseline levels 24h after CLP induction. Rho-kinase inhibition decreased CLP-provoked F-actin formation in neutrophils. CXCL2 rapidly increased Mac-1 expression and F-actin formation in neutrophils. Co-incubation with Y-27632 abolished CXCL2-induced Mac-1 up-regulation and formation of F-actin in neutrophils. Notably, co-incubation with cytochalasin B inhibited formation of F-actin but did not reduce Mac-1 expression on activated neutrophils. Adoptive transfer experiments revealed that co-incubation of neutrophils with the anti-Mac-1 antibody or cytochalasin B significantly decreased pulmonary accumulation of neutrophils in septic mice. Our data show that targeting Rho-kinase effectively reduces neutrophil recruitment and tissue damage in abdominal sepsis. Moreover, these findings demonstrate that Rho-kinase-dependent neutrophil accumulation in septic lung injury is regulated by both adhesive and mechanical mechanisms.
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| 37. |
- Papareddy, Praveen, et al.
(author)
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The role of extracellular vesicle fusion with target cells in triggering systemic inflammation
- 2024
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In: Nature Communications. - 2041-1723. ; 15
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Journal article (peer-reviewed)abstract
- Extracellular vesicles (EVs) play a crucial role in intercellular communication by transferring bioactive molecules from donor to recipient cells. As a result, EV fusion leads to the modulation of cellular functions and has an impact on both physiological and pathological processes in the recipient cell. This study explores the impact of EV fusion on cellular responses to inflammatory signaling. Our findings reveal that fusion renders non-responsive cells susceptible to inflammatory signaling, as evidenced by increased NF-κB activation and the release of inflammatory mediators. Syntaxin-binding protein 1 is essential for the merge and activation of intracellular signaling. Subsequent analysis show that EVs transfer their functionally active receptors to target cells, making them prone to an otherwise unresponsive state. EVs in complex with their agonist, require no further stimulation of the target cells to trigger mobilization of NF-κB. While receptor antagonists were unable to inhibit NF-κB activation, blocking of the fusion between EVs and their target cells with heparin mitigated inflammation in mice challenged with EVs.
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| 38. |
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| 39. |
- Rahman, Milladur, et al.
(author)
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Metalloproteinases regulate CD40L shedding from platelets and pulmonary recruitment of neutrophils in abdominal sepsis
- 2012
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In: Inflammation Research. - : Springer Science and Business Media LLC. - 1420-908X .- 1023-3830. ; 61:6, s. 571-579
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Journal article (peer-reviewed)abstract
- Abstract in UndeterminedOBJECTIVE: Platelets promote sepsis-induced activation of neutrophils via secretion of CD40L. However, the mechanism regulating the release of platelet-derived CD40L is not known. We hypothesized that matrix metalloproteinases (MMPs) might regulate shedding of platelet-expressed CD40L and neutrophil activation in sepsis.METHODS: Wild-type C57BL/6 mice were subjected to cecal ligation and puncture (CLP). Animals were pretreated with a broad-range MMP inhibitor, GM6001, prior to CLP induction. Edema formation, CXC chemokine and myeloperoxidase (MPO) levels and bronchoalveolar neutrophils in the lung as well as plasma levels of CD40L were quantified. Flow cytometry was used to determine expression of Mac-1 on neutrophils and CD40L on platelets. Intravital fluorescence microscopy was used to analyze leukocyte-endothelial cell interactions in the pulmonary microcirculation.RESULTS: The MMP inhibitor reduced sepsis-induced release of CD40L and maintained normal levels of CD40L on platelets. Inhibition of MMP decreased CLP-induced neutrophil expression of Mac-1, formation of CXC chemokines and edema as well as neutrophil infiltration in the lung. Intravital fluorescence microscopy revealed that the MMP inhibitor attenuated leukocyte adhesion in venules whereas capillary trapping of leukocytes was not affected by MMP inhibition.CONCLUSIONS: We describe a novel role of metalloproteinases in regulating platelet-dependent activation and infiltration of neutrophils in septic lung injury which might be related to controlling CD40L shedding from platelets. We conclude that targeting metalloproteinases may be a useful strategy for limiting acute lung injury in abdominal sepsis.
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| 40. |
- Rahman, Milladur
(author)
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Platelet-dependent pulmonary recruitment of neutrophils in abdominal sepsis
- 2012
-
Doctoral thesis (other academic/artistic)abstract
- Sepsis and subsequent multiple organ failure remain the major cause of mortality in intensive care units. Leukocyte-mediated tissue damage is a key feature in septic lung injury. Accumulating data suggest that platelets play a role in inflammation and tissue injury. However, the role of platelets in sepsis-induced leukocyte recruitment and lung edema formation in abdominal sepsis is not demonstrated yet. We hypothesized that platelets may play a significant role in pulmonary neutrophil recruitment and tissue damage in abdominal sepsis. For this purpose, we used the mice cecal ligation and puncture (CLP) model of abdominal sepsis. CLP causes significant pulmonary damage characterized by neutrophil infiltration, increased levels of CXC chemokines and increased edema formation in the lung. CLP also provoked Mac-1 expression on circulating neutrophils. Interestingly, depletion of platelets reduced CLP-induced lung damage, neutrophil recruitment in the bronchoalveolar space and edema formation as well as up-regulation of Mac-1 on neutrophils. However, blocking of platelet-neutrophil aggregates formation did not attenuate CLP-induced lung damage and neutrophil activation suggesting that platelets regulate sepsis-induced lung damage via up-regulation of Mac-1 in a contact independent manner. We also found that plasma levels of soluble CD40L was significantly increased in septic mice. Use of CD40L-deficient mice confirmed that platelet-derived CD40L is a pivotal mediator of neutrophil activation and recruitment in abdominal sepsis and this platelet mediated neutrophil activation was indirect and mediated via formation of MIP-2 and CXCR2 signaling. In addition, we observed a significant increase of soluble CD40L levels in septic patients. Interestingly, we found that inhibition of matrix MMPs reduced Mac-1 up-regulation on neutrophils and CXC chemokine formation in the septic lung injury. We also found that MMP-9 levels are significantly increased in septic mice but not MMP-2. In vitro studies revealed that activated platelets up-regulate surface expression of MMP-9 and that inhibition of MMP-9 decreased platelet shedding of CD40L. Use of MMP-9-deficient mice suggested that MMP-9 regulates platelet CD40L shedding in abdominal sepsis. Moreover, pulmonary infiltration of neutrophils as well as edema formation and lung injury were markedly decreased in septic animals lacking MMP-9. Plasma levels of MMP-9 were significantly increased in patients with septic shock compared to healthy controls. Taken together, platelets regulate neutrophil activation in abdominal sepsis via MMP-9-dependent shedding of platelet-derived CD40L. Thus, MMP-9 and CD40L may constitute novel and effective therapeutic targets in abdominal sepsis.
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