| 41. |
- Vilhjalmsson, Dadi, et al.
(author)
-
Compression anastomotic ring-locking procedure (CARP) is a safe and effective method for intestinal anastomoses following left-sided colonic resection.
- 2015
-
In: International Journal of Colorectal Disease. - : Springer Science and Business Media LLC. - 1432-1262 .- 0179-1958. ; 30:7, s. 969-975
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Journal article (peer-reviewed)abstract
- Compression anastomotic ring-locking procedure (CARP) is a novel procedure for creating colonic anastomoses. The surgical procedure allows perioperative quantification of the compression pressure between the intestinal ends within the anastomosis and postoperative monitoring of the anastomotic integrity. We have recently shown that CARP is a safe and effective method for colonic anastomoses in pigs, and the purpose of the present study was to evaluate CARP for colonic anastomoses in humans.
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| 42. |
- Vilhjalmsson, Dadi, et al.
(author)
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The compression anastomotic ring-locking procedure : a novel technique for creating a sutureless colonic anastomosis
- 2015
-
In: European Surgical Research. - : S. Karger AG. - 0014-312X .- 1421-9921. ; 54:3-4, s. 139-147
-
Journal article (peer-reviewed)abstract
- BACKGROUND/AIM: Compression anastomoses might represent an improvement over traditional hand-sewn or stapled techniques. Herein, we describe a novel concept of sutureless colonic anastomosis named compression anastomotic ring-locking procedure (CARP).MATERIALS AND METHODS: The surgical device consists of two anastomotic rings and their associated helping tools, facilitating the placement of the rings into the intestinal ends. Furthermore, four catheters are connected to the surgical device, allowing the evaluation of the anastomosis during and after surgery. A total of 31 pigs underwent a low colocolic anastomosis using the anastomotic rings. The compression pressure was measured perioperatively and up to 96 h after surgery. Anastomotic integrity and morphology were analyzed by use of radiology and histology, respectively. A long-term follow-up was conducted in a subgroup of pigs up to 108 days after surgery when the bursting pressure and stricture formation were examined.RESULTS: All animals recovered uneventfully, and macroscopic examination revealed intact anastomoses without signs of pathological inflammation or adhesions. The perioperative compression pressure was inversely proportional to the gap size between the anastomotic rings. For example, an anastomotic gap of 1.5 mm created a colonic anastomosis with a perioperative compression pressure of 91 mbar, which remained constant for up to 48 h and resulted in a markedly increased compression pressure. Contrast infusion via the catheters effectively visualized the anastomoses, and no leakage was detected within the study. The surgical device was spontaneously evacuated from the intestines within 6 days after surgery. Histology showed collagen bridging of the anastomoses already 72 h after surgery. Long-term follow-up (54-108 days) revealed no stricture formation in the anastomoses, and the bursting pressure ranged from 120 to 235 mbar. The majority of bursts (10/12) occurred distant from the anastomoses.CONCLUSION: We conclude that the surgical device associated to CARP is safe and efficient for creating colonic anastomoses. Further studies in patients undergoing colorectal surgery are warranted.
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| 43. |
- Wang, Yongzhi, et al.
(author)
-
Monocytes regulate systemic coagulation and inflammation in abdominal sepsis.
- 2015
-
In: American Journal of Physiology: Heart and Circulatory Physiology. - : American Physiological Society. - 1522-1539 .- 0363-6135. ; 308:5, s. 540-547
-
Journal article (peer-reviewed)abstract
- Abdominal sepsis is associated with significant changes in systemic inflammation and coagulation. The purpose of this study was to examine the role of peripheral blood monocytes for systemic coagulation, including thrombin generation and consumption of coagulation factors. Abdominal sepsis was induced by cecal ligation and puncture (CLP) in C57BL/6 mice. Plasma and lung levels of interleukin-6 (IL-6), CXC chemokines (CXCL1, CXCL2 and CXCL5) as well as pulmonary activity of myeloperoxidase (MPO), thrombin generation and coagulation factors were determined 6h after CLP induction. Administration of clodronate liposomes decreased circulating levels of monocytes by 96%. Time to peak thrombin formation was increased and peak and total thrombin generation was decreased in plasma from CLP animals. Monocyte depletion decreased time to peak formation of thrombin and increased peak and total generation of thrombin in septic animals. In addition, monocyte depletion decreased the CLP-induced increase in the levels of thrombin-antithrombin complexes in plasma. Depletion of monocytes increased plasma levels of prothrombin, factor V, factor X, protein C and in septic mice. Moreover, depletion of monocytes decreased CLP-induced levels of IL-6 and CXC chemokines in plasma and lung by more than 59% and 20%, respectively. CLP-induced MPO activity in the lung was attenuated by 44% in animals depleted of monocytes. Taken together, our findings show for the first time that peripheral blood monocytes regulates systemic coagulation and improve our understanding of the pathophysiology of sepsis and encourage further attempts to target innate immune cell functions in abdominal sepsis.
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| 44. |
- Wang, Yongzhi, et al.
(author)
-
Neutrophil extracellular trap-microparticle complexes enhance thrombin generation via the intrinsic pathway of coagulation in mice
- 2018
-
In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1
-
Journal article (peer-reviewed)abstract
- Abdominal sepsis is associated with dysfunctional hemostasis. Thrombin generation (TG) is a rate-limiting step in systemic coagulation. Neutrophils can expell neutrophil extracellular traps (NETs) and/or microparticles (MPs) although their role in pathological coagulation remains elusive. Cecal ligation and puncture (CLP)-induced TG in vivo was reflected by a reduced capacity of plasma from septic animals to generate thrombin. Depletion of neutrophils increased TG in plasma from CLP mice. Sepsis was associated with increased histone 3 citrullination in neutrophils and plasma levels of cell-free DNA and DNA-histone complexes and administration of DNAse not only eliminated NET formation but also elevated TG in sepsis. Isolated NETs increased TG and co-incubation with DNAse abolished NET-induced formation of thrombin. TG triggered by NETs was inhibited by blocking factor XII and abolished in factor XII-deficient plasma but intact in factor VII-deficient plasma. Activation of neutrophils simultaneously generated large amount of neutrophil-derived MPs, which were found to bind to NETs via histone-phosphatidylserine interactions. These findings show for the first time that NETs and MPs physically interact, and that NETs might constitute a functional assembly platform for MPs. We conclude that NET-MP complexes induce TG via the intrinsic pathway of coagulation and that neutrophil-derived MPs play a key role in NET-dependent coagulation.
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| 45. |
- Wang, Yongzhi, et al.
(author)
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Neutrophil extracellular trap-microparticle complexes trigger neutrophil recruitment via high-mobility group protein 1 (HMGB1)-toll-like receptors(TLR2)/TLR4 signalling
- 2019
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In: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 176:17, s. 3350-3363
-
Journal article (peer-reviewed)abstract
- Background and Purpose: Recent data suggest that neutrophil extracellular traps (NETs) form aggregates with microparticles (MPs) upon activation of neutrophils although the functional role of NET-MP complexes remain elusive. The objective of this study was to examine the role of NET-MP aggregates in leukocyte recruitment in vivo. Experimental Approach: PMA stimulation of murine bone marrow neutrophils generated NET-MP complexes and pretreatment with caspase and calpain inhibitors resulted in the formation of NETs depleted of MPs. Leukocyte–endothelium interactions were studied by using intravital microscopy of the mouse cremaster microcirculation. Key Results: Intrascrotal injection of NET-MP aggregates dose-dependently increased leukocyte recruitment. In contrast, leukocyte responses were markedly reduced after administration of NETs depleted of MPs. Neutrophil depletion abolished intravascular and extravascular leukocytes in response to challenge with NET-MP complexes. Electron microscopy revealed that NET-associated MPs express HMGB1. Notably, immunoneutralization of HMGB1 markedly decreased NET-MP complex-induced neutrophil accumulation. Moreover, inhibition of TLR2 and TLR4 significantly reduced neutrophil recruitment in response to NET-MP aggregates. Conclusions and Implications: These data show that NET-MP complexes are potent inducers of neutrophil recruitment, which is dependent on HMGB1 expressed on MPs and mediated via TLR2 and TLR4. Blocking MP binding to NETs or downstream inhibition of the HMGB1-TLR2/TLR4 axis might provide useful targets to attenuating NET-dependent tissue damage in acute inflammation.
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| 46. |
- Wang, Yongzhi, et al.
(author)
-
Platelet-derived microparticles regulates thrombin generation via phophatidylserine in abdominal sepsis
- 2018
-
In: Journal of Cellular Physiology. - : Wiley. - 1097-4652 .- 0021-9541. ; 233:2, s. 1051-1060
-
Journal article (peer-reviewed)abstract
- Sepsis is associated with dysfunctional coagulation. Recent data suggest that platelets play a role in sepsis by promoting neutrophil accumulation. Herein, we show that cecal ligation and puncture (CLP) triggered systemic inflammation, which is characterized by formation of IL-6 and CXC chemokines as well as neutrophil accumulation in the lung. Platelet depletion decreased neutrophil accumulation, IL-6, and CXC chemokines formation in septic lungs. Depletion of platelets increased peak thrombin formation and total thrombin generation (TG) in plasma from septic animals. CLP elevated circulating levels of platelet-derived microparticles (PMPs). In vitro generated PMPs were a potent inducer of TG. Interestingly, in vitro wild-type recombinant annexin V abolished PMP-induced thrombin formation whereas a mutant annexin V protein, which does not bind to phosphatidylserine (PS), had no effect. Administration of wild-type, but not mutant annexin V, significantly inhibited thrombin formation in septic animals. Moreover, CLP-induced formation of thrombin-antithrombin complexes were reduced in platelet-depleted mice and in animals pretreated with annexin V. PMP-induced TG attenuated in FXII- and FVII-deficient plasma. These findings suggest that sepsis-induced TG is dependent on platelets. Moreover, PMPs formed in sepsis are a potent inducer of TG via PS exposure, and activation of both the intrinsic and extrinsic pathway of coagulation. In conclusion, these observations suggest that PMPs and PS play an important role in dysfunctional coagulation in abdominal sepsis.
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| 47. |
- Wang, Yongzhi, et al.
(author)
-
Rac1 regulates bacterial toxin-induced thrombin generation.
- 2016
-
In: Inflammation Research. - : Springer Science and Business Media LLC. - 1420-908X .- 1023-3830.
-
Journal article (peer-reviewed)abstract
- Systemic inflammatory response syndrome is associated with severe coagulopathy. The purpose of this study was to examine thrombin generation in systemic inflammation triggered by the endotoxin lipopolysaccharide (LPS) and the exotoxin streptococcal M1 protein.
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| 48. |
- Wang, Yongzhi, et al.
(author)
-
Rac1 regulates sepsis-induced formation of platelet-derived microparticles and thrombin generation
- 2017
-
In: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 0006-291X. ; 487:4, s. 887-891
-
Journal article (peer-reviewed)abstract
- Dysfunctional coagulation aggravates clinical outcome in patients with sepsis. The aim of this study was to define the role of Rac-1 in the formation of platelet-derived microparticles (PMPs) and thrombin generation (TG) in abdominal sepsis. Male C57BL/6 mice underwent cecal ligation and puncture (CLP). Scanning electron microscopy and flow cytometry were used to quantify PMPs. TG was determined by use of a fluorimetric assay. It was found that CLP increased Rac1 activity in platelets, which was abolished by administration of the Rac1 inhibitor NSC23766. Sepsis-induced TG in vivo was reflected by reduced capacity of plasma from septic animals to generate thrombin ex vivo. Administration of NSC23766 increased peak and total TG in plasma from CLP mice indicating that Rac-1 regulates sepsis-induced formation of thrombin. The number of circulating PMPs was markedly elevated in animals with abdominal sepsis. Treatment with NSC23766 significantly decreased formation of PMPs in septic mice. Platelet activation in vitro caused release of numerous MPs. Notably, NSC23766 abolished PMP formation in activated platelets in vitro. These findings suggest that Rac-1 regulates PMP formation and TG in sepsis and that inhibition of Rac1 activity could be a useful target to inhibit dysfunctional coagulation in abdominal sepsis.
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| 49. |
- Wang, Yongzhi, et al.
(author)
-
Thrombin generation in abdominal sepsis is Rho-kinase-dependent.
- 2015
-
In: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 460:3, s. 691-696
-
Journal article (peer-reviewed)abstract
- Sepsis causes severe derangements of the coagulation system. However, the signaling mechanisms regulating sepsis-induced thrombin generation remain elusive. Herein, we hypothesized that Rho-kinase might be an important regulator of thrombin generation in abdominal sepsis. Abdominal sepsis was induced by cecal ligation and puncture (CLP) in C57Bl/6 mice. Thrombin generation, coagulation factors, lung histology and myeloperoxidase (MPO) activity were determined 6 h and 24 h after induction of CLP. Induction of CLP triggered a systemic inflammatory response characterized by neutrophil accumulation and tissue injury in the lung as well as thrombocytopenia and leukocytopenia. Administration of Y-27632, a Rho-kinase inhibitor, attenuated these markers of systemic inflammation in CLP animals. Moreover, peak thrombin formation was decreased by 77% and 81% in plasma from mice 6 h and 24 h after induction of CLP. Total thrombin generation was reduced by 64% and 67% 6 h and 24 h after CLP induction, respectively. Notably, administration of Y-27632 increased peak formation by 99% and total thrombin generation by 66% in plasma from septic animals. In addition, CLP markedly decreased plasma levels of prothrombin, factor V and factor X at 6 h and 24 h. Interestingly, Rho-kinase inhibition significantly enhanced levels of prothrombin, factor V and factor X in plasma from septic mice. In addition, inhibition of Rho-kinase decreased CLP-induced elevations of CXCL2 by 36%and interleukin-6 by 38%. These novel findings suggest that sepsis-induced thrombin generation is regulated by Rho-kinase. Moreover, inhibition of Rho-kinase reverses sepsis-evoked consumption of coagulation factors. Thus, our results show that targeting Rho-kinase signaling might protect against coagulation dysfunction in abdominal sepsis.
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| 50. |
- Wetterholm, Erik, et al.
(author)
-
Platelet-derived CXCL4 regulates neutrophil infiltration and tissue damage in severe acute pancreatitis
- 2016
-
In: Translational Research. - : Elsevier BV. - 1931-5244. ; 176, s. 105-118
-
Journal article (peer-reviewed)abstract
- Platelets are known to play an important role in acute pancreatitis (AP) via promotion of neutrophil accumulation, although mechanisms behind platelet-dependent accumulation of neutrophils in the pancreas remain elusive. Platelets contain a wide spectrum of different pro-inflammatory compounds, such as chemokines. CXCL4 (platelet factor 4) is one of the most abundant chemokine in platelets, and we hypothesized that CXCL4 might be involved in platelet-dependent accumulation of neutrophils in the inflamed pancreas. The aim of this study was to examine the role of CXCL4 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 an antibody against platelets or CXCL4 before induction of pancreatitis. Plasma and lung levels of CXCL2, CXCL4, and interleukin (IL)-6 were determined by use of enzyme-linked immunosorbent assay. Flow cytometry was used to examine surface expression of macrophage-1 (Mac-1) on neutrophils. Plasma was obtained from healthy individuals (controls) and patients with AP. Challenge with taurocholate increased plasma levels of CXCL4, and depletion of platelets markedly reduced plasma levels of CXCL4 indicating that circulating levels of CXCL4 are mainly derived from platelets in AP. Inhibition of CXCL4 reduced taurocholate-induced neutrophil recruitment, IL-6 secretion, edema formation, amylase release, and tissue damage in the pancreas. However, immunoneutralization of CXCL4 had no effect on CXCL2-evoked neutrophil expression of Mac-1 or chemotaxis in vitro, suggesting an indirect effect of CXCL4 on neutrophil recruitment in AP. Targeting CXCL4 significantly attenuated plasma and lung levels of CXCL2, which is a potent neutrophil chemoattractant, and inhibition of the CXCL2 receptor attenuated neutrophil infiltration and tissue damage in the inflamed pancreas. A significant role of CXCL4 was confirmed in an alternate model of AP induced by L-arginine challenge. Moreover, patients with AP had significantly increased plasma levels of CXCL4 compared with healthy controls. These findings’ results suggest that platelet-derived CXCL4 is a potent stimulator of neutrophil accumulation in AP and that this is mediated via generation of CXCL2 in the inflamed pancreas. We conclude that CXCL4 plays an important role in pancreatic inflammation and that targeting CXCL4 might be a useful way to ameliorate tissue damage in AP.
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