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- Thorlacius, Karin, et al.
(författare)
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Protective effect of fasudil, a Rho-kinase inhibitor, on chemokine expression, leukocyte recruitment, and hepatocellular apoptosis in septic liver injury.
- 2006
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Ingår i: Journal of Leukocyte Biology. - : Oxford University Press (OUP). - 1938-3673 .- 0741-5400. ; 79:5, s. 923-931
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Tidskriftsartikel (refereegranskat)abstract
- Rho-kinase signaling regulates important features of inflammatory reactions. Herein, we investigated the effect and mechanisms of action of the Rho-kinase inhibitor fasudil in endotoxemic liver injury. C57/BL/6 mice were challenged with lipopolysaccharide (LPS) and D-galactosamine, with or without pretreatment with the Rho-kinase inhibitor fasudil. Six hours after endotoxin challenge, leukocyte-endothelium interactions in the hepatic microvasculature were studied by use of intravital fluorescence microscopy and tumor necrosis factor {alpha} (TNF-{alpha}); CXC chemokines as well as liver enzymes and apoptosis were determined. Administration of fasudil reduced LPS-induced leukocyte adhesion in postsinusoidal venules and sequestration in sinusoids. Moreover, we found that fasudil abolished extravascular infiltration of leukocytes as well as production of TNF-{alpha} and CXC chemokines in the liver of endotoxemic mice. Liver enzymes and hepatocellular apoptosis were markedly reduced, and sinusoidal perfusion was improved significantly in endotoxemic mice pretreated with fasudil. Our novel data document that fasudil is a potent inhibitor of endotoxin-induced expression of TNF-{alpha} and CXC chemokines as well as leukocyte infiltration and hepatocellular apoptosis in the liver. Based on the present findings, it is suggested that inhibition of the Rho-kinase signaling pathway may be a useful target in the treatment of septic liver injury.
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| 4. |
- Zawadzki, Antoni, et al.
(författare)
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Verapamil Inhibits L-type Calcium Channel Mediated Apoptosis in Human Colon Cancer Cells.
- 2008
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Ingår i: Diseases of the Colon & Rectum. - : Ovid Technologies (Wolters Kluwer Health). - 0012-3706. ; 51, s. 1696-1702
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Treatment with calcium channel blockers have been associated with increased colon cancer mortality in epidemiologic studies. We examined the potential expression and function of calcium channels in two human colon cancer cell lines. METHODS: Both primary (collected at operation) and commercially-available human colon cancer cell lines were used. The colon cancer cells were incubated with a calcium channel blocker (verapamil) and a calcium channel agonist (BayK 8644) at clinically relevant concentrations. L-type calcium channel mRNA was determined by reverse-transcription polymerase chain reaction. Intracellular calcium ion levels were measured with fluorometry and apoptosis with flow cytometry. RESULTS: Both types of cells expressed L-type calcium channel mRNA, comprising an alpha-1D and a beta-3 subunit, whereas the cells were negative for N-type and P-type channels. The selective calcium channel agonist (BayK 8644), dose-dependently increased intracellular calcium ion levels and the level of apoptosis in primary human colon cancer cells. Pretreatment with verapamil completely abolished both calcium channel agonist-induced influx of calcium and apoptosis in these cells. CONCLUSIONS: These data demonstrate that human colon cancer cells express L-type calcium channels that mediate calcium influx and apoptosis, which warrants further studies to determine whether calcium channel blockers may promote colon cancer growth.
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| 5. |
- Röme, Andrada, et al.
(författare)
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Critical Role of P-Selectin and Lymphocyte Function Antigen-1 in Radiation-Induced Leukocyte-Endothelial Cell Interactions in the Colon.
- 2007
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Ingår i: Diseases of the Colon & Rectum. - : Ovid Technologies (Wolters Kluwer Health). - 0012-3706. ; 50:12, s. 2194-2202
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Radiation therapy is frequently used in treating different types of tumors, although associated with serious side effects, such as fibrosis and complicated diarrhea. This study was designed to define the adhesive mechanisms behind radiotherapy-induced leukocyte recruitment in the colon. Methods All mice, except control animals, were radiated with a single dose of 20 Gy. Mice were pretreated with an isotype-matched control antibody or a monoclonal antibody directed against P-selectin. In separate experiments, lymphocyte function antigen-1–deficient animals were used. Leukocyte rolling and firm adhesion were determined by use of inverted intravital fluorescence microscopy 16 hours after radiation. Results It was found that immunoneutralization of P-selectin reduced leukocyte rolling by 83 percent and adhesion by 87 percent in radiated mice. Moreover, radiation-induced leukocyte adhesion in LFA-1-deficient mice was decreased by 94 percent compared with wild-type animals. Conclusions This study demonstrates that leukocyte rolling is mediated by P-selectin and that firm leukocyte adhesion is supported by lymphocyte function antigen-1 in radiation-induced enteritis. Moreover, P-selectin-dependent leukocyte rolling is a precondition for subsequent leukocyte adhesion in radiation-induced intestinal injury. Thus, targeting P-selectin and/or lymphocyte function antigen-1 may protect against pathologic inflammation in the colon induced by radiotherapy.
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| 7. |
- Muhammad, Asad, et al.
(författare)
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Platelets support pulmonary recruitment of neutrophils in abdominal sepsis
- 2009
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Ingår i: Critical Care Medicine. - 1530-0293. ; 37:4, s. 1389-1396
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Tidskriftsartikel (refereegranskat)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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| 8. |
- Slotta, Jan, et al.
(författare)
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Central Role of Rho Kinase in Lipopolysaccharide-Induced Platelet Capture on Venous Endothelium.
- 2008
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Ingår i: Journal of Investigative Medicine. - 1708-8267. ; 56:4, s. 720-725
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:: Platelet-endothelial cell interactions play a key role in hemostasis and pathological coagulation and are dependent on different surface molecules that are expressed upon activation (eg, mediated by lipopolysaccharide [LPS]). Recently, we have shown that Rho kinase plays a central role in LPS-mediated leukocyte-endothelial cell interactions. We investigated the role of Rho-kinase in inflammatory interactions between platelets and the endothelium in femoral veins in vivo. METHODS:: Mice were injected intravenously with LPS (0.5 mg/kg)/D-galactosamine (900 mg/kg), and Rho kinase was blocked with fasudil 15 minutes before LPS application. Four hours after LPS administration, intravital fluorescence microscopy of the femoral vein was performed, and primary and secondary platelet-endothelial cell interactions were visualized after in vivo platelet staining with rhodamine 6G. RESULTS:: Intravital microscopy showed a significant increase in platelet tethering, rolling, and firm adhesion as well as platelet secondary capture in LPS-treated mice. Rho-kinase inhibition by fasudil significantly reduced platelet tethering, rolling, and firm adhesion. Interestingly, functional blockade of Rho kinase was also able to diminish secondary platelet capture by 79%. CONCLUSIONS:: From our data, we conclude that Rho-kinase signaling plays a central role in the regulation of LPS-induced platelet-endothelial cell interactions in large veins in vivo. Thus, Rho-kinase inhibition might be useful in prevention or treatment of pathological inflammation and endotoxin-mediated hypercoagulation.
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| 9. |
- Asaduzzaman, Muhammad, et al.
(författare)
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LFA-1 AND MAC-1 MEDIATE PULMONARY RECRUITMENT OF NEUTROPHILS AND TISSUE DAMAGE IN ABDOMINAL SEPSIS.
- 2008
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Ingår i: Shock. - : Ovid Technologies (Wolters Kluwer Health). - 1540-0514 .- 1073-2322. ; 30, s. 254-259
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophil-mediated lung damage is an insidious feature in septic patients, although the adhesive mechanisms behind pulmonary recruitment of neutrophils in polymicrobial sepsis remain elusive. The aim of the present study was to define the role of lymphocyte function-antigen 1 (LFA-1) and membrane-activated complex 1 (Mac-1) in septic lung injury. Pulmonary edema, bronchoalveolar infiltration of neutrophils, levels of myeloperoxidase, and CXC chemokines were determined after cecal ligation and puncture (CLP). Mice were treated with monoclonal antibodies directed against LFA-1 and Mac-1 before CLP induction. Cecal ligation and puncture induced clear-cut pulmonary damage characterized by edema formation, neutrophil infiltration, and increased levels of CXC chemokines in the lung. Notably, immunoneutralization of LFA-1 or Mac-1 decreased CLP-induced neutrophil recruitment in the bronchoalveolar space by more than 64%. Moreover, functional inhibition of LFA-1 and Mac-1 abolished CLP-induced lung damage and edema. However, formation of CXC chemokines in the lung was intact in mice pretreated with the anti-LFA-1 and anti-Mac-1 antibodies. Our data demonstrate that both LFA-1 and Mac-1 regulate pulmonary infiltration of neutrophils and lung edema associated with abdominal sepsis. Thus, these novel findings suggest that LFA-1 or Mac-1 may serve as targets to protect against lung injury in polymicrobial sepsis.
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