| 1. |
- Laschke, Matthias, et al.
(författare)
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Rho-Kinase Inhibitor Attenuates Cholestasis-Induced CXC Chemokine Formation, Leukocyte Recruitment, and Hepatocellular Damage in the Liver.
- 2010
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Ingår i: The Journal of surgical research. - : Elsevier BV. - 1095-8673 .- 0022-4804. ; 159, s. 666-673
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In the present experimental study, we analyzed the role of Rho-kinase during obstructive cholestasis by studying the effect of the Rho-kinase inhibitor Y-27632 on hepatic CXC chemokine formation, leukocyte recruitment and hepatocellular damage. MATERIALS AND METHODS: C57BL/6 mice underwent bile duct ligation (BDL) to induce obstructive cholestasis. Mice were pretreated with Y-27632 (1 and 10mg/kg) or the vehicle PBS. Sham-operated animals served as controls. After 12h, hepatic accumulation of leukocytes and sinusoidal perfusion were determined using intravital fluorescence microscopy. Hepatocellular damage was monitored by measuring serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). CXC chemokines in the liver were analyzed by ELISA. RESULTS: Administration of 10mg/kg of Y-27632 protected against cholestasis-induced hepatocellular damage indicated by a more than 87% reduction of ALT and AST in BDL mice. Moreover, this Rho-kinase inhibitor significantly decreased BDL-induced production of CXC chemokines by 44-83% and leukocyte recruitment by 60%. Finally, treatment with Y-27632 restored sinusoidal perfusion in cholestatic animals. CONCLUSIONS: Our findings indicate that the Rho-kinase signaling pathway plays a key role in the pathophysiology of cholestatic liver injury. Thus, targeting Rho-kinase activity may represent a new therapeutic approach in the treatment of inflammation and liver injury in cholestatic liver diseases.
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| 2. |
- Roller, Jonas, et al.
(författare)
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How to detect a dwarf - in vivo imaging of nanoparticles in the lung.
- 2011
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Ingår i: Nanomedicine: Nanotechnology, Biology and Medicine. - : Elsevier BV. - 1549-9642 .- 1549-9634. ; 7:6, s. 753-762
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Tidskriftsartikel (refereegranskat)abstract
- Nanotechnology is a rapidly developing field in science and industry. The exposure to nanoparticles (NPs) will steadily grow in the future and, thus, there is an urgent need to study potential impacts of the interaction between NPs and the human body. The respiratory tract is the route of entry for all accidentally inhaled NPs. Moreover, NPs may intentionally be delivered into the lung as contrast agents and drug delivery systems. The present review provides an overview of currently used techniques for the in vivo imaging of NPs in the lung, including X-ray, computed tomography (CT), gamma camera imaging, positron emission tomography (PET), magnetic resonance imaging (MRI), near-infrared imaging and intravital fluorescence microscopy. Studies based on these techniques may contribute to the development of novel NP-based drug delivery systems and contrast agents. In addition, they may provide completely new insights into nanotoxicological processes.
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| 3. |
- Santén, Stefan, et al.
(författare)
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Rho-kinase signalling regulates CXC chemokine formation and leukocyte recruitment in colonic ischemia-reperfusion.
- 2010
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Ingår i: International Journal of Colorectal Disease. - : Springer Science and Business Media LLC. - 1432-1262 .- 0179-1958. ; 25, s. 1063-1070
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: Leukocyte recruitment is a key feature in ischemia-reperfusion (I/R)-induced tissue injury. The aim of the present study was to investigate the effect of Rho-kinase inhibition on I/R-provoked leukocyte recruitment in the colon. METHODS: C57BL/6 mice were subjected to 30 min of ischemia by clamping of the superior mesenteric artery followed by 120 min of reperfusion. Intraperitoneal pretreatment with the selective Rho-kinase inhibitors fasudil (4-40 mg/kg) and Y-27632 (1-10 mg/kg) was administered prior to induction of colonic I/R. Leukocyte-endothelium interactions were analyzed by intravital fluorescence microscopy. Colonic content of tumour necrosis factor-alpha (TNF-alpha) and the CXC chemokines macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (KC) were determined by ELISA. Additionally, colonic activity of myeloperoxidase (MPO), a marker of leukocyte infiltration, and malondialdehyde (MDA), were quantified. RESULTS: Fasudil and Y-27632 pretreatment decreased I/R-induced leukocyte rolling and adhesion by 76% and 96%, respectively. Moreover, Rho-kinase interference reduced formation of TNF-alpha, MIP-2 and KC by more than 68% in the reperfused colon. Additionally, the reperfusion-provoked increase in the levels of MPO and MDA in the colon decreased after Rho-kinase inhibition by 69% and 42%, respectively. CONCLUSIONS: Our data demonstrate that inhibition of Rho-kinase activity decrease I/R-induced leukocyte rolling, adhesion and recruitment in the colon. Moreover, these findings show that Rho-kinase signalling regulates TNF-alpha and CXC chemokine formation as well as lipid peroxidation in the reperfused colon. Thus, targeting Rho-kinase signalling may be a useful strategy in order to protect against pathological inflammation in the colon.
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| 4. |
- Schramm, Rene, et al.
(författare)
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Atherosclerosis aggravates ischemia/reperfusion injury in the gut and remote damage in the liver and the lung
- 2011
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Ingår i: Inflammation Research. - : Springer Science and Business Media LLC. - 1420-908X .- 1023-3830. ; 60:6, s. 555-567
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Tidskriftsartikel (refereegranskat)abstract
- Objective We investigated whether mesenteric ischemia/reperfusion (I/R)-associated gut injury and remote liver and lung damage are affected by prevalent atherosclerosis. Methods Mesenteric ischemia was induced in atherosclerotic ApoE-deficient (ApoE(-/-)) and control C57BL/6 mice by clamping the superior mesenteric artery for 30 min. Mesenteric microcirculatory dysfunction and leukocytic inflammation were studied in the terminal ileum by intravital fluorescence microscopy (IVM). Histological analyses included quantitative assessment of parenchymal injury in the terminal ileum, liver and lung. Results In the gut, IVM of the terminal ileum revealed aggravated postischemic microcirculatory dysfunction and absence of reactive hyperemia-induced vasodilation in atherosclerotic mice compared to controls. In addition, leukocyte-endothelial cell adhesive interactions, i.e. rolling and firm adhesion, were significantly increased in atherosclerotic animals. This was associated with enhanced mucosal tissue damage in ApoE(-/-) mice. Moreover, mesenteric I/R-provoked remote parenchymal injury in the liver was found to be significantly aggravated in atherosclerotic mice. This was accompanied by enhanced neutrophilic lung inflammation in ApoE(-/-) mice. Conclusion Prevalent generalized atherosclerosis not only aggravates splanchnic microcirculatory dysfunction and leukocytic inflammation in response to mesenteric I/R, but also exacerbates mucosal tissue damage and remote injury in the liver and the lung.
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| 5. |
- Slotta, Jan E, et al.
(författare)
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Simvastatin Attenuates Hepatic Sensitization to Lipopolysaccharide After Partial Hepatectomy.
- 2010
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Ingår i: The Journal of surgical research. - : Elsevier BV. - 1095-8673 .- 0022-4804. ; 162, s. 184-192
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Hepatic resection may be curative in patients with hepatobiliary malignancies but excessive loss of liver volume may cause hepatic dysfunction and increase susceptibility to subsequent postoperative infections and sepsis. Herein, we hypothesized that pretreatment with simvastatin may protect against lipopolysaccharide (LPS)-induced liver damage after partial hepatectomy. MATERIALS AND METHODS: Male C57Bl/6 mice underwent 68% hepatectomy and exposed to LPS after 24h. Animals were pretreated with simvastatin (0.02 and 0.2mg/kg). Serum alanine aminotransferase (ALT) and tumor necrosis factor-alpha (TNF-alpha) as well as leukocyte infiltration and hepatocyte apoptosis were examined 6h after LPS challenge. An in vitro endothelial cell adhesion assay was used to study the mechanisms of simvastatin on leukocyte adhesion and the role of P-selectin and lymphocyte function antigen-1 (LFA-1). RESULTS: Partial hepatectomy increased the sensitivity of the remnant liver tissue to LPS-provoked tissue injury. Simvastatin pretreatment reduced the LPS-induced increase in serum levels of ALT by 65% in hepatectomized animals. Moreover, simvastatin decreased leukocyte infiltration and hepatocyte apoptosis in the liver remnant of endotoxemic mice. LPS-provoked serum levels of TNF-alpha were decreased by 83% in hepatectomized animals treated with simvastatin. TNF-alpha-induced leukocyte adhesion as well as P-selectin expression in endothelial cells and LFA-1 function were inhibited by simvastatin in vitro. CONCLUSIONS: These novels findings demonstrate that simvastatin protects the remnant liver against endotoxemic injury following major hepatectomy. Thus, simvastatin reduced LPS-induced leukocyte recruitment and hepatocyte apoptosis in the liver remnant. One key mechanism appears to be related to the inhibition of TNF-alpha formation and function (P-selectin expression) as well as to direct actions on LFA-1 function. Thus, simvastatin may represent a novel therapeutic approach to prevent septic liver damage after partial liver resection.
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| 6. |
- Wang, Yongzhi, et al.
(författare)
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Distinct patterns of leukocyte recruitment in the pulmonary microvasculature in response to local and systemic inflammation
- 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. 298-305
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Tidskriftsartikel (refereegranskat)abstract
- Wang Y, Roller J, Slotta JE, Zhang S, Luo L, Rahman M, Syk I, Menger MD, Thorlacius H. Distinct patterns of leukocyte recruitment in the pulmonary microvasculature in response to local and systemic inflammation. Am J Physiol Lung Cell Mol Physiol 304: L298-L305, 2013. First published December 28, 2012; doi:10.1152/ajplung.00246.2012.The mechanisms of leukocyte recruitment in the pulmonary microvasculature in response to local and systemic inflammation remain elusive. Male C57BL/6 mice received lipopolysaccharide (LPS) intrapulmonary (intratracheally, it) or systemically (intravenously, iv) for 1-18 h. Leukocyte responses in lung were analyzed by use of intravital fluorescence microscopy. Plasma and lung levels of CXC chemokines as well as Mac-1 and F-actin expression in leukocytes and bronchoalveolar leukocytes were quantified. Venular leukocyte rolling was markedly increased in response to local LPS but only marginally after systemic LPS. Leukocyte adhesion in venules was enhanced in both groups although adhesion was higher in mice receiving LPS intratracheally compared with LPS intravenously. Systemic LPS caused more leukocytes trapping in capillaries compared with local LPS. The ratio of adherent leukocytes in venules compared with capillaries was higher in response to local LPS, suggesting that leukocytes were more prone to accumulate in venules in local inflammation and in capillaries in systemic inflammation. Systemic LPS triggered higher F-actin formation and Mac-1 expression in leukocytes compared with local LPS. Local and systemic LPS caused similar increases in CXC chemokines in the lung whereas intravenous endotoxin provoked higher levels of CXC chemokines in the circulation. Interestingly, intratracheal LPS increased recruitment of leukocytes in the alveolar space whereas intravenous LPS was ineffective in promoting leukocyte accumulation in the bronchoalveolar space. In conclusion, our data demonstrate that pulmonary microvascular recruitment of leukocytes differs in local and systemic inflammation, which might be related to premature activation and stiffening of circulating leukocytes in endotoxemia.
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| 7. |
- Wang, Yongzhi, et al.
(författare)
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Sepsis-induced leukocyte adhesion in the pulmonary microvasculature in vivo is mediated by CD11a andCD11b.
- 2013
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Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 702:1-3, s. 135-141
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Tidskriftsartikel (refereegranskat)abstract
- Leukocyte accumulation is a rate-limiting step in inflammatory lung injury. The aim of this study was to define the role of CD11a/CD18 and CD11b/CD18 in sepsis-induced leukocyte rolling and adhesion in lung arterioles, capillaries and venules in male C57BL/6 mice using intravital fluorescence microscopy. Cecal ligation and puncture (CLP) markedly increased leukocyte rolling in arterioles and venules but not in capillaries in the lung. Immunoneutralization of CD11a, but not CD11b, decreased CLP-provoked leukocyte rolling in lung arterioles. Inhibition of CD11a or CD11b abolished CLP-induced arteriolar and venular leukocyte adhesion. Immunoneutralization of CD11a and CD11b reduced sepsis-induced leukocyte sequestration in pulmonary capillaries. Moreover, blocking CD11a or CD11b function improved microvascular blood flow in the lung of CLP animals. Considered together, our novel findings show that CD11a and CD11b mediate leukocyte adhesion in both arterioles and venules as well as trapping in capillaries in the lung. In addition, our data demonstrate that CD11a but not CD11b supports leukocyte rolling in pulmonary arterioles. Thus, these findings elucidate the molecular mechanisms behind leukocyte-endothelium interactions in the lung during systemic inflammation.
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