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Sökning: WFRF:(Kenne Ellinor)

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  • Fenhammar, Johan, et al. (författare)
  • Renal effects of treatment with a TLR4-inhibitor in conscious septic sheep
  • 2014
  • Ingår i: Critical Care. - 1364-8535 .- 1466-609X. ; 18:5, s. 488-
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Acute kidney injury (AKI) is a common and feared complication of sepsis. The pathogenesis of sepsis-induced AKI is largely unknown, and therapeutic interventions are mainly supportive. In the present study, we tested the hypothesis that pharmacological inhibition of Toll-like receptor 4 (TLR4) would improve renal function and reduce renal damage in experimental sepsis, even after AKI had already developed. Methods: Sheep were surgically instrumented and subjected to a 36-hour intravenous infusion of live Escherichia coli. After 12 hours, they were randomized to treatment with a selective TLR4 inhibitor (TAK-242) or vehicle. Results: The E. coli caused normotensive sepsis characterized by fever, increased cardiac index, hyperlactemia, oliguria, and decreased creatinine clearance. TAK-242 significantly improved creatinine clearance and urine output. The increase in N-acetyl-beta-D-glucosaminidas, a marker of tubular damage, was attenuated. Furthermore, TAK-242 reduced the renal neutrophil accumulation and glomerular endothelial swelling caused by sepsis. These effects were independent of changes in renal artery blood flow and renal microvascular perfusion in both cortex and medulla. TAK-242 had no effect per se on the measured parameters. Conclusions: These results show that treatment with a TLR4 inhibitor is able to reverse a manifest impairment in renal function caused by sepsis. In addition, the results provide evidence that the mechanism underlying the effect of TAK-242 on renal function does not involve improved macro-circulation or micro-circulation, enhanced renal oxygen delivery, or attenuation of tubular necrosis. TLR4-mediated inflammation resulting in glomerular endothelial swelling may be an important part of the pathogenesis underlying Gram-negative septic acute kidney injury.
  • Kenne, Ellinor, et al. (författare)
  • Neutrophil depletion reduces edema formation and tissue loss following traumatic brain injury in mice
  • 2012
  • Ingår i: Journal of Neuroinflammation. - 1742-2094 .- 1742-2094. ; 9, s. 17-
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Brain edema as a result of secondary injury following traumatic brain injury (TBI) is a major clinical concern. Neutrophils are known to cause increased vascular permeability leading to edema formation in peripheral tissue, but their role in the pathology following TBI remains unclear. Methods: In this study we used controlled cortical impact (CCI) as a model for TBI and investigated the role of neutrophils in the response to injury. The outcome of mice that were depleted of neutrophils using an anti-Gr-1 antibody was compared to that in mice with intact neutrophil count. The effect of neutrophil depletion on blood-brain barrier function was assessed by Evan's blue dye extravasation, and analysis of brain water content was used as a measurement of brain edema formation (24 and 48 hours after CCI). Lesion volume was measured 7 and 14 days after CCI. Immunohistochemistry was used to assess cell death, using a marker for cleaved caspase-3 at 24 hours after injury, and microglial/macrophage activation 7 days after CCI. Data were analyzed using Mann-Whitney test for non-parametric data. Results: Neutrophil depletion did not significantly affect Evan's blue extravasation at any time-point after CCI. However, neutrophil-depleted mice exhibited a decreased water content both at 24 and 48 hours after CCI indicating reduced edema formation. Furthermore, brain tissue loss was attenuated in neutropenic mice at 7 and 14 days after injury. Additionally, these mice had a significantly reduced number of activated microglia/macrophages 7 days after CCI, and of cleaved caspase-3 positive cells 24 h after injury. Conclusion: Our results suggest that neutrophils are involved in the edema formation, but not the extravasation of large proteins, as well as contributing to cell death and tissue loss following TBI in mice.
  • Kenne, Ellinor, et al. (författare)
  • Neutrophils engage the kallikrein-kinin system to open up the endothelial barrier in acute inflammation
  • Ingår i: FASEB journal : official publication of the Federation of American Societies for Experimental Biology. - : The Federation of American Societies for Experimental Biology. - 1530-6860. ; 33:2, s. 2599-2609
  • Tidskriftsartikel (refereegranskat)abstract
    • Neutrophil recruitment and plasma exudation are key elements in the immune response to injury or infection. Activated neutrophils stimulate opening of the endothelial barrier; however, the underlying mechanisms have remained largely unknown. In this study, we identified a pivotal role of the proinflammatory kallikrein-kinin system and consequent formation of bradykinin in neutrophil-evoked vascular leak. In mouse and hamster models of acute inflammation, inhibitors of bradykinin generation, and signaling markedly reduced plasma exudation in response to chemoattractant activation of neutrophils. The neutrophil-driven leak was likewise suppressed in mice deficient in either the bradykinin B2 receptor or factor XII (initiator of the kallikrein-kinin system). In human endothelial cell monolayers, material secreted from activated neutrophils induced cytoskeletal rearrangement, leading to paracellular gap formation in a bradykinin-dependent manner. As a mechanistic basis, we found that a neutrophil-derived heparin-binding protein (HBP/azurocidin) displaced the bradykinin precursor high-molecular-weight kininogen from endothelial cells, thereby enabling proteolytic processing of kininogen into bradykinin by neutrophil and plasma proteases. These data provide novel insight into the signaling pathway by which neutrophils open up the endothelial barrier and identify the kallikrein-kinin system as a target for therapeutic interventions in acute inflammatory reactions.-Kenne, E., Rasmuson, J., Renné, T., Vieira, M. L., Müller-Esterl, W., Herwald, H., Lindbom, L. Neutrophils engage the kallikrein-kinin system to open up the endothelial barrier in acute inflammation.
  • Soehnlein, Oliver, et al. (författare)
  • Neutrophil primary granule proteins HBP and HNP1-3 boost bacterial phagocytosis by human and murine macrophages.
  • 2008
  • Ingår i: Journal of Clinical Investigation. - : Am Soc Clin Investig. - 0021-9738. ; 118:10, s. 3491-3502
  • Tidskriftsartikel (refereegranskat)abstract
    • In acute inflammation, infiltrating polymorphonuclear leukocytes (also known as PMNs) release preformed granule proteins having multitudinous effects on the surrounding environment. Here we present what we believe to be a novel role for PMN-derived proteins in bacterial phagocytosis by both human and murine macrophages. Exposure of macrophages to PMN secretion markedly enhanced phagocytosis of IgG-opsonized Staphylococcus aureus both in vitro and in murine models in vivo. PMN secretion activated macrophages, resulting in upregulation of the Fcgamma receptors CD32 and CD64, which then mediated the enhanced phagocytosis of IgG-opsonized bacteria. The phagocytosis-stimulating activity within the PMN secretion was found to be due to proteins released from PMN primary granules; thorough investigation revealed heparin-binding protein (HBP) and human neutrophil peptides 1-3 (HNP1-3) as the mediators of the macrophage response to PMN secretion. The use of blocking antibodies and knockout mice revealed that HBP acts via beta(2) integrins, but the receptor for HNP1-3 remained unclear. Mechanistically, HBP and HNP1-3 triggered macrophage release of TNF-alpha and IFN-gamma, which acted in an autocrine loop to enhance expression of CD32 and CD64 and thereby enhance phagocytosis. Thus, we attribute what may be a novel role for PMN granule proteins in regulating the immune response to bacterial infections.
  • Steinz, Maarten M., et al. (författare)
  • Oxidative hotspots on actin promote skeletal muscle weakness in rheumatoid arthritis
  • 2019
  • Ingår i: JCI Insight. - : American Society for Clinical Investigation. - 2324-7703 .- 2325-4556 .- 2379-3708. ; 4:9, s. 1-16
  • Tidskriftsartikel (refereegranskat)abstract
    • Skeletal muscle weakness in patients suffering from rheumatoid arthritis (RA) adds to their impaired working abilities and reduced quality of life. However, little molecular insight is available on muscle weakness associated with RA. Oxidative stress has been implicated in the disease pathogenesis of RA. Here we show that oxidative post-translational modifications of the contractile machinery targeted to actin result in impaired actin polymerization and reduced force production. Using mass spectrometry, we identified the actin residues targeted by oxidative 3-nitrotyrosine (3-NT) or malondialdehyde adduct (MDA) modifications in weakened skeletal muscle from mice with arthritis and patients afflicted by RA. The residues were primarily located to three distinct regions positioned at matching surface areas of the skeletal muscle actin molecule from arthritis mice and RA patients. Moreover, molecular dynamic simulations revealed that these areas, here coined “hotspots”, are important for the stability of the actin molecule and its capacity to generate filaments and interact with myosin. Together, these data demonstrate how oxidative modifications on actin promote muscle weakness in RA patients and provide novel leads for targeted therapeutic treatment to improve muscle function.
  • Kenne, Ellinor (författare)
  • Leukocyte recruitment and control of vascular permeability in acute inflammation
  • 2010
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • The inflammatory process is fundamental in host defense against tissue injury or infection. However, the inflammatory reaction may itself cause harm to the host and contribute to tissue damage and organ dysfunction. Leukocyte recruitment and edema formation are key components of the inflammatory response. This thesis reports experiments that were undertaken to further elucidate the mechanisms controlling leukocyte extravasation and concurrent alteration of vascular permeability in acute inflammation. In order for leukocytes to penetrate the vessel wall they need to sequentially interact with the endothelial lining and the perivascular basement membrane (BM) of which laminin-411 is a major constituent. The role of BM laminin-411 in leukocyte recruitment to inflammatory loci was addressed using α4 chain deficient (Lam4-/-) and wild-type (WT) mice. Recruitment of all major leukocyte subsets (neutrophils, monocytes, and lymphocytes) was reduced in Lam4-/- mice compared to WT. With the use of intravital microscopy it was concluded that this decrease was due to impaired diapedesis through the vessel wall. Concurrent with neutrophil recruitment to extravascular tissue, there is an increase in vascular permeability. However, the mechanism behind this alteration is unknown. It was shown that stimulation of neutrophils with the potent chemoattractant leukotriene B4 (LTB4) leads to degranulation and release of, amongst others, heparin binding protein (HBP). Further, postsecretory supernatants from LTB4-stimulated neutrophils induced intracellular calcium mobilization in endothelial cells in vitro and increase in vascular permeability in vivo. Selective removal of HBP from the supernatant significantly reduced these activities indicating a role for HBP in LTB4-induced plasma extravasation. The mechanism behind neutrophil-induced alteration of endothelial barrier function was further investigated and revealed a pivotal role of the kallikrein-kinin system. Neutrophil activation was shown to enable proteolytic processing of high molecular weight kininogen bound to endothelial cells. Accordingly, plasma exudation in vivo in response to challenge with leukocyte chemoattractants was largely annulled by antagonists of the kallikrein-kinin system. Collectively, the data provide novel insight into the regulation of neutrophil-induced plasma extravasation and may help to identify better therapeutic strategies for interventions in inflammatory disease. To investigate the role of neutrophil-induced alterations in vascular permeability in a clinically relevant setting, experiments were performed using controlled cortical impact (CCI) as a model for traumatic brain injury (TBI) in normal mice and in mice that were depleted of neutrophils. Neutrophil depletion did not significantly affect plasma leakage across the bloodbrain barrier after CCI. Yet, neutrophils were found to play a role in edema formation in brain tissue after injury. At a later phase, neutropenic mice displayed a decreased number of activated microglia, and an attenuation of tissue loss after injury. These results suggest that neutrophils contribute to the secondary injury following TBI. Altogether, this thesis provides insight into the role of the BM in leukocyte recruitment and clarifies the mechanism behind neutrophil-induced edema formation in acute inflammation.
  • Mader, Theresa, et al. (författare)
  • Metabolic alteration and muscle dysfunction in mice with breast cancer
  • 2018
  • Konferensbidrag (refereegranskat)abstract
    • Breast cancer accounts for ~25% of diagnosed cancer types in woman [1]. Decreased physical fitness and muscle weakness are common complications in patients with breast cancer. In cancer, muscle weakness has traditionally been linked to muscle wasting and significant weight loss (cachexia) [2]. However, muscle weakness is present in non-cachectic, weight-stable patients with breast cancer [3]. In fact, cancer-induced muscle dysfunction is a broad clinical challenge that is not restricted to palliative or advanced stage patients, but also observed in newly diagnosed patients with low tumor burden [4]. Further, with the breast cancer treatment improving, it is important to take a look on the patients quality of life [5]. However, little is known about the features underlying breast cancer-induced muscle impairments and no drug preventing cancer-induced muscle weakness is clinically proven. Here we aim at characterizing the metabolic status and the muscle function in mice with breast cancer.The breast cancer mouse-model MMTV-PyMT (PyMT) used here, is characterized by an early onset of mammary cancer (from 5 weeks of age) and follows a similar progression pattern as the one observed in human patients [6]. Soleus muscle from PyMT mice exhibited ~30% lower specific force (kN/m2) than soleus muscle from wildtype (WT) mice (n=28-29, p ≤ 0.05, mice were 12 week old at sacrifice). There were no significant differences in muscle mass, fiber size or fiber type distribution between PyMT and WT muscle. Furthermore, there were no differences in glycogen content (μg/g muscle) in soleus muscle from PyMT and WT mice. Simultaneous measurement of numerous parameters (e.g. oxygen consumption (VO2), carbon dioxide production (VCO2), and food and water intake) was carried out using comprehensive lab animal monitoring system (CLAMS) to gain insight into the metabolic status of the mice. The mice were monitored over a week and the average respiratory exchange ratio (RER = CO2production: O2 uptake) were significantly differed between PyMT and WT mice, with mean PyMT RER of 0.95±0.01 and WT RER of 1.0±0.01 (mean data +/-SEM, n=8, p<0.001). Thus, indicative that PyMT have an altered metabolism towards fatty acid utilization.In summary, soleus muscles are weaker and the whole-body metabolism appears altered in mice with breast cancer as compared with healthy control mice. Gene and molecular analysis are currently being performed to further assess mitochondrial and glucose metabolism. Nevertheless, further studies are needed to gain insight into cancer-derived factors that contributes to skeletal muscle dysfunction and altered metabolism.1. Jemal, A., et al., Cancer statistics, 2008. CA Cancer J Clin, 2008. 58(2): p. 71-96.2. Johns, N., N.A. Stephens, and K.C. Fearon, Muscle wasting in cancer. Int J Biochem Cell Biol, 2013. 45(10): p. 2215-29.3. Klassen, O., et al., Muscle strength in breast cancer patients receiving different treatment regimes. Journal of Cachexia, Sarcopenia and Muscle, 2017. 8(2): p. 305-316.4. Villasenor, A., et al., Prevalence and prognostic effect of sarcopenia in breast cancer survivors: the HEAL Study. J Cancer Surviv, 2012. 6(4): p. 398-406.5. Perry, S., T.L. Kowalski, and C.H. Chang, Quality of life assessment in women with breast cancer: benefits, acceptability and utilization. Health Qual Life Outcomes, 2007. 5: p. 24.6. Fantozzi, A. and G. Christofori, Mouse models of breast cancer metastasis. Breast Cancer Res, 2006. 8(4): p. 212.
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