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Sökning: WFRF:(Rasmuson Joel)

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  • 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.
  • Rasmuson, Joel (författare)
  • Neutrophil-induced endothelial barrier dysfunction in acute inflammation : mechanisms and therapeutic strategies
  • 2020
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • The acute inflammatory response is characterized by recruitment of leukocytes and increased vascular permeability, resulting in the cardinal signs of inflammation; redness, heat, swelling, pain and loss of function. Permeability changes of the vascular wall are important in functional immune responses and host defense. On the other hand, derangement of the vascular barrier is a principal cause for plasma leakage and edema formation in severe disease states such as sepsis, substantially accounting for high morbidity and mortality by contributing to organ dysfunction and circulatory failure. Neutrophil granulocytes, a subtype of leukocytes, are first on sight in the acute inflammatory response where they adhere to, and migrate through, a monolayer of endothelial cells that constitute the innermost layer of the vascular wall. Neutrophil-derived proteins, released from activated neutrophils, cause endothelial barrier disruption via partly unknown mechanisms. Since neutrophil activation and degranulation are considered central in the pathogenesis of acute inflammatory disease states, and novel treatment strategies are sought after, this thesis work aimed to further expand our understanding of mechanisms regulating neutrophil-evoked alterations of the endothelial barrier. In paper I, the role of the kallikrein-kinin system (KKS) in neutrophil- induced vascular leakage was investigated. The KKS is a pro-inflammatory protein complex found in plasma that is responsible for formation of bradykinin (BK), a known inducer of vascular hyperpermeability via binding of bradykinin receptors on endothelial cells. In three different in vivo models of acute inflammation in two different species, we found that inhibition of KKS attenuated neutrophil-mediated plasma leakage. Further, in vitro studies with isolated human neutrophils and endothelial cells showed that factors secreted from activated neutrophils caused BK-mediated endothelial barrier disruption, and that neutrophil-derived heparin-binding protein facilitated KKS activation caused by neutrophil granule proteases. In paper II, we investigated the therapeutic potential and mode of action of the heparin derivative sevuparin in neutrophil-mediated vascular leak caused by group A Streptococcus. In vivo and in vitro studies showed that sevuparin attenuated endothelial barrier disruption and lung plasma leakage by neutralizing neutrophil-derived proteins. Affinity chromatography and mass spectrometry were utilized to identify proteins targeted by sevuparin, confirming the previously established disruptive role of several neutrophil- derived proteins on endothelial barrier function. In paper III, we tested the hypothesis that platelet-derived polyphosphates (polyP) activate neutrophils, and investigated polyP as a potential therapeutic target in acute inflammation. During inflammation, interaction of activated platelets with neutrophils results in neutrophil activation. Also, platelets are known to release polyP that have been attributed roles in both inflammation and coagulation. We found in vitro that polyP induced neutrophil degranulation and in vivo that systemic administration of polyP caused lung plasma leakage in a neutrophil-dependent manner. Furthermore, inhibition of polyP decreased lung plasma leakage in a mouse model of acute systemic inflammation induced by group A Streptococcus. In paper IV, we set out to investigate the effect of phenylbutyrate (PBA), a short-chain fatty acid suggested to have immunomodulatory properties, on the inflammatory response in a mouse model of pneumonia with Pseudomonas aeruginosa. PBA treatment altered the kinetics of neutrophil recruitment in lungs in response to P. aeruginosa resulting in enhanced initial mobilization of neutrophils followed by a more rapid decline in cell recruitment compared to no treatment. Coincident with the decline in cell recruitment, lung edema and protein leakage was reduced. In vitro, PBA was found to promote release of neutrophil chemotactic factors from lung epithelium. In conclusion, this thesis work provides new insights into mechanisms regulating endothelial barrier function in neutrophilic inflammation and suggests potential therapeutic strategies.
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