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On leukocyte recruitment in endotoxemic liver injury

Klintman, Daniel LU (2002)
Abstract
Leukocyte recruitment is a key feature of liver injury associated with endotoxemia and systemic inflammation. The aim of this thesis was to define the adhesive mechanisms underlying leukocyte endothelial cell interactions, and the therapeutic potential of interference with specific adhesion molecules in endotoxemic liver damage. Moreover, the causal relationship between leukocyte recruitment on one hand and hepatocellular injury and apoptosis on the other hand was investigated. For these purposes, intravital fluorescence microscopy of the liver microcirculation was adopted. It was found that TNF-alpha- and LPS-induced leukocyte rolling in hepatic postsinusoidal venules is primarily mediated by P-selectin, and not by E- nor L-selectin. This... (More)
Leukocyte recruitment is a key feature of liver injury associated with endotoxemia and systemic inflammation. The aim of this thesis was to define the adhesive mechanisms underlying leukocyte endothelial cell interactions, and the therapeutic potential of interference with specific adhesion molecules in endotoxemic liver damage. Moreover, the causal relationship between leukocyte recruitment on one hand and hepatocellular injury and apoptosis on the other hand was investigated. For these purposes, intravital fluorescence microscopy of the liver microcirculation was adopted. It was found that TNF-alpha- and LPS-induced leukocyte rolling in hepatic postsinusoidal venules is primarily mediated by P-selectin, and not by E- nor L-selectin. This initial P-selectin-dependent leukocyte rolling was found to be a prerequisite for subsequent firm adhesion in postsinusoidal venules of the liver. Firm adhesion of leukocytes was found to be dependent on CD18/CD11a (LFA-1). Notably, inhibition of P-selectin and LFA-1 function protected against septic liver injury. For example, leukocyte recruitment, perfusion failure, hepatocellular injury and apoptosis were nearly abolished. In contrast, sinusoidal sequestration of leukocytes was not found to be a major determinant in endotoxemic liver injury. Moreover, the immunomodulator Linomide exerted potent protection against liver damage associated with endotoxemia. Taken together, this thesis indentifies fundamental adhesive mechanisms of leukocyte recruitment in septic liver injury, and defines a causal relationship between leukocyte recruitment in postsinusoidal venules and hepatic injury and apoptosis in endotoxemia. The beneficial effect of Linomide in endotoxemic liver injury demonstrated herein warrants further studies in clinical settings. Finally, it is suggested that P-selectin and LFA-1 constitute potential pharmacological targets against pathological inflammation in the liver. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Prof. Vollmar, Brigitte, Homburg, Germany
organization
publishing date
type
Thesis
publication status
published
subject
keywords
ortopedi, traumatology, Kirurgi, orthopaedics, Surgery, Sepsis, Liver, Inflammation, Adhesion, Endotoxemia, traumatologi
pages
120 pages
publisher
Daniel Klintman, Dept. of Surgery, Malmö University Hospital,
defense location
Department of Surgery, Malmö University Hospital
defense date
2002-10-12 10:15:00
ISBN
91-628-5400-3
language
English
LU publication?
yes
additional info
Article: I. Daniel Klintman, René Schramm, Michael D. Menger and Henrik Thorlacius. Leukocyte recruitment in hepatic injury: Selectin-mediated leukocyte rolling is a prerequisite for CD18-dependent firm adhesion. J Hepatol 2002;36:53-59. Article: II. Daniel Klintman, Li Xiang and Henrik Thorlacius. Important role of P-selectin for leukocyte recruitment, hepatocellular injury and apoptosis in endotoxemic mice. Submitted to Hepatology. Article: III. Li Xiang, Daniel Klintman, Gabriele Weitz-Schmidt, René Schramm and Henrik Thorlacius. Lymphocyte function antigen-1 mediates leukocyte adhesion in postsinusoidal venules in endotoxemic mice. Submitted to J Leukoc Biol. Article: IV. Daniel Klintman, Gunnar Hedlund and Henrik Thorlacius. Protective effect of Linomide on TNF-alpha-induced hepatic injury. J Hepatol 2002;36:226-232.
id
c0e935c0-f466-4f6b-b914-958901d1579f (old id 464899)
date added to LUP
2016-04-04 11:53:46
date last changed
2018-11-21 21:07:52
@phdthesis{c0e935c0-f466-4f6b-b914-958901d1579f,
  abstract     = {Leukocyte recruitment is a key feature of liver injury associated with endotoxemia and systemic inflammation. The aim of this thesis was to define the adhesive mechanisms underlying leukocyte endothelial cell interactions, and the therapeutic potential of interference with specific adhesion molecules in endotoxemic liver damage. Moreover, the causal relationship between leukocyte recruitment on one hand and hepatocellular injury and apoptosis on the other hand was investigated. For these purposes, intravital fluorescence microscopy of the liver microcirculation was adopted. It was found that TNF-alpha- and LPS-induced leukocyte rolling in hepatic postsinusoidal venules is primarily mediated by P-selectin, and not by E- nor L-selectin. This initial P-selectin-dependent leukocyte rolling was found to be a prerequisite for subsequent firm adhesion in postsinusoidal venules of the liver. Firm adhesion of leukocytes was found to be dependent on CD18/CD11a (LFA-1). Notably, inhibition of P-selectin and LFA-1 function protected against septic liver injury. For example, leukocyte recruitment, perfusion failure, hepatocellular injury and apoptosis were nearly abolished. In contrast, sinusoidal sequestration of leukocytes was not found to be a major determinant in endotoxemic liver injury. Moreover, the immunomodulator Linomide exerted potent protection against liver damage associated with endotoxemia. Taken together, this thesis indentifies fundamental adhesive mechanisms of leukocyte recruitment in septic liver injury, and defines a causal relationship between leukocyte recruitment in postsinusoidal venules and hepatic injury and apoptosis in endotoxemia. The beneficial effect of Linomide in endotoxemic liver injury demonstrated herein warrants further studies in clinical settings. Finally, it is suggested that P-selectin and LFA-1 constitute potential pharmacological targets against pathological inflammation in the liver.},
  author       = {Klintman, Daniel},
  isbn         = {91-628-5400-3},
  language     = {eng},
  publisher    = {Daniel Klintman, Dept. of Surgery, Malmö University Hospital,},
  school       = {Lund University},
  title        = {On leukocyte recruitment in endotoxemic liver injury},
  year         = {2002},
}