On Leukocyte Recruitment in Cholestatic Liver Injury
(2008) In Lund University Faculty of Medicine Doctoral Dissertation Series 2008:132.- Abstract
- Cholestasis is a frequent clinical syndrome, which is caused by a dysfunction in bile formation of the hepatocyte or from obstruction of the biliary tract. This is associated with inflammation of the liver tissue, resulting in severe liver injury. In this inflammatory process, leukocyte recruitment has emerged as a key feature. Therefore, the aim of this thesis was to analyze the detailed mechanisms behind intrahepatic leukocyte accumulation and its regulation in the pathophysiology of sepsis-associated or obstructive cholestasis and their impact on hepatocellular function and damage. For this purpose, cholestatic conditions were induced in C57BL/6 mice in the weIl established experimental models of LPS sepsis and obstructive cholestasis... (More)
- Cholestasis is a frequent clinical syndrome, which is caused by a dysfunction in bile formation of the hepatocyte or from obstruction of the biliary tract. This is associated with inflammation of the liver tissue, resulting in severe liver injury. In this inflammatory process, leukocyte recruitment has emerged as a key feature. Therefore, the aim of this thesis was to analyze the detailed mechanisms behind intrahepatic leukocyte accumulation and its regulation in the pathophysiology of sepsis-associated or obstructive cholestasis and their impact on hepatocellular function and damage. For this purpose, cholestatic conditions were induced in C57BL/6 mice in the weIl established experimental models of LPS sepsis and obstructive cholestasis foIlowing bile duct ligation. Analyses included intravital fluorescence microscopy, histology, ELISA, RT-PCR, flow cytometry, determination of bilirubin and liver enzyme levels as well as measurement of bile flow and secretion. In doing so, it was found that P-selectin-mediated recruitment of leukocytes, but not the local production of pro-inflammatory mediators, is the primary cause of sepsis-associated cholestasis. Moreover, obstructive cholestasis is associated with P-selectin-mediated intrahepatic platelet accumulation, which crucially contributes to leukocyte recruitment and liver in jury. Besides, LFA-l mediates firm leukocyte adhesion in the liver microcirculation during obstructive cholestasis. Finally, inhibition of rhokinase attenuates cholestasis-induced CXC chemokine formation, leukocyte recruitment and hepatocellular damage in the liver. Thus, the results of this thesis clearly demonstrate that leukocyte recruitment in the liver plays a key role in the pathophysiology of cholestasis. Accordingly, it may be concluded that targeting leukocyte recruitment may be an effective strategy to preserve bile flow under septic conditions and to reduce cholestasis-induced liver injury. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1263750
- author
- Laschke, Matthias LU
- supervisor
- opponent
-
- Professor Minor, Thomas, University of Bonn, Clinic of Surgery, Bonn, Germany
- organization
- publishing date
- 2008
- type
- Thesis
- publication status
- published
- subject
- keywords
- Leukocyte and Liver, Inflammation, Cholestasis, Endothelium
- in
- Lund University Faculty of Medicine Doctoral Dissertation Series
- volume
- 2008:132
- pages
- 126 pages
- publisher
- Department of Clinical Sciences, Lund University
- defense location
- CRC (Clinical Research Centre), Public Forum, Entrance 72, Malmö University Hospital, Malmö
- defense date
- 2008-11-28 13:15:00
- ISSN
- 1652-8220
- ISBN
- 978-91-86059-85-9
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Emergency medicine/Medicine/Surgery (013240200), Surgery Research Unit (013242220)
- id
- 0bce498c-3885-4551-a5e4-e6230d74b01b (old id 1263750)
- date added to LUP
- 2016-04-01 13:20:26
- date last changed
- 2019-05-22 02:10:05
@phdthesis{0bce498c-3885-4551-a5e4-e6230d74b01b, abstract = {{Cholestasis is a frequent clinical syndrome, which is caused by a dysfunction in bile formation of the hepatocyte or from obstruction of the biliary tract. This is associated with inflammation of the liver tissue, resulting in severe liver injury. In this inflammatory process, leukocyte recruitment has emerged as a key feature. Therefore, the aim of this thesis was to analyze the detailed mechanisms behind intrahepatic leukocyte accumulation and its regulation in the pathophysiology of sepsis-associated or obstructive cholestasis and their impact on hepatocellular function and damage. For this purpose, cholestatic conditions were induced in C57BL/6 mice in the weIl established experimental models of LPS sepsis and obstructive cholestasis foIlowing bile duct ligation. Analyses included intravital fluorescence microscopy, histology, ELISA, RT-PCR, flow cytometry, determination of bilirubin and liver enzyme levels as well as measurement of bile flow and secretion. In doing so, it was found that P-selectin-mediated recruitment of leukocytes, but not the local production of pro-inflammatory mediators, is the primary cause of sepsis-associated cholestasis. Moreover, obstructive cholestasis is associated with P-selectin-mediated intrahepatic platelet accumulation, which crucially contributes to leukocyte recruitment and liver in jury. Besides, LFA-l mediates firm leukocyte adhesion in the liver microcirculation during obstructive cholestasis. Finally, inhibition of rhokinase attenuates cholestasis-induced CXC chemokine formation, leukocyte recruitment and hepatocellular damage in the liver. Thus, the results of this thesis clearly demonstrate that leukocyte recruitment in the liver plays a key role in the pathophysiology of cholestasis. Accordingly, it may be concluded that targeting leukocyte recruitment may be an effective strategy to preserve bile flow under septic conditions and to reduce cholestasis-induced liver injury.}}, author = {{Laschke, Matthias}}, isbn = {{978-91-86059-85-9}}, issn = {{1652-8220}}, keywords = {{Leukocyte and Liver; Inflammation; Cholestasis; Endothelium}}, language = {{eng}}, publisher = {{Department of Clinical Sciences, Lund University}}, school = {{Lund University}}, series = {{Lund University Faculty of Medicine Doctoral Dissertation Series}}, title = {{On Leukocyte Recruitment in Cholestatic Liver Injury}}, url = {{https://lup.lub.lu.se/search/files/3312115/1263861.pdf}}, volume = {{2008:132}}, year = {{2008}}, }