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On Neutrophil and Platelet Adhesive Interactions in Septic Lung Injury

Muhammad, Asad LU (2008) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2008:74.
Abstract
Sepsis induced by intestinal perforation is a life-threatening illness and is a frequent cause of

leukocyte-mediated lung injury. Although antimicrobial therapy has been the central clinical strategy for these

patients, the survival rates in such patients are still very low because of their impaired host defense

mechanisms. Therefore, control of amplified leukocyte recruitment in the lung may be a potential target to treat

septic patients. The aim of the thesis was to define the role of p38 mitogen activated protein kinase (MAPK)

signaling pathway and the role LFA-1, Mac-1 and PSGL-1 as well as the role of platelets in septic lung injury.

Accumulation of water in lung, infiltration of... (More)
Sepsis induced by intestinal perforation is a life-threatening illness and is a frequent cause of

leukocyte-mediated lung injury. Although antimicrobial therapy has been the central clinical strategy for these

patients, the survival rates in such patients are still very low because of their impaired host defense

mechanisms. Therefore, control of amplified leukocyte recruitment in the lung may be a potential target to treat

septic patients. The aim of the thesis was to define the role of p38 mitogen activated protein kinase (MAPK)

signaling pathway and the role LFA-1, Mac-1 and PSGL-1 as well as the role of platelets in septic lung injury.

Accumulation of water in lung, infiltration of leukocytes in bronchoalveolar space, levels of myeloperoxidase

and CXC chemokines were measured after cecal ligation and puncture (CLP). Animals were treated with the

specific p38 MAPK inhibitors, SB 239063 and SKF 86002, corresponding blocking antibodies to LFA-1,

Mac-1 or PSGL-1 and plateletes were depleted with an antibody directed against GP1b-alpha from the

circulation prior to CLP induction. Clear-cut damage in the lung tissue was observed in CLP animals which

was characterized by edema formation, excessive leukocyte accumulation and increased levels of CXC chemokines in the tissue. CLP induced phosphorylation and activity of p38 MAPK in lung which was markedly inhibited by using SB 239063. Moreover, functional inhibition of p38 MAPK signaling reduced CLP-induced formation of CXC chemokines, leukocyte recruitment and protected against septic lung injury. In addition, the results showed that both LFA-1, Mac-1 play important roles in leukocyte recruitment and fluid accumulation in the bronchoalveolar space although the tissue production of CXC chemokines was unaffected

by antibody treatments in abdominal sepsis. Notably, inhibition of PSGL-1 reduced CLP-induced leukocyte

recruitment and lung injury in a platelet-independent manner. Platelet depletion decreased Mac-1 upregulation

on leukocytes as well as the accumulation of leukocyte in septic lung injury. This effect of platelet was

independent of platelet-leukocyte aggregate formation. Thus, this work delineates new mechanisms regulating

pathological inflammation in the lung during abdominal sepsis. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Dr. Schilling, Martin, University of Saarland, Germany
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Leukocytes, chemokines, platelets, lung, sepsis
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2008:74
pages
108 pages
publisher
Department of Clinical Sciences, Lund University
defense location
CRC
defense date
2008-06-13 09:00
ISSN
1652-8220
ISBN
978-91-86059-27-9
language
English
LU publication?
yes
id
c75ba0cf-97bf-422c-84cd-04d9781ee4e1 (old id 1149847)
date added to LUP
2008-05-23 12:04:12
date last changed
2016-09-19 08:44:49
@phdthesis{c75ba0cf-97bf-422c-84cd-04d9781ee4e1,
  abstract     = {Sepsis induced by intestinal perforation is a life-threatening illness and is a frequent cause of<br/><br>
leukocyte-mediated lung injury. Although antimicrobial therapy has been the central clinical strategy for these<br/><br>
patients, the survival rates in such patients are still very low because of their impaired host defense<br/><br>
mechanisms. Therefore, control of amplified leukocyte recruitment in the lung may be a potential target to treat<br/><br>
septic patients. The aim of the thesis was to define the role of p38 mitogen activated protein kinase (MAPK)<br/><br>
signaling pathway and the role LFA-1, Mac-1 and PSGL-1 as well as the role of platelets in septic lung injury.<br/><br>
Accumulation of water in lung, infiltration of leukocytes in bronchoalveolar space, levels of myeloperoxidase<br/><br>
and CXC chemokines were measured after cecal ligation and puncture (CLP). Animals were treated with the<br/><br>
specific p38 MAPK inhibitors, SB 239063 and SKF 86002, corresponding blocking antibodies to LFA-1,<br/><br>
Mac-1 or PSGL-1 and plateletes were depleted with an antibody directed against GP1b-alpha from the<br/><br>
circulation prior to CLP induction. Clear-cut damage in the lung tissue was observed in CLP animals which<br/><br>
was characterized by edema formation, excessive leukocyte accumulation and increased levels of CXC chemokines in the tissue. CLP induced phosphorylation and activity of p38 MAPK in lung which was markedly inhibited by using SB 239063. Moreover, functional inhibition of p38 MAPK signaling reduced CLP-induced formation of CXC chemokines, leukocyte recruitment and protected against septic lung injury. In addition, the results showed that both LFA-1, Mac-1 play important roles in leukocyte recruitment and fluid accumulation in the bronchoalveolar space although the tissue production of CXC chemokines was unaffected<br/><br>
by antibody treatments in abdominal sepsis. Notably, inhibition of PSGL-1 reduced CLP-induced leukocyte<br/><br>
recruitment and lung injury in a platelet-independent manner. Platelet depletion decreased Mac-1 upregulation<br/><br>
on leukocytes as well as the accumulation of leukocyte in septic lung injury. This effect of platelet was<br/><br>
independent of platelet-leukocyte aggregate formation. Thus, this work delineates new mechanisms regulating<br/><br>
pathological inflammation in the lung during abdominal sepsis.},
  author       = {Muhammad, Asad},
  isbn         = {978-91-86059-27-9},
  issn         = {1652-8220},
  keyword      = {Leukocytes,chemokines,platelets,lung,sepsis},
  language     = {eng},
  pages        = {108},
  publisher    = {Department of Clinical Sciences, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {On Neutrophil and Platelet Adhesive Interactions in Septic Lung Injury},
  volume       = {2008:74},
  year         = {2008},
}