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Innate immune cell response in sepsis

Wang, Yongzhi LU (2015) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2015:77.
Abstract
Leukocyte recruitment is known to be a key feature at sites of inflammation and important in the combat against infectious agents. However, the mechanisms of leukocyte recruitment in the pulmonary microvasculature in response to local and systemic inflammation remain elusive. Abdominal sepsis is associated with significant changes in systemic inflammation and coagulation. We hypothesized that leukocytes might exhibit different spatial patterns of accumulation in the pulmonary microvasculature in local versus systemic inflammation induced by injection lipopolysaccharide (LPS) intratracheally (i.t.) or intravenously (i.v.), monocytes and platelets might be important regulators of thrombin generation in abdominal sepsis induced by cecal... (More)
Leukocyte recruitment is known to be a key feature at sites of inflammation and important in the combat against infectious agents. However, the mechanisms of leukocyte recruitment in the pulmonary microvasculature in response to local and systemic inflammation remain elusive. Abdominal sepsis is associated with significant changes in systemic inflammation and coagulation. We hypothesized that leukocytes might exhibit different spatial patterns of accumulation in the pulmonary microvasculature in local versus systemic inflammation induced by injection lipopolysaccharide (LPS) intratracheally (i.t.) or intravenously (i.v.), monocytes and platelets might be important regulators of thrombin generation in abdominal sepsis induced by cecal ligation and puncture (CLP). We observed that systemic LPS caused more leukocytes trapping in capillaries compared to local LPS. The ratio of adherent leukocytes in venules compared to capillaries was higher in response to local LPS, suggesting that leukocytes were more prone to accumulate in venules in local inflammation and in capillaries in systemic inflammation. Alveolar accumulation of leukocytes was more efficient in local compared to systemic inflammation. Rho-kinase signaling appears to regulate both adhesive and mechanical aspects of endotoxin-induced leukocyte infiltration in the lung. In study II, It was found that dynamic changes in the coagulation system characterized by a hypercoagulable phase followed by a hypocoagulable phase in response to a septic insult. In addition, we found peripheral blood monocytes regulate sepsis-induced thrombin generation and consumption of coagulation factors. Moreover, monocytes are critical for formation of pro-inflammatory compounds and neutrophil accumulation in the lung in abdominal sepsis. We also found platelets regulate thrombin generation in abdominal sepsis and platelet-derived microparticles (PMPs) have the capacity to trigger thrombin formation and that this effect could be due to PS-mediated activation of the coagulation system. Moreover, our data demonstrated that Rac1 signaling is critical for the formation of PMPs and thrombin generation in sepsis. Taken together, these findings increase our understanding of the important role of neutrophils, monocytes and platelets in the pathophysiology of sepsis and data of this thesis may help to develop potential therapies in management of patients with sepsis. (Less)
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author
supervisor
opponent
  • Professor Németh, Norbert, Department of Operative Techniques and Surgical Research, Institute of Surgery, University of Debrecen, Hungary
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Inflammation, abdominal sepsis, neutrophil, monocyte, platelet, coagulation, lung
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2015:77
pages
70 pages
publisher
Department of Clinical Sciences, Lund University
defense location
CRC Aula, Entrance 72, Jan Waldenströms Gata 35, Skåne University Hospital, Malmö
defense date
2015-06-05 13:00
ISSN
1652-8220
ISBN
978-91-7619-156-9
language
English
LU publication?
yes
id
4ef5c357-baa5-44e0-adb3-a51db3836f37 (old id 5384988)
date added to LUP
2015-05-13 12:43:51
date last changed
2016-09-19 08:44:49
@phdthesis{4ef5c357-baa5-44e0-adb3-a51db3836f37,
  abstract     = {Leukocyte recruitment is known to be a key feature at sites of inflammation and important in the combat against infectious agents. However, the mechanisms of leukocyte recruitment in the pulmonary microvasculature in response to local and systemic inflammation remain elusive. Abdominal sepsis is associated with significant changes in systemic inflammation and coagulation. We hypothesized that leukocytes might exhibit different spatial patterns of accumulation in the pulmonary microvasculature in local versus systemic inflammation induced by injection lipopolysaccharide (LPS) intratracheally (i.t.) or intravenously (i.v.), monocytes and platelets might be important regulators of thrombin generation in abdominal sepsis induced by cecal ligation and puncture (CLP). We observed that systemic LPS caused more leukocytes trapping in capillaries compared to local LPS. The ratio of adherent leukocytes in venules compared to capillaries was higher in response to local LPS, suggesting that leukocytes were more prone to accumulate in venules in local inflammation and in capillaries in systemic inflammation. Alveolar accumulation of leukocytes was more efficient in local compared to systemic inflammation. Rho-kinase signaling appears to regulate both adhesive and mechanical aspects of endotoxin-induced leukocyte infiltration in the lung. In study II, It was found that dynamic changes in the coagulation system characterized by a hypercoagulable phase followed by a hypocoagulable phase in response to a septic insult. In addition, we found peripheral blood monocytes regulate sepsis-induced thrombin generation and consumption of coagulation factors. Moreover, monocytes are critical for formation of pro-inflammatory compounds and neutrophil accumulation in the lung in abdominal sepsis. We also found platelets regulate thrombin generation in abdominal sepsis and platelet-derived microparticles (PMPs) have the capacity to trigger thrombin formation and that this effect could be due to PS-mediated activation of the coagulation system. Moreover, our data demonstrated that Rac1 signaling is critical for the formation of PMPs and thrombin generation in sepsis. Taken together, these findings increase our understanding of the important role of neutrophils, monocytes and platelets in the pathophysiology of sepsis and data of this thesis may help to develop potential therapies in management of patients with sepsis.},
  author       = {Wang, Yongzhi},
  isbn         = {978-91-7619-156-9},
  issn         = {1652-8220},
  keyword      = {Inflammation,abdominal sepsis,neutrophil,monocyte,platelet,coagulation,lung},
  language     = {eng},
  pages        = {70},
  publisher    = {Department of Clinical Sciences, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Innate immune cell response in sepsis},
  volume       = {2015:77},
  year         = {2015},
}