Neutrophil and endothelial cell-mediated inflammation in abdominal sepsis
(2022) In Lund University, Faculty of Medicine Doctoral Dissertation Series- Abstract
- Sepsis is defined as a life-threatening condition caused by a dysregulated host response to infection. Neutrophils are themost abundant innate immune cells of the body and play a key role in septic pathogenesis. During sepsis activatedneutrophils release web-like traps decorated with various cellular proteins known as neutrophil extracellular traps(NET). The primary task of NET and NET-associated proteins are to kill pathogens; however, excessive accumulationof NET is known to cause tissue damage. Endothelial cells are important for regulating vascular permeability andbarrier functions; however, during sepsis endothelial cells get activated and contribute to tissue damage andorgan failure. The four original studies included in this thesis... (More)
- Sepsis is defined as a life-threatening condition caused by a dysregulated host response to infection. Neutrophils are themost abundant innate immune cells of the body and play a key role in septic pathogenesis. During sepsis activatedneutrophils release web-like traps decorated with various cellular proteins known as neutrophil extracellular traps(NET). The primary task of NET and NET-associated proteins are to kill pathogens; however, excessive accumulationof NET is known to cause tissue damage. Endothelial cells are important for regulating vascular permeability andbarrier functions; however, during sepsis endothelial cells get activated and contribute to tissue damage andorgan failure. The four original studies included in this thesis aimed to investigate new mechanisms involved information of NET, lung injury and pulmonary endothelial cell activation in abdominal sepsis. In study I, we havefound that c-Abl kinase regulate NET formation through ROS signaling pathway. Blocking of c-Abl kinase notonly inhibited NET formation but also reduced inflammation and tissue damage in sepsis. In study II, weinvestigated the role of actin-related protein 2/3 complex (Arp2/3 complex) and found that it regulates neutrophiltrap expulsion both in vivo and in vitro. Inhibition of Arp2/3 complex not only reduced the neutrophil infiltration inbronchoalveolar space, but also alleviated lung damage in abdominal sepsis. In study III, we investigated the roleof S100A9, a pro-inflammatory alarmin, in regulating inflammation and tissue damage in abdominal sepsis.Inhibition of S100A9 by a specific inhibitor, ABR-238901, decreased sepsis-induced neutrophil activation,cytokine formation as well as damage to the lung tissue. In study IV, we examined global transcriptomic changesin a subgroup of lung endothelial cells during sepsis. We found that sepsis caused transcriptomic changes ofgenes related to regulation of coagulation, vascular permeability as well as wound healing and lipid metabolic incapillary endothelial cells. In contrast, postcapillary venules were found to be more enriched with genes related tochemotaxis, cell-cell adhesion of integrins, chemokine biosynthesis, regulation of actin polymerization andneutrophil homeostasis after sepsis. Together, these results demonstrated that targeting c-Abl, Arp2/3 complex,S100A9 or endothelial functions could be useful targets to ameliorate neutrophil mediated tissue injury in sepsis. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/e6e865e5-66ea-4f26-ab2d-cf3def466cc8
- author
- Ding, Zhiyi LU
- supervisor
- opponent
-
- Professor, MD, PhD, DSc Nemeth, Norbert, Department of Operative Techniques and Surgical Research, Faculty of Medicine, University of Debrecen, Hungary
- organization
- publishing date
- 2022
- type
- Thesis
- publication status
- published
- subject
- keywords
- sepsis, lung, neutrophil, endothelial cell, neutrophil extracellular traps, inflammation, capillary, post capillary venules, cytoskeleton, RNAseq
- in
- Lund University, Faculty of Medicine Doctoral Dissertation Series
- issue
- 2022:60
- pages
- 88 pages
- publisher
- Lund University, Faculty of Medicine
- defense location
- CRC, Rum 91-10-014, Jan Waldenströms gata 35, Skånes Universitetssjukhus i Malmö. Join by Zoom: https://lu-se.zoom.us/j/65932622923
- defense date
- 2022-04-28 09:00:00
- ISSN
- 1652-8220
- ISBN
- 978-91-8021-221-2
- language
- English
- LU publication?
- yes
- id
- e6e865e5-66ea-4f26-ab2d-cf3def466cc8
- date added to LUP
- 2022-04-07 12:18:12
- date last changed
- 2022-04-13 07:36:49
@phdthesis{e6e865e5-66ea-4f26-ab2d-cf3def466cc8,
abstract = {{Sepsis is defined as a life-threatening condition caused by a dysregulated host response to infection. Neutrophils are themost abundant innate immune cells of the body and play a key role in septic pathogenesis. During sepsis activatedneutrophils release web-like traps decorated with various cellular proteins known as neutrophil extracellular traps(NET). The primary task of NET and NET-associated proteins are to kill pathogens; however, excessive accumulationof NET is known to cause tissue damage. Endothelial cells are important for regulating vascular permeability andbarrier functions; however, during sepsis endothelial cells get activated and contribute to tissue damage andorgan failure. The four original studies included in this thesis aimed to investigate new mechanisms involved information of NET, lung injury and pulmonary endothelial cell activation in abdominal sepsis. In study I, we havefound that c-Abl kinase regulate NET formation through ROS signaling pathway. Blocking of c-Abl kinase notonly inhibited NET formation but also reduced inflammation and tissue damage in sepsis. In study II, weinvestigated the role of actin-related protein 2/3 complex (Arp2/3 complex) and found that it regulates neutrophiltrap expulsion both in vivo and in vitro. Inhibition of Arp2/3 complex not only reduced the neutrophil infiltration inbronchoalveolar space, but also alleviated lung damage in abdominal sepsis. In study III, we investigated the roleof S100A9, a pro-inflammatory alarmin, in regulating inflammation and tissue damage in abdominal sepsis.Inhibition of S100A9 by a specific inhibitor, ABR-238901, decreased sepsis-induced neutrophil activation,cytokine formation as well as damage to the lung tissue. In study IV, we examined global transcriptomic changesin a subgroup of lung endothelial cells during sepsis. We found that sepsis caused transcriptomic changes ofgenes related to regulation of coagulation, vascular permeability as well as wound healing and lipid metabolic incapillary endothelial cells. In contrast, postcapillary venules were found to be more enriched with genes related tochemotaxis, cell-cell adhesion of integrins, chemokine biosynthesis, regulation of actin polymerization andneutrophil homeostasis after sepsis. Together, these results demonstrated that targeting c-Abl, Arp2/3 complex,S100A9 or endothelial functions could be useful targets to ameliorate neutrophil mediated tissue injury in sepsis.}},
author = {{Ding, Zhiyi}},
isbn = {{978-91-8021-221-2}},
issn = {{1652-8220}},
keywords = {{sepsis; lung; neutrophil; endothelial cell; neutrophil extracellular traps; inflammation; capillary; post capillary venules; cytoskeleton; RNAseq}},
language = {{eng}},
number = {{2022:60}},
publisher = {{Lund University, Faculty of Medicine}},
school = {{Lund University}},
series = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
title = {{Neutrophil and endothelial cell-mediated inflammation in abdominal sepsis}},
url = {{https://lup.lub.lu.se/search/files/116410627/Thesis_e_nailing_Zhiyi_Ding.pdf}},
year = {{2022}},
}