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Rac1 signaling regulates platelet-dependent inflammation abdominal sepsis

Hwaiz, Rundk LU (2015) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2015:39.
Abstract (Swedish)
Popular Abstract in Swedish

Sepsis, blodförgiftning är en systemisk inflammatorisk reaktion syndrom vid en lokal eller systemisk infektion som leder till överproduktion av proinflammatoriska cytokiner och det ultimata misslyckandet av flera organsystem. Sepsis är ett potentiellt allvarligt och komplicerat kliniskt syndrom samt är en av de vanligaste orsakerna till döden på intensivvårdsavdelningar. Cirka 200 per 100 000 invånare i Sverige drabbas årligen av svår sepsis.

Rac1 är en Rho familjen GTPases, som spelar en viktig roll i celladhesion och motilitet, men lite är känt om en potentiell roll Rac1 i kontrollen sepsis mediterad intracellulära signalvägar. Vi antog att Rac1 skulle vara inblandade i sepsis... (More)
Popular Abstract in Swedish

Sepsis, blodförgiftning är en systemisk inflammatorisk reaktion syndrom vid en lokal eller systemisk infektion som leder till överproduktion av proinflammatoriska cytokiner och det ultimata misslyckandet av flera organsystem. Sepsis är ett potentiellt allvarligt och komplicerat kliniskt syndrom samt är en av de vanligaste orsakerna till döden på intensivvårdsavdelningar. Cirka 200 per 100 000 invånare i Sverige drabbas årligen av svår sepsis.

Rac1 är en Rho familjen GTPases, som spelar en viktig roll i celladhesion och motilitet, men lite är känt om en potentiell roll Rac1 i kontrollen sepsis mediterad intracellulära signalvägar. Vi antog att Rac1 skulle vara inblandade i sepsis mediterad signalvägar som leder till aktivering av inflammatoriska celler. Syftet med den här avhandlingen var studera den potentielle betydelsen av Rac1 vid sepsis.

Delarbete (I), Rac1 signalering spelar en viktig roll i polymikrobiella sepsis inducerad med cecal ligation och punktering (CLP). Denna studie visar att Rac1 signalering reglerar sepsisinducerad inflammation i lungan genom att minska kemokin produktion och Mac-1 expression på neutrofiler. Rac1 hämmare (NSC23766 5 mg/kg) sänker lungödem, vävnadsskada och systemisk proinflammatoriska cytokiner i septisk mös, vilket tyder på att målsökning Rac1 kan vara användbart tillvägagångssätt för att skydda mot lungskada i buksepsis. Delarbete (II), i denna studie visar vi att inhibering av Rac1 signalering skydda mot sepsisinducerad lungskada genom två olika mekanismer, först Rac1 kontrollerar ytan mobilisering av CD40L på aktiverade trombocyter och andra, Rac1 reglerar MMP-9 sekret från neutrofiler. Våra resultat visar att hämning av Rac1 signalering kan spela en viktig roll för att kontrollera patologisk sekretion och utsöndring av CD40L i den systemiska cirkulationen i buksepsis. Delarbete (III), denna studie visar att Rac1 aktivitet ökar i trombocyter och reglerar trombocyter sekretion av CCL5 i buksepsis. Våra resultat visar att CCL5 reglerar neutrofila rekrytering i septisk lungskada via aktivering av alveolära makrofager som leder till lokal utsöndring av CXCL2. Således, vårt resultat avslöjar inte bara komplexa mekanismer som reglerar lung neutrofila rekryt i sepsis men också tyder på att hämningen av Rac1 signalering och trombocytderiverad CCL5 kan vara ett bra sätt att kontrollera patologisk inflammation och vävnadsskada i lungan i buksepsis. Delarbete (IV), Rac1 aktivitet ökad i trombocyter



och reglerar trombocyt utsöndring av CXCL4 i buksepsis. Denna studie visar att CXCL4 kontrollerar neutrofil ackumulering via utsöndring av CXCL2 från alveolära makrofager i septisk lungskada. Dessa fynd inte bara beskriva komplexa mekanismer av neutrofila infiltrationen med sepsis, men också tyder på att hämningen av trombocytderiverad CXCL4 kan vara ett effektivt sätt att hindra inflammation och vävnadsskada i septiska lungskador. (Less)
Abstract
Sepsis is a systemic inflammatory response syndrome to a localized or systemic infection that leads to the over production of proinflammatory cytokines and the ultimate failure of multiple organ systems. However, little is known about the potential role of Rac1 in controlling sepsis-induced intracellular signaling pathways. We hypothesized that Rac1 might be involved in sepsis mediated signaling pathways leading to the activation of inflammatory cells.

Paper (I), Rac1 signaling plays an important role in polymicrobial sepsis induced by cecal ligation and puncture (CLP). This study shows that Rac1 signaling regulates sepsis-induced inflammation in the lung by reducing chemokine production and Mac-1 expression on neutrophils. Rac1... (More)
Sepsis is a systemic inflammatory response syndrome to a localized or systemic infection that leads to the over production of proinflammatory cytokines and the ultimate failure of multiple organ systems. However, little is known about the potential role of Rac1 in controlling sepsis-induced intracellular signaling pathways. We hypothesized that Rac1 might be involved in sepsis mediated signaling pathways leading to the activation of inflammatory cells.

Paper (I), Rac1 signaling plays an important role in polymicrobial sepsis induced by cecal ligation and puncture (CLP). This study shows that Rac1 signaling regulates sepsis-induced inflammation in the lung by reducing chemokine production and Mac-1 expression on neutrophils. Rac1 inhibitor NSC23766 attenuates lung edema, tissue destruction and systemic pro-inflammatory cytokines in septic animals, suggesting that targeting Rac1 may be useful approach to protect against pulmonary injury in abdominal sepsis. Paper (II), in this study we showed that inhibition of Rac1 signaling protect sepsis-induced lung injury through two different mechanisms. First, Rac1 controls surface mobilization of CD40L on activated platelets and second, Rac1 regulates MMP-9 secretion from neutrophils. Our data indicate that inhibition of Rac1 signaling might be a useful target in order to control pathological secretion and shedding of CD40L into the systemic circulation in abdominal sepsis. Paper (III) This study indicates that Rac1 activity is increased in platelets and regulates platelet secretion of CCL5 in abdominal sepsis. Our findings show that CCL5 regulates neutrophil recruitment in septic lung injury via activation of alveolar macrophages leading to local secretion of CXCL2. Thus, our novel data not only elucidates complex mechanisms regulating pulmonary neutrophil trafficking in sepsis but also suggest that targeting Rac1 signaling and platelet-derived CCL5 might be a useful way to control pathological inflammation and tissue damage in the lung in abdominal sepsis. Paper (IV) Rac1 signaling is enhanced in platelets and regulates platelet secretion of CXCL4 in abdominal sepsis. This study indicates that CXCL4 controls neutrophil accumulation via secretion of CXCL2 from alveolar macrophages in septic lung injury. These findings not only delineate complex mechanisms of neutrophil trafficking in sepsis but also suggest that targeting platelet-derived CXCL4 might be an effective way to ameliorate inflammation and tissue damage in septic lung damage. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Tolba, Rene, University Hospital Aachen, Germany
organization
publishing date
type
Thesis
publication status
published
subject
keywords
abdominal sepsis, Rac1, platelet, neutrophil, chemokine, inflammation
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2015:39
pages
152 pages
publisher
Lund University
defense location
Surgical Clinic library, Inga Marie Nilssons gata 47, plan 3, Skånes Universitetssjukhus i Malmö.
defense date
2015-04-24 09:00
ISSN
1652-8220
ISBN
978-91-7619-118-7
language
English
LU publication?
yes
id
c270a1a3-cf1a-4fba-892d-2b712b248b47 (old id 5268340)
date added to LUP
2015-04-13 09:31:45
date last changed
2016-09-19 08:44:47
@phdthesis{c270a1a3-cf1a-4fba-892d-2b712b248b47,
  abstract     = {Sepsis is a systemic inflammatory response syndrome to a localized or systemic infection that leads to the over production of proinflammatory cytokines and the ultimate failure of multiple organ systems. However, little is known about the potential role of Rac1 in controlling sepsis-induced intracellular signaling pathways. We hypothesized that Rac1 might be involved in sepsis mediated signaling pathways leading to the activation of inflammatory cells.<br/><br>
Paper (I), Rac1 signaling plays an important role in polymicrobial sepsis induced by cecal ligation and puncture (CLP). This study shows that Rac1 signaling regulates sepsis-induced inflammation in the lung by reducing chemokine production and Mac-1 expression on neutrophils. Rac1 inhibitor NSC23766 attenuates lung edema, tissue destruction and systemic pro-inflammatory cytokines in septic animals, suggesting that targeting Rac1 may be useful approach to protect against pulmonary injury in abdominal sepsis. Paper (II), in this study we showed that inhibition of Rac1 signaling protect sepsis-induced lung injury through two different mechanisms. First, Rac1 controls surface mobilization of CD40L on activated platelets and second, Rac1 regulates MMP-9 secretion from neutrophils. Our data indicate that inhibition of Rac1 signaling might be a useful target in order to control pathological secretion and shedding of CD40L into the systemic circulation in abdominal sepsis. Paper (III) This study indicates that Rac1 activity is increased in platelets and regulates platelet secretion of CCL5 in abdominal sepsis. Our findings show that CCL5 regulates neutrophil recruitment in septic lung injury via activation of alveolar macrophages leading to local secretion of CXCL2. Thus, our novel data not only elucidates complex mechanisms regulating pulmonary neutrophil trafficking in sepsis but also suggest that targeting Rac1 signaling and platelet-derived CCL5 might be a useful way to control pathological inflammation and tissue damage in the lung in abdominal sepsis. Paper (IV) Rac1 signaling is enhanced in platelets and regulates platelet secretion of CXCL4 in abdominal sepsis. This study indicates that CXCL4 controls neutrophil accumulation via secretion of CXCL2 from alveolar macrophages in septic lung injury. These findings not only delineate complex mechanisms of neutrophil trafficking in sepsis but also suggest that targeting platelet-derived CXCL4 might be an effective way to ameliorate inflammation and tissue damage in septic lung damage.},
  author       = {Hwaiz, Rundk},
  isbn         = {978-91-7619-118-7},
  issn         = {1652-8220},
  keyword      = {abdominal sepsis,Rac1,platelet,neutrophil,chemokine,inflammation},
  language     = {eng},
  pages        = {152},
  publisher    = {Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Rac1 signaling regulates platelet-dependent inflammation abdominal sepsis},
  volume       = {2015:39},
  year         = {2015},
}