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Inflammatory response and intervention in experimental acute pancreatitis

Shi, Changbin LU (2006)
Abstract
Acute pancreatitis (AP) is a common disease where underlying mechanisms for the local initiating events in the pancreas, the systemic dissemination of the inflammatory response and remote organ dysfunction still are unclear. The overall aim of the thesis was to study mechanisms of the inflammatory response in AP with special emphasis on local, systemic, and distant organ injury directed at different signalling pathways, and potential therapeutic strategies to prevent the development of inflammation and cell injury following AP. Experimental AP was induced by the intraductal administration of 5% sodium taurodeoxycholate in SD rats. Treatment attempts with NF-?B inhibitors (NAC and PDTC), ERK inhibitor (PD-98059), tyrosine kinase inhibitor... (More)
Acute pancreatitis (AP) is a common disease where underlying mechanisms for the local initiating events in the pancreas, the systemic dissemination of the inflammatory response and remote organ dysfunction still are unclear. The overall aim of the thesis was to study mechanisms of the inflammatory response in AP with special emphasis on local, systemic, and distant organ injury directed at different signalling pathways, and potential therapeutic strategies to prevent the development of inflammation and cell injury following AP. Experimental AP was induced by the intraductal administration of 5% sodium taurodeoxycholate in SD rats. Treatment attempts with NF-?B inhibitors (NAC and PDTC), ERK inhibitor (PD-98059), tyrosine kinase inhibitor (genistein), protease inhibitors (aprotinin, pefabloc, and trypsin inhibitor), and PKC inhibitors (polymyxin B and staurosporine) were tested. AP induced local pancreatic inflammation and injury, with increased levels of IL-6, CINC, and MCP-1 in pancreatic acini, and neutrophil accumulation in the pancreas. In parallel, an inflammatory response in the lungs was observed. However, a hyporesponsiveness in circulating monocytes occurred. Moreover, a reverse relationship of the expression of NF-?B, cytokine and chemokine mRNA in pancreatic acini and circulating monocytes exists and cytokines and chemokines are primarily produced by the local inflamed compartment rather than by circulating monocytes. This indicates that SIRS predominates within the inflamed tissues, in parallel with a downregulation of circulating monocytes. Consequently, comparing the immune status and inflammatory response of circulating monocytes and pancreatic acini may provide understanding of mechanisms by which SIRS, CARS and MODS potentially develop in severe AP. This process was closely regulated by NF-?B. The use of an immune stimulator delivered systemically in cases of immune suppression of monocytes could be of potential benefit. Various inhibitors targeting the different signalling pathways could prevent AP-induced local, systemic, and distant organ inflammatory responses. In addition, we further investigated PKC signalling transduction in AP-induced lung injury. Our results showed that an activation of the PKC signalling transduction could play an important role in the pathogenesis of pancreatitis-associated lung injury and that the PKC inhibitor polymyxin B prevented against AP-induced lung injury. (Less)
Abstract (Swedish)
Popular Abstract in Swedish

Akut bukspottkörtelinflammation (akut pankreatit - AP) är en tämligen frekvent förekommande åkomma med en årlig incidens på 300-350/100 000 invånare i Sverige. De underliggande mekanismerna för den lokalt initierande skadan i bukspottkörteln, spridning till ett systemiskt (i hela kroppen) inflammatoriskt svar och den eventuella utvecklingen av organdysfunktion (organsvikt) är fortfarande tämligen oklara. Syftet med denna avhandling var att studera mekanismer underliggande det inflammatoriska svaret vid AP såväl lokalt som systemiskt och åtföljande organskada samt de olika signalvägar som kan vara inblandade. Dessutom syftade vi att undersöka möjliga behandlingsinsatser för att motverka... (More)
Popular Abstract in Swedish

Akut bukspottkörtelinflammation (akut pankreatit - AP) är en tämligen frekvent förekommande åkomma med en årlig incidens på 300-350/100 000 invånare i Sverige. De underliggande mekanismerna för den lokalt initierande skadan i bukspottkörteln, spridning till ett systemiskt (i hela kroppen) inflammatoriskt svar och den eventuella utvecklingen av organdysfunktion (organsvikt) är fortfarande tämligen oklara. Syftet med denna avhandling var att studera mekanismer underliggande det inflammatoriska svaret vid AP såväl lokalt som systemiskt och åtföljande organskada samt de olika signalvägar som kan vara inblandade. Dessutom syftade vi att undersöka möjliga behandlingsinsatser för att motverka utvecklingen av inflammation och cellskada vid AP.



Experimentell AP framkallades genom att gallsalt sprutades i den gemensamma bukspottkörtel-gallgången på råtta. Hämmare av olika inflammatoriskt styrande signalsubstanser och signalsystem riktade mot t ex NF-kB (NAC, PDTC), ERK (PD-98059), tyrosinkinas (genistein), proteaser (aprotinin, pefabloc, trypsininhibitor) och PKC (polymyxin B, staurosporine) testades.



AP resulterade i inflammation och skada i bukspottkörteln med ökade nivåer av inflammatoriska markörer som IL-6, CINC och MCP-1 samt ansamling av vita blodkroppar i bukspottkörteln. Samtidigt utvecklades ett inflammatoriskt svar i lungorna. Med tiden allt tilltagande nedsättning av immunfunktionen kunde ses hos cirkulerande vita blodkroppar (monocyter). En motsatsreaktion förelåg vad avser aktivering av inflammatoriska regulatorer (NF-kB, cytokiner och kemokin mRNA) i bukspottkörteln och cirkulerande monocyter. Den fortsatta inflammatoriska reaktionen förefaller därför dominera i de lokalt skadade vävnaderna (bukspottkörteln) samtidigt som en nedreglering av immunsvaret sker systemiskt (cirkulerande monocyter). Denna process kan möjligen regleras av NF-kB. Hämmare riktade mot olika signalvägar kunde förhindra den AP-orsakade såväl lokala och systemiska inflammationen samt utvecklingen av organskada. En aktivering av PKC-signalering kan spela en betydelsefull roll i utvecklingen av pankreatitorsakad lungskada och PKC-hämmaren polymyxin B förebyggde effektivt utvecklingen av detta.



Sammanfattningsvis belyses det dynamiska och divergerande inflammatoriska svaret i bukspottkörtel respektive systemiskt (blod) vid experimentell akut bukspottkörtelinflammation. Möjligheter föreligger, åtminstone experimentellt, att modulera detta inflammatoriska svar och motverka bukspottkörtelinflammationens skadeverkningar. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Löhr, Matthias, University of Heidelberg, Germany
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Kirurgi, ortopedi, traumatologi, traumatology, Surgery, orthopaedics, signalling pathways, protein kinase C, nuclear factor-kB, leukocytes, inflammatory mediators, immunosuppression, acute pancreatitis, extracellular signal-regulated kinase
pages
126 pages
publisher
Department of Surgery, Clinical Sciences Lund, Lund University
defense location
Lecture room 1, Central building, Lund University Hospital, Lund.
defense date
2006-02-10 13:00:00
ISBN
91-85481-39-4
language
English
LU publication?
yes
additional info
C Shi, X Zhao, A Lagergren, M Sigvardsson, XD Wang and R Andersson. 2005. Immune status and inflammatory response differ locally and systemically in severe acute pancreatitis. Scandinavian Journal of Gastroenterology, (inpress)
C Shi, X Zhao, XD Wang and R Andersson. 2005. Role of nuclear factor- Scandinavian Journal of Gastroenterology, vol 40 pp 103-108.
C Shi, X Zhao, XD Wang, L Zhao and R Andersson. . Potential effects of PKC or protease inhibitors on acute pancreatitis-induced tissue injury in rats. (submitted)
X Zhao, C Shi, XD Wang and R Andersson. 2005. Protein kinase C modulates the pulmonary inflammatory response in acute pancreatitis. Respiratory Physiology & Neurobiology, (inpress)
id
9a7fd97a-be3b-41ad-8cda-ec05322ffe89 (old id 546153)
date added to LUP
2016-04-01 15:46:32
date last changed
2018-11-21 20:36:15
@phdthesis{9a7fd97a-be3b-41ad-8cda-ec05322ffe89,
  abstract     = {{Acute pancreatitis (AP) is a common disease where underlying mechanisms for the local initiating events in the pancreas, the systemic dissemination of the inflammatory response and remote organ dysfunction still are unclear. The overall aim of the thesis was to study mechanisms of the inflammatory response in AP with special emphasis on local, systemic, and distant organ injury directed at different signalling pathways, and potential therapeutic strategies to prevent the development of inflammation and cell injury following AP. Experimental AP was induced by the intraductal administration of 5% sodium taurodeoxycholate in SD rats. Treatment attempts with NF-?B inhibitors (NAC and PDTC), ERK inhibitor (PD-98059), tyrosine kinase inhibitor (genistein), protease inhibitors (aprotinin, pefabloc, and trypsin inhibitor), and PKC inhibitors (polymyxin B and staurosporine) were tested. AP induced local pancreatic inflammation and injury, with increased levels of IL-6, CINC, and MCP-1 in pancreatic acini, and neutrophil accumulation in the pancreas. In parallel, an inflammatory response in the lungs was observed. However, a hyporesponsiveness in circulating monocytes occurred. Moreover, a reverse relationship of the expression of NF-?B, cytokine and chemokine mRNA in pancreatic acini and circulating monocytes exists and cytokines and chemokines are primarily produced by the local inflamed compartment rather than by circulating monocytes. This indicates that SIRS predominates within the inflamed tissues, in parallel with a downregulation of circulating monocytes. Consequently, comparing the immune status and inflammatory response of circulating monocytes and pancreatic acini may provide understanding of mechanisms by which SIRS, CARS and MODS potentially develop in severe AP. This process was closely regulated by NF-?B. The use of an immune stimulator delivered systemically in cases of immune suppression of monocytes could be of potential benefit. Various inhibitors targeting the different signalling pathways could prevent AP-induced local, systemic, and distant organ inflammatory responses. In addition, we further investigated PKC signalling transduction in AP-induced lung injury. Our results showed that an activation of the PKC signalling transduction could play an important role in the pathogenesis of pancreatitis-associated lung injury and that the PKC inhibitor polymyxin B prevented against AP-induced lung injury.}},
  author       = {{Shi, Changbin}},
  isbn         = {{91-85481-39-4}},
  keywords     = {{Kirurgi; ortopedi; traumatologi; traumatology; Surgery; orthopaedics; signalling pathways; protein kinase C; nuclear factor-kB; leukocytes; inflammatory mediators; immunosuppression; acute pancreatitis; extracellular signal-regulated kinase}},
  language     = {{eng}},
  publisher    = {{Department of Surgery, Clinical Sciences Lund, Lund University}},
  school       = {{Lund University}},
  title        = {{Inflammatory response and intervention in experimental acute pancreatitis}},
  year         = {{2006}},
}