Acute pancreatitis (AP) is an inflammatory disease with variable severity ranging from mild interstitial edematous to severe necrotizing disease. The overall mortality rate of AP is 8-9%. Specific treatment of AP is lacking which is partly related to an incomplete understanding of the basic pathophysiology behind the disease. It is widely held that premature intra-cellular trypsinogen activation and leukocyte recruitment play key roles in the pathophysiology of the AP. However, the signaling and adhesive mechanisms remain elusive. The aim of this thesis was to investigate the signaling and adhesive mechanisms in AP.
In this thesis, biliary pancreatitis was induced by retrograde infusion of taurocholate into the pancreatic duct in different mice strains to elucidate the role of toll-like receptor 2 (TLR2), TLR4, lymphocyte function antigen-1 (LFA-1), matrix metalloproteinases (MMPs) and Rho-kinase as well as nuclear factor of activated T-cell (NFAT) signaling in AP.
We found that TLR4 but not TLR2 plays a role in AP. LFA-1 adhesive mechanisms play a role in tissue damage and leukocyte recruitment but not trypsinogen activation. Furthermore, neutrophil-derived MMP-9 mediates tissue damage and neutrophil-dependent trypsinogen activation. Rho-kinase signaling regulates trypsinogen activation, leukocyte recruitment and tissue damage in AP. Moreover, NFATc3 is activated and translocated to the acinar cell nucleus and regulates trypsinogen activation, leukocyte recruitment and tissue damage in AP.
Taken together, the results of this thesis demonstrate that signaling and adhesive mechanisms are of particular importance in the pathophysiology of AP and could be used as useful targets in the management of patients with AP.
- Thorlacius, Henrik, Supervisor
- Regnér, Sara, Supervisor
- Qader, Saleem, Supervisor
- Gomez, Maria F, Supervisor
|Award date||2011 Dec 9|
|Publication status||Published - 2011|
Place: MFC, entrance 59, Skåne University Hospital
Name: Löhr, Matthias
Affiliation: Karolinska Institute
- trypsinogen activation
- Acute pancreatitis
- leukocyte recruitment and adhesion