Effects of immunosuppressive and immunostimulative treatment on pancreatic injury and mortality in severe acute experimental pancreatitis.
OBJECTIVE
Acute pancreatitis is associated with substantial alterations of the immunologic host response which has been claimed to promote remote organ dysfunction, septic complications, and mortality. Treatment with immunomodulating substances has been subject of few experimental studies with still conflicting results.


METHODS
We used the taurocholate-induced model of severe acute pancreatitis (SAP) in rats which were assigned to different treatment regimen: isotonic saline (SAP-S) for nontreated controls, recombinant rat interferon-gamma for immunostimulation (SAP-IFN-gamma), and FK506 for immunosuppression (SAP-FK506). Animals were killed after 3, 6, and 24 hours as well as 3 and 7 days, and parameters of local and systemic severity were assessed.


RESULTS
Treatment with IFN-gamma and FK506 attenuated the progression of intrapancreatic necrosis within the first 24 hours after pancreatitis induction along with a substantial reduction of subsequent neutrophil tissue infiltration as shown by decreased myeloperoxidase activity. Enhanced cell death by apoptosis during the postacute course was reduced in FK506-treated animals only. Pancreatic interleukin (IL) 1beta messenger RNA up-regulation occurred early and was slightly suppressed in both treatment groups; tumor necrosis factor alpha (TNF-alpha) and IL-2 messenger RNA expression paralleled the onset of apoptosis and was markedly decreased in IFN-gamma- and FK506-treated rats. The 2 therapeutic regimens had similar effects on intrapancreatic and systemic IL-1beta and TNF-alpha protein release; however, the profiles of both cytokines were differently influenced. Whereas IFN-gamma and FK506 treatment lead to an enhanced intrapancreatic and systemic TNF-alpha protein release during the early course, IL-1beta concentrations were significantly reduced within the late intervals. Seven-day mortality was 44% in saline-, 29% in IFN-gamma-, and 25% in FK506-treated rats (P = not significant).


CONCLUSIONS
Severe acute pancreatitis is associated with early alterations of the immune response comprising overt T-cell activation and impaired monocyte/macrophage function alike. Targeting either immunologic derangement improves local pancreatic damage and systemic severity. However, because mortality was not improved, a therapeutic benefit of immunomodulating substances in clinical SAP remains to be defined.
Rau
Bettina M
BM
Department of General, Visceral, and Vascular Surgery, University of the Saarland, Homburg/Saar, Germany. bettina.rau@uniklinikum-saarland.de
Krüger
Colin M
CM
Hasel
Cornelia
C
Oliveira
Vilma
V
Rubie
Claudia
C
Beger
Hans G
HG
Schilling
Martin K
MK
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D008297:Male; D009336:Necrosis; D010179:Pancreas / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D019283:Pancreatitis, Acute Necrotizing / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016559:Tacrolimus / Q000494:pharmacology; D013656:Taurocholic Acid; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D000276:Adjuvants, Immunologic; D007166:Immunosuppressive Agents; D053583:Interleukin-1beta; D007376:Interleukin-2; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D013656:Taurocholic Acid; D007371:Interferon-gamma; D016559:Tacrolimus