Protective effects and anti-inflammatory pathways of exogenous calcitonin gene-related peptide in severe necrotizing pancreatitis.
BACKGROUND
Microcirculatory disturbances are known to play a pivotal role in the pathogenesis of severe necrotizing pancreatitis (SNP). Calcitonin gene-related peptide (CGRP) is a vasodilatatory neuropeptide with potential anti-inflammatory effects. This study characterizes the protective effects and the anti-inflammatory pathway of exogenous CGRP in SNP.


METHODS
SNP was induced in rats using the glycodeoxycholic acid model. CGRP was injected prophylactically before or therapeutically after initiation of the disease. Pancreatic damage was assessed using intravital microscopy, histology, NF-kappaB p50/p65 electrophoretic mobility shift assay, serum cytokine assay and ICAM-1 immunohistochemistry at 6 or 12 h after the onset of disease.


RESULTS
Pancreatic microcirculatory disturbances, nuclear NF-kappaB levels and pancreatic ICAM-1 expression were increased in SNP compared to controls. After CGRP application, microcirculatory disturbances, NF-kappaB levels and pancreatic ICAM-1 expression were attenuated compared to pancreatitis alone. Moreover, pancreatic morphologic damage was significantly reduced by both prophylactic and therapeutic application of CGRP.


CONCLUSIONS
CGRP is a neuropeptide that ameliorates the development of SNP in rats and may provide new treatment options. Its anti-inflammatory effects appear to be mediated by the modulation of pancreatic microcirculation and the inflammatory cascade.
Schneider
Lutz
L
Department of General Surgery, University of Heidelberg, Heidelberg, Germany.
Hartwig
Werner
W
Flemming
Thomas
T
Hackert
Thilo
T
Fortunato
Franco
F
Heck
Matthias
M
Gebhard
Martha-Maria
MM
Nawroth
Peter P
PP
Bierhaus
Angelika
A
Buchler
Markus W
MW
Werner
Jens
J
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D015740:Calcitonin Gene-Related Peptide / Q000627:therapeutic use*; D018925:Chemokines / Q000097:blood; D016207:Cytokines / Q000097:blood; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D008297:Male; D008833:Microcirculation; D016328:NF-kappa B / Q000378:metabolism; D010179:Pancreas / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D019283:Pancreatitis, Acute Necrotizing / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar
D000893:Anti-Inflammatory Agents; D018925:Chemokines; D016207:Cytokines; D016328:NF-kappa B; D018799:Intercellular Adhesion Molecule-1; D015740:Calcitonin Gene-Related Peptide