IT 9302, a synthetic interleukin-10 agonist, diminishes acute lung injury in rabbits with acute necrotizing pancreatitis.
BACKGROUND
Proinflammatory cytokines (eg, tumor necrosis factor [TNF]-alpha, interleukin [IL]-1 and Il- 8) are believed to play an important role in the pathogenesis of acute necrotizing pancreatitis (ANP) and its systemic complications. Recently, IL-10 has emerged as a major anti-inflammatory cytokine, inhibiting the secretion and activities of inflammatory cytokines. Further, a protective effect of IL-10 has recently been shown in experimental acute pancreatitis. The purpose of this study was to test the potential role of a newly developed IL-10 agonist, IT 9302, in a model of ANP in rabbits.


METHODS
ANP was induced in 18 rabbits by retrograde injection of 5% chenodeoxycholic acid in the pancreatic duct, followed by duct ligation. The rabbits were allocated to pretreatment with intravenous physiologic saline solution or IT 9302 (200 micrograms/kg) 30 minutes before the induction of ANP.


RESULTS
Injection of IT 9302 resulted in a significant reduction in the blood levels of TNF-alpha and IL-8 from 3 to 6 hours. IT 9302 also reduced the amount of ascitic fluid and significantly inhibited neutrophil infiltration and margination, as well as the number of CD11b- and CD18-positive cells in the lung tissues. By contrast, the local pancreatic necrosis, as well as the biochemical changes such as serum amylase, lipase, and calcium, was sever and similar in both groups. Survival was improved significantly after treatment with IT 9302.


CONCLUSIONS
As expected, IT 9302 cannot change the degree of ANP induced by 5% bile acid but does reduce mortality rates and the development of acute lung injury, probably through the inhibition of circulating levels of TNF-alpha, IL-8, and the expression of the adhesion molecule complex CD11b/CD18.
Osman
M O
MO
Department of Surgery L Aarhus University Hospital, Denmark.
Jacobsen
N O
NO
Kristensen
J U
JU
Deleuran
B
B
Gesser
B
B
Larsen
C G
CG
Jensen
S L
SL
D000681:Amylases / Q000097:blood; D000818:Animals; D001201:Ascites / Q000201:enzymology; D001646:Bile; D001786:Blood Glucose; D018821:CD18 Antigens / Q000032:analysis; D002118:Calcium / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D016753:Interleukin-10 / Q000819:agonists*; D016209:Interleukin-8 / Q000097:blood; D007958:Leukocyte Count; D007962:Leukocytes / Q000502:physiology; D008049:Lipase / Q000097:blood; D008171:Lung Diseases / Q000150:complications* / Q000188:drug therapy* / Q000276:immunology; D016177:Macrophage-1 Antigen / Q000032:analysis; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology*; D010179:Pancreas / Q000201:enzymology / Q000276:immunology; D019283:Pancreatitis, Acute Necrotizing / Q000209:etiology* / Q000276:immunology / Q000401:mortality; D011650:Pulmonary Alveoli / Q000276:immunology; D011817:Rabbits; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D001786:Blood Glucose; D018821:CD18 Antigens; D016209:Interleukin-8; D016177:Macrophage-1 Antigen; D009842:Oligopeptides; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; C114519:alanyl-tyrosyl-methionyl-threonyl-methionyl-lysyl-isoleucyl-arginyl-asparagine; D008049:Lipase; D000681:Amylases; D002118:Calcium