Inhibition of matrix metalloproteinases reduces local and distant organ injury following experimental acute pancreatitis.
BACKGROUND
Pulmonary complications from pancreatitis involve parenchymal destruction via proteolytic enzymes. Matrix metalloproteinases (MMPs) may play an important role in pulmonary injury following acute severe pancreatitis. We hypothesized that local and distant organ injury would be decreased by the presence of an MMP inhibitor (Batimistat; BB-94) following severe acute pancreatitis (AP).


METHODS
Eighteen male rats were randomized into two groups: BB-94 (AP + 40 mg/kg/24 h BB-94 ip x three doses) or control (AP + 20 ml/kg/24 h normal saline ip x three doses). Necrotizing AP was induced by retrograde infusion of 5% sodium taurocholate (1.5 ml/kg) into the pancreatic duct. Twenty additional animals were randomized into BB-94 and control groups for the survival study. Serum was evaluated for amylase and MMP activity. Pancreatic sections were graded for edema, necrosis, neutrophil infiltrate, and hemorrhage. Myloperoxidase (MPO) activity was used to determine PMN infiltration in the lung. Evan's Blue dye extravasation was used to quantify vascular permeability.


RESULTS
Animals in the BB-94 group had decreased amylase levels (1086.0 +/- 61.7 U/L vs 2232.7 +/- 309.9 U/L; P < 0.05), decreased cellular infiltrate (1.4 +/- 0.2 vs 2.3 +/- 0.2; P < 0.02), and decreased necrosis (4.1 +/- 0.3 vs 6.1 +/- 0.4; P < 0.005) compared to the control group. Lung tissue following pancreatitis in the BB-94 group demonstrated decreased MPO activity (41.5 +/- 2.4 units vs 57.3 +/- 2.9 units; P < 0.05) and decreased vascular permeability (18.3 +/- 2.8 mg/100 g vs 30.1 +/- 4.6 mg/100 g; P < 0.05). Animals treated with BB-94 had 100% survival compared to 50% survival in control at 72 h.


CONCLUSIONS
Pancreatitis results in increased local and distant MMP activity. Pulmonary and pancreatic injury following AP can be abrogated by treatment with an MMP inhibitor (Batimistat; BB-94) which may result in decreased morbidity and mortality.
Muhs
Bart E
BE
S.A. Localio, Laboratory for Surgical Research, Department of Surgery, New York University School of Medicine, New York, New York 10016, USA.
Patel
Sundeep
S
Yee
Herman
H
Marcus
Stuart
S
Shamamian
Peter
P
D000681:Amylases / Q000097:blood; D000818:Animals; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D008171:Lung Diseases / Q000209:etiology* / Q000503:physiopathology* / Q000517:prevention & control; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000502:physiology*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D023421:Models, Animal; D010179:Pancreas / Q000187:drug effects*; D010182:Pancreatic Diseases / Q000517:prevention & control; D019283:Pancreatitis, Acute Necrotizing / Q000139:chemically induced / Q000150:complications* / Q000503:physiopathology*; D009195:Peroxidase / Q000378:metabolism; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018746:Systemic Inflammatory Response Syndrome / Q000209:etiology / Q000517:prevention & control; D013876:Thiophenes / Q000494:pharmacology*
D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D013876:Thiophenes; D010649:Phenylalanine; C080985:batimastat; D009195:Peroxidase; D000681:Amylases; D020782:Matrix Metalloproteinases; D008666:Metalloendopeptidases