Inhibition of matrix metalloproteinases reduces local and distant organ injury following experimental acute pancreatitis

Bart E. Muhs, Sundeep Patel, Herman Yee, Stuart Marcus, Peter Shamamian

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

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 × three doses) or control (AP + 20 ml/kg/24 h normal saline ip × 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.

Original languageEnglish (US)
Pages (from-to)110-117
Number of pages8
JournalJournal of Surgical Research
Volume109
Issue number2
DOIs
StatePublished - Feb 2003
Externally publishedYes

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Matrix Metalloproteinases
Pancreatitis
Wounds and Injuries
Matrix Metalloproteinase Inhibitors
Capillary Permeability
Lung Injury
Amylases
Lung
Necrosis
Acute Necrotizing Pancreatitis
Evans Blue
Taurocholic Acid
Control Groups
batimastat
Pancreatic Ducts
Edema
Neutrophils
Peptide Hydrolases
Coloring Agents
Hemorrhage

Keywords

  • Batimistat
  • BB-94
  • Lung injury
  • Matrix metalloproteinase
  • MMP
  • MMP-2
  • MMP-9
  • Pancreatitis

ASJC Scopus subject areas

  • Surgery

Cite this

Inhibition of matrix metalloproteinases reduces local and distant organ injury following experimental acute pancreatitis. / Muhs, Bart E.; Patel, Sundeep; Yee, Herman; Marcus, Stuart; Shamamian, Peter.

In: Journal of Surgical Research, Vol. 109, No. 2, 02.2003, p. 110-117.

Research output: Contribution to journalArticle

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abstract = "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 × three doses) or control (AP + 20 ml/kg/24 h normal saline ip × 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.",
keywords = "Batimistat, BB-94, Lung injury, Matrix metalloproteinase, MMP, MMP-2, MMP-9, Pancreatitis",
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T1 - Inhibition of matrix metalloproteinases reduces local and distant organ injury following experimental acute pancreatitis

AU - Muhs, Bart E.

AU - Patel, Sundeep

AU - Yee, Herman

AU - Marcus, Stuart

AU - Shamamian, Peter

PY - 2003/2

Y1 - 2003/2

N2 - 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 × three doses) or control (AP + 20 ml/kg/24 h normal saline ip × 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.

AB - 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 × three doses) or control (AP + 20 ml/kg/24 h normal saline ip × 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.

KW - Batimistat

KW - BB-94

KW - Lung injury

KW - Matrix metalloproteinase

KW - MMP

KW - MMP-2

KW - MMP-9

KW - Pancreatitis

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U2 - 10.1016/S0022-4804(02)00084-7

DO - 10.1016/S0022-4804(02)00084-7

M3 - Article

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JO - Journal of Surgical Research

JF - Journal of Surgical Research

SN - 0022-4804

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