Matrix metalloproteinase-9 derived from polymorphonuclear neutrophils increases gut barrier dysfunction and bacterial translocation in rat severe acute pancreatitis.
BACKGROUND
The role of polymorphonuclear neutrophil granulocytes (PMNs) and the PMN-derived protease, which is called matrix metalloproteinase-9 (MMP-9), for the gut barrier dysfunction in severe acute pancreatitis (SAP) has not yet been clarified. The aim of this study was to evaluate the effects of PMNs and MMP-9 on gut barrier dysfunction in rat SAP.


METHODS
SAP was induced by the injection of 5% sodium taurocholate, and anti-rat PMN serum or BB-94 were administered 48 h and 24 h, respectively, before the induction of acute pancreatitis. Twenty-four hours after the induction of acute pancreatitis, the gut barrier dysfunction and the incidence of bacterial translocation (BT) and PMN transmigration were investigated by bacterial, histologic, and biochemical (MPO) analysis. Inhibition of MMP-9 was achieved by depletion of PMNs or inhibition of MMP-activity by a broad-spectrum MMP inhibitor and confirmed by zymography. In addition, reactive oxygen species were evaluated by spin trap assay.


RESULTS
The mucosal injury and the infiltration of PMNs into the gut tissue of rats with SAP were significantly increased in comparison with rats treated with anti-rat PMN serum or BB-94. The levels of MMP-9 and reactive oxygen species in the gut of rats with SAP were significantly higher than those of the rats treated with anti-rat PMN serum or BB-94. Pretreatment with anti-rat PMN serum or BB-94 reduced the incidence of BT in SAP.


CONCLUSIONS
The incidence of BT in SAP was prevented by the depletion of PMNs or less pronounced by the injection of the MMP inhibitor BB-94. PMNs play an important pathophysiologic role in the occurrence of BT, and MMP-9 is involved in both BT and PMN transmigration in rat SAP.
Mikami
Yukio
Y
Department of General and Visceral Surgery, University Hospital Freiburg, Freiburg, Germany. y-mikami@surg1.med.tohoku.ac.jp
Dobschütz
Ernst V
EV
Sommer
Olaf
O
Wellner
Ulrich
U
Unno
Michiaki
M
Hopt
Ulrich
U
Keck
Tobias
T
D000818:Animals; D018988:Bacterial Translocation; D007077:Ileal Diseases / Q000201:enzymology / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D007082:Ileum / Q000276:immunology / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D009283:Naphthol AS D Esterase; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000201:enzymology*; D010179:Pancreas / Q000473:pathology; D019283:Pancreatitis, Acute Necrotizing / Q000150:complications* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D009195:Peroxidase / Q000032:analysis; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013656:Taurocholic Acid; D013876:Thiophenes / Q000627:therapeutic use
D061965:Matrix Metalloproteinase Inhibitors; D017382:Reactive Oxygen Species; D013876:Thiophenes; D010649:Phenylalanine; D013656:Taurocholic Acid; C080985:batimastat; D009195:Peroxidase; D009283:Naphthol AS D Esterase; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9