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Published on: May 10, 2024
Matrix metalloproteinase-9 derived from polymorphonuclear neutrophils increases gut barrier dysfunction and bacterial
Yukio Mikami1, Ernst V Dobschütz, Olaf Sommer
1Department of General and Visceral Surgery, University Hospital Freiburg, Freiburg, Germany. y-mikami@surg1.med.tohoku.ac.jp
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.
Conclusion:
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.
Insights
Polymorphonuclear neutrophils (PMNs) and matrix metalloproteinase-9 (MMP-9) worsen gut barrier dysfunction in severe acute pancreatitis (SAP). Inhibiting PMNs or MMP-9 reduces bacterial translocation, highlighting their roles in SAP pathogenesis.
Area of Science:
- Gastroenterology
- Immunology
- Pathophysiology
Background:
- The role of polymorphonuclear neutrophil granulocytes (PMNs) and matrix metalloproteinase-9 (MMP-9) in severe acute pancreatitis (SAP)-induced gut barrier dysfunction remains unclear.
- This study investigated the impact of PMNs and MMP-9 on gut barrier integrity in a rat model of SAP.
Purpose of the Study:
- To elucidate the contribution of PMNs and MMP-9 to gut barrier dysfunction in severe acute pancreatitis (SAP).
- To evaluate the therapeutic potential of targeting PMNs and MMP-9 in SAP.
Main Methods:
- Severe acute pancreatitis (SAP) was induced in rats using sodium taurocholate.
- Rats were treated with anti-rat PMN serum or the MMP inhibitor BB-94 to deplete PMNs or inhibit MMP-9 activity, respectively.
- Gut barrier function, bacterial translocation (BT), PMN transmigration, and reactive oxygen species (ROS) were assessed.
Main Results:
- SAP significantly increased mucosal injury, PMN infiltration, MMP-9 levels, and ROS in the gut.
- Depletion of PMNs or inhibition of MMP-9 significantly reduced gut injury and bacterial translocation (BT).
- PMN transmigration was also reduced by PMN depletion and MMP-9 inhibition.
Conclusions:
- PMNs play a critical role in the pathogenesis of bacterial translocation (BT) in severe acute pancreatitis (SAP).
- MMP-9 is implicated in both BT and PMN transmigration during SAP.
- Targeting PMNs and MMP-9 shows promise for preventing gut barrier dysfunction in SAP.
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