Abstract
Methods AP was induced in Balb/C mice by ten hourly intraperitoneal injections of caerulein (100 μg/kg) and LPS (5 mg/kg). The MMP inhibitor, BB-94 (20 mg/kg) was intraperitoneally administered 30 min before AP induction. Pancreatitis was confirmed by histology and serum amylase and lipase. Expression of pancreatic proinflammatory mediators and NF-κB activation were assessed. Bone marrow-derived neutrophils (BMDNs) and macrophages (BMDMs) were isolated. BMDNs were activated by phorbol 12-myristate 13-acetate (PMA, 50 ng/ml) and neutrophil reactive oxygen species (ROS) production was recorded. BMDMs were stimulated with 10 ng/ml IFN-γ and 100 ng/ml LPS to induce M1 macrophage polarization. Results Pancreatic MMP-9 was markedly upregulated and serum MMP-9 was increased in caerulein-induced pancreatitis. Inhibition of MMP with BB-94 ameliorated pancreatic tissue damage and decreased the expression of proinflammatory cytokines (TNFα and IL-6) or chemokines (CCL2 and CXCL2) and NF-κB activation. Furthermore, using isolated BMDNs and BMDMs, we found that inhibition of MMP with BB-94 markedly decreased neutrophil ROS production, inhibited inflammatory macrophage polarization and NF-κB activation. Conclusions Our results showed that inhibition of MMP with BB-94 protected against pancreatic inflammatory responses in caerulein-induced pancreatitis via modulating neutrophil and macrophage activation.
Highlights
Acute pancreatitis (AP) is a common and potentially lifethreatening inflammatory disorder of the pancreas and is the leading cause of hospital admission for gastrointestinal disorders worldwide [1,2,3]
In caerulein-induced pancreatitis, we measured pancreatic matrix metalloproteinases (MMPs)-9 mRNA and protein levels by Quantitative PCR (qPCR) and western blotting and found that both mRNA and protein levels of MMP-9 were markedly upregulated in caerulein-induced pancreatitis (Figure 1(a) and 1(b))
Consistent with previously published studies [19], we showed that MMP-9 is upregulated in AP, suggesting that it may be a primary regulator in the pathogenesis of AP
Summary
Acute pancreatitis (AP) is a common and potentially lifethreatening inflammatory disorder of the pancreas and is the leading cause of hospital admission for gastrointestinal disorders worldwide [1,2,3]. Inhibition of MMP with BB-94 attenuated pancreatic edema, inflammatory infiltration, necrosis, and markedly reduced pancreatic proinflammatory cytokine or chemokine expression and NF-κB activation. Using isolated bone marrow-derived neutrophils (BMDNs) and macrophages (BMDMs), we found that inhibition of MMP with BB-94 significantly reduced neutrophil reactive oxygen species (ROS) and inhibited inflammatory macrophage polarization. These findings revealed that MMPs, MMP-9, play a crucial role in mediating inflammatory cell activation during AP, suggesting that targeting MMP-9 could be a potential therapeutic approach for treating AP
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