MMP-9 in Serum Correlates with the Development of Pulmonary Complications in Experimental Acute Pancreatitis

Keck, Tobias; Jargon, D.; Klünsch, A.; Thomusch, Oliver; Richter, Sabine; Friebe, V.; Adam, Ulrich; Hopt, Ulrich T.

doi:10.1159/000092797

Cited by 10 publications

(10 citation statements)

References 31 publications

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“…For a rodent ventilator-induced lung injury model, Kim et al reported that lungs impaired by high tidal volume had higher expression of MMP-9 than lungs ventilated by low tidal volume and related this finding to neutrophilic inflammation [38]. Keck et al reported that MMP-9 was a valid marker for predicting the development of lung damage and was required for migration of neutrophils into lung tissue in the rodent acute pancreatitis model [27], [39]. Johnson et al reported that MMP-9 was required for angiogenesis in ischemic limbs and suggested that macrophages act as the source of MMP-9 [40]…”

Section: Discussionmentioning

confidence: 99%

Pathophysiology of Lung Injury Induced by Common Bile Duct Ligation in Mice

et al. 2014

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BackgroundLiver dysfunction and cirrhosis affect vasculature in several organ systems and cause impairment of organ functions, thereby increasing morbidity and mortality. Establishment of a mouse model of hepatopulmonary syndrome (HPS) would provide greater insights into the genetic basis of the disease. Our objectives were to establish a mouse model of lung injury after common bile duct ligation (CBDL) and to investigate pulmonary pathogenesis for application in future therapeutic approaches.MethodsEight-week-old Balb/c mice were subjected to CBDL. Immunohistochemical analyses and real-time quantitative reverse transcriptional polymerase chain reaction were performed on pulmonary tissues. The presence of HPS markers was detected by western blot and microarray analyses.ResultsWe observed extensive proliferation of CD31-positive pulmonary vascular endothelial cells at 2 weeks after CBDL and identified 10 upregulated and 9 down-regulated proteins that were associated with angiogenesis. TNF-α and MMP-9 were highly expressed at 3 weeks after CBDL and were less expressed in the lungs of the control group.ConclusionsWe constructed a mouse lung injury model by using CBDL. Contrary to our expectation, lung pathology in our mouse model exhibited differences from that of rat models, and the mechanisms responsible for these differences are unknown. This phenomenon may be explained by contrasting processes related to TNF induction of angiogenic signaling pathways in the inflammatory phase. Thus, we suggest that our mouse model can be applied to pulmonary pathological analyses in the inflammatory phase, i.e., to systemic inflammatory response syndrome, acute lung injury, and multiple organ dysfunction syndrome.

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Section: Discussionmentioning

confidence: 99%

Pathophysiology of Lung Injury Induced by Common Bile Duct Ligation in Mice

et al. 2014

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“…A notable study that examined the time course of serum MMP-9, the binding partner for NGAL, in relation to the development of pulmonary complications in rats found that the peak of serum MMP-9 occurred at 6 h in animals who developed SAP (40). This coincided with the first appearance of histological signs of pancreatic damage in these animals.…”

Section: Discussionmentioning

confidence: 99%

Elevated Serum Neutrophil Gelatinase-Associated Lipocalin Is an Early Predictor of Severity and Outcome in Acute Pancreatitis

Chakraborty¹,

Kaur²,

Muddana³

et al. 2010

American Journal of Gastroenterology

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OBJECTIVES About 210,000 new cases of acute pancreatitis (AP) involving reversible inflammation of the pancreas are reported in the United States every year. About one-fourth of all patients with AP go on to develop severe acute pancreatitis (SAP), which, unlike uncomplicated or mild acute pancreatitis (MAP, usually a self-limiting disease), constitutes a life-threatening condition with systemic complications, chiefly multiorgan dysfunction. An early prediction of the severity and outcome of patients with acute pancreatitis (AP) can lead to better treatment regimens for patients with SAP. There is currently no established biomarker for the early diagnosis of SAP. In this study, we investigated the potential of serum neutrophil gelatinase-associated lipocalin (NGAL) as an early marker to distinguish severe (SAP) from MAP and examine its ability to predict the prognosis of patients with SAP. METHODS To check the time kinetics of rise in NGAL during AP, we quantified NGAL levels in sera from mice with MAP or SAP at various time points (6, 12, 24 and 48 h) using sandwich enzyme-linked immunosorbent assay. NGAL levels were also quantified in serum from 28 MAP and 16 SAP cases and compared with 28 chronic pancreatitis and 30 healthy control samples. Samples collected within 5 days from onset of symptoms were included. The relationship of NGAL levels with survival and multiorgan failure (MOF) in SAP was also examined. RESULTS Although NGAL levels were significantly higher in mice with both MAP and SAP 6 h after induction (compared to control animals), only mice with SAP exhibited a significant increase in NGAL levels at 24 h (P=0.003). NGAL levels declinedx at 48 h after induction in animals with both MAP and SAP but did not reach baseline levels. Among patients, mean (±s.e.) serum NGAL level was significantly higher in SAP (634±139 ng/ml) compared to MAP (84.7±7 ng/ml, P=0.0001). On subanalysis, the difference between MAP and SAP cases was significant in the first 48 h but not at 72, 96, or 120 h. NGAL was 100%, 96%, 97%, and 84% specific and 100%, 87.5%, 92%, and 94% sensitive in distinguishing SAP from MAP at 48, 72, 96, and 120 h, respectively, after the onset of symptoms. NGAL levels were significantly higher in SAP cases complicated by MOF (P=0.004), and high NGAL levels in SAP appeared to correlate with a fatal outcome. CONCLUSIONS Our data provide the first evidence for the potential of serum NGAL as an early marker to distinguish MAP from SAP. Further, high NGAL levels predict MOF and fatal outcome in patients with SAP. This study provides sufficient evidence for multi-institutional randomized trials for estimating the potential of NGAL as early biomarker for SAP.

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“…MMPs comprise a superfamily of Ͼ25 structurally and functionally related endopeptidases [11] with capacity to cleave the majority of matrix proteins, as well as many nonmatrix targets, such as chemokines, cytokines, adhesion molecules, and surface receptors [12]. In this context, it is interesting to note that previous investigations have reported that certain MMPs, in particular, members of the gelatinase subfamily (MMP-2 and MMP-9), are increased in the plasma in different experimental models of pancreatitis [13][14][15][16]. In addition, one recent study showed that MMP-9 is elevated in the serum of patients with pancreatitis and was forwarded as a potential prognostic marker in AP [17].…”

Section: Introductionmentioning

confidence: 99%

Neutrophil-derived matrix metalloproteinase-9 is a potent activator of trypsinogen in acinar cells in acute pancreatitis

Awla

Abdulla

Syk

et al. 2012

Journal of Leukocyte Biology

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MMPs are generally considered to regulate degradation and remodeling of the ECM. Convincing data also implicate a role for MMPs in inflammatory conditions, such as AP, although the mechanisms are not known. The aim of this study was to define the role of MMPs in regulating activation of trypsinogen and tissue damage in AP, which was induced by infusion of taurocholate into the pancreatic duct in mice. A broad-spectrum MMP inhibitor (BB-94) and MMP-9 gene-deficient mice were used. Neutrophil secretions and rMMP-9 were used to stimulate trypsinogen activation in isolated acinar cells. Taurocholate challenge increased serum amylase, neutrophil infiltration, MIP-2 (CXCL2) formation, trypsinogen activation, and tissue damage in the pancreas. Treatment with the broad-spectrum inhibitor of MMPs, BB-94, markedly reduced activation of trypsinogen, levels of CXCL2, infiltration of neutrophils, and tissue damage in AP. Taurocholate challenge increased serum levels of MMP-9 but not MMP-2. Taurocholate-induced amylase levels, neutrophil accumulation, production of CXCL2, trypsinogen activation, and tissue damage in the pancreas were abolished in MMP-9-deficient mice. Moreover, secretions from activated neutrophils isolated from WT but not from MMP-9-deficient animals stimulated trypsinogen activation in acinar cells. Notably, rMMP-9 greatly enhanced activation of trypsinogen in acinar cells. These findings demonstrate that neutrophil-derived MMP-9 is a potent activator of trypsinogen in acinar cells and regulates pathological inflammation and tissue damage in AP.

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MMP-9 in Serum Correlates with the Development of Pulmonary Complications in Experimental Acute Pancreatitis

Cited by 10 publications

References 31 publications

Pathophysiology of Lung Injury Induced by Common Bile Duct Ligation in Mice

Pathophysiology of Lung Injury Induced by Common Bile Duct Ligation in Mice

Elevated Serum Neutrophil Gelatinase-Associated Lipocalin Is an Early Predictor of Severity and Outcome in Acute Pancreatitis

Neutrophil-derived matrix metalloproteinase-9 is a potent activator of trypsinogen in acinar cells in acute pancreatitis

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