| Acute pancreatitis (AP) is one of the common acute clinical abdominal diseases. It is divided into two types clinically: mild acute pancreatitis (MAP) and severe acute pancreatitis (SAP) based on its severity. SAP occupies 10~20% of AP, though its mortality has decreased obviously compared with the mortality twenty years ago ,still remains 20.8~36% .Recent researches showed that the incidence of acute lung injury (ALI) followed with SAP may be as high as 60%~70% , ALI developed into acute respiratory distress syndrome (ARDS) at about 20% , was an important cause of mortality in SAP patients. It is vital that early prevent and treatment of ALI to decrease the mortality and improve the prognosis. Researches showed that massive inflammatory cells migrated into and invaded lung tissue, so called leukocyte sequestration was the key to damage pulmonary parenchyma cells and form pulmonary edema during SAP. Lung tissue contained massive extracellular matrix (ECM), during above-mentioned pathological course, inflammatory cells released excessive matrix metalloproteinases (MMPs). MMPs leaded to massive decomposed ECM, increased pulmonary vascular permeability and pulmonary edema. At the same time inflammatory cells were actived, migrated into and invaded lung tissue, which leaded to more serious lung injury, collapse of alveolus and maladjusted proportion of ventilate/quantity. It represented clinically progressive hypoxemia. TIMPs (tissue inhibitor of metalloproteinases) can exist in normal tissue, regulating the expression of MMPs. MMPs are zinc-dependent proteolytic enzymes that acting in concert with their tissue inhibitors, tightly orchestrate extracellular matrixmorphogenesis and repair after injury. Imbalances in their levels relative to that of their inhibitors may be implicated in the development of pancreatitis associated acute lung injury. The study was conducted to investigate the dynamic expression of MMP-9 and TIMP-1 in the lung, the potential roles of them in the development of pancreatitis associated acute lung injury, the effect of somatostatin in the treatment of lung injury following SAP in a rat model.MethodsSeventy-two Wistar rats were randomly allocated into three groups: sham operation group (group S), severe acute pancreatitis group (group A), treatment group with somatostatin (group T). Each group was divided into 3,6 and 12h subgroups (n=8 in each subgroup). Rat SAP model was induced by injection of 5% sodium taurocholate below pancreatic covering membrane. Ten minutes after operation, somatostatin was given by continuous intravenous infusions (lOug/kg/h) through right jugular in the rats of group T. Put rats to death after operation at 3h, 6h, and 12h. The following parameters were measured at three time points: serum level of amylase, TNF- a and IL-6, lung-body index (whole lung wet weight/ weight ratio X 100, to evaluate pulmonary edema), the myeloperoxidase(MPO) activity of lung tissue. The serum levels of amylase were detected with biochemical analyzer; the serum levels of TNF- a and IL-6 were detected with radioimmunoassay; the MPO activity were detected with spectrophotometer.And intrapulmonary MMP-9 and TIMP-1 expression was assayed by immunohistochemistry, the pathological change of lung and pancreas was observed under microscope. All data were analyzed with statistic software SPSS 10.0.Results1. At the three time points, levels of serum AMY in group A and T were obviously higher than those in group S (P<0.05). Levels of serum AMY were significant difference between group A and T at the three time points after pancreatitis induction (PO.05).2. At the three time points, levels of TNF- a and IL-6 in group A and T were significantly higher than those in group S with the development of SAP (PO.05, PO.05). In group T they significantly declined compared with those in group A at the three time points (PO.05).3. At the three time points, levels of lung-body index in group A and T were significantly higher than those in group SCPO.05). In group T they significantly declined compared with those in group A at 6h and 12h(/*<0.05).4. The MPO activities of lung tissue in group A were significantly higher than those in group S at 6h and 12h(P<0.05). In group T they significantly declined compared with those in group A at 6h and 12h(P<0.05).5. At the three time points, intrapulmonary MMP-9 activities in group A and T were obviously higher than those in group S (P<0.05). The expression of MMP-9 was gradually upregulated after the onset of SAP and reached their peaks at 12h. In group T they significantly declined compared with those in group A at 6h and 12h(/><0.-05). At the three time points, intrapulmonary TIMP-1 activities in group A and T were obviously higher than those in group S (P<0.05). But there was no statistical significant between group A and group T. In group S MMP-9/TIMP-1 ratio closed to 1, the ratios in group A and T exceeding 1 were obviously higher than those in group S at 6h and 12h (/*<0.05). In group T they significantly declined compared with those in group A at 6h and 12h (PO.05).6. In group S pathological damage was gradually aggravated in a time-dependent manner. Cloudy bloody ascites, mesenteric saponification spots, pancreatic edema and pancreatic local or lamellar necrosis could be observed. Under microscopic examination acinar cell edema, necrosis, interstitial haemorrhage and neutrophil and monocyte infiltratoin were obvious in the pancreatic tissue. The changes were milder in group T at the three time points. Puhnonary edema, dispersed hemorrhagic spots on the surface of lungs and a little hydrothorax could be observed. Under microscopic examination ruptured alveolar wall, congestive and edematous broadening puhnonary mesenchyme, lots of neutrophil infiltratoin in puhnonary alveoli and puhnonary mesenchyme could be observed. The changes were alleviated in group T at the three time points. The scores of pathological change of lung in group A were significantly higher than those in group S at the three time points (P<0.05). There was statistical significant between group A and group T at 12h(P<0.05).7. The result of linear correlation analysis indicated that in group A levels of TNF- a and MPO activity (r=0.863,P<0.001) or MMP-9 activity (r=0.624^<0.01) both have apositive correlation; MMP-9 activity and levels of lung-body index (f^.SM^O.OS) or MPO activity (r=0.443,.P<0.05) also have a positive correlation; the score of pathological change of lung and MMP-9 activity (r=0.509^<0.05 ) or MMP-9/TIMP-1 ratio (r=0.766^P<0.01) also have a positive correlation. Conclusions1. Severe acute pancreatitis was early associated with subsequent acute lung injury such as pulmonary edema and inflammatory cell infiltration in rats.2. In the early period of SAP, inflammatory mediator and cytokines stimulated intrapulmonary overexpression of the MMP-9 promoting neutrophil migration and infiltratoin in the lung tissue and the form of pulmonary edema.3. Intrapuhnonary overexpression of the MMP-9 and suppression of TIMP-1 resulted in the imbalance of MMP-9/TIMP-1, which is likely to play an import role in the pathogenesis of experimental SAP associated lung injury in rats.4. Somatostatin effectively inhibiting the secretion and activation of pancreatic enzyme and depressing the excessive release of inflammatory mediator and cytokines can downregulate the expression of the MMP-9, restore in part the imbalance of MMP-9/ TIMP-1, sequentially alleviate lung injury.
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