Reducing Extracellular pH Sensitizes the Acinar Cell to Secretagogue-Induced Pancreatitis Responses in Rats
Reducing Extracellular pH Sensitizes the Acinar Cell to Secretagogue-Induced Pancreatitis Responses in Rats
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DOI：
10.1053/j.gastro.2009.05.041
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发表时间：
2009-09-01
期刊：
影响因子：
29.4
通讯作者：
Gorelick, Fred S.
中科院分区：
文献类型：
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作者：
Bhoomagoud, Madhavi;Jung, Thomas;Gorelick, Fred S.
背景与目的：胰腺腺泡细胞内的蛋白酶激活是急性胰腺炎的关键早期事件，可能需要低pH值的细胞内隔室。临床研究表明，酸中毒可能会影响发生胰腺炎的风险。我们推测，暴露于酸负荷可能会使腺泡细胞对促分泌剂诱导的胰腺炎敏感。方法：促分泌剂(雨蛙素、卡巴胆碱和蛙黄素)在较高浓度(分别为100nmo1/L、1 mmo1/L和10mUmo1/L)时均能诱导腺泡细胞中的蛋白水解酶活性，但在生理相关浓度时不能诱导其激活。在大鼠(1)离体腺泡模型和(2)酸刺激的体内模型上，观察了降低细胞外pH(Phe)在促分泌剂诱导的早期胰腺炎中的作用(酶原激活和损伤)。结果：在腺泡中，将Phe从7.6降至6.8可增强促分泌剂诱导的酶原激活和损伤，但不影响分泌。对于蓝蓝蛋白，这种增敏作用可在一定浓度范围内观察到(0.01-100.00 nmol/L)。然而，单独降低Phe对酶原激活、淀粉酶分泌或细胞损伤没有影响。我们已经报道，酶原的激活是由质子转运体空泡ATPase(VATPase)介导的。用刀豆素(100nmol/L)抑制vATPase可阻断低Phe对酶原激活的影响。体内给予急性酸负荷可增强蓝蛋白诱导的(50微克/公斤)胰蛋白酶原激活和胰腺水肿。结论：酸刺激使胰腺腺泡细胞对促分泌剂诱导的酶原激活和损伤变得敏感，并可能增加急性胰腺炎发生和严重程度的风险。
BACKGROUND & AIMS: Protease activation within the pancreatic acinar cell is a key early event in acute pancreatitis and may require low pH intracellular compartments. Clinical studies suggest that acidosis may affect the risk for developing pancreatitis. We hypothesized that exposure to an acid load might sensitize the acinar cell to secretagogue-induced pancreatitis. METHODS: Secretagogues (cerulein, carbachol, and bombesin) can induce protease activation in acinar cells at high (100 nmol/L, 1 mmol/L, and 10 mu mol/L, respectively) but not at physiologically relevant concentrations. The effects of decreasing extracellular pH (pHe) in early secretagogue-induced pancreatitis (zymogen activation and injury) were examined in rats (1) in vitro with isolated acini and (2) in vivo with an acid challenge. RESULTS: In acini, lowering pHe from 7.6 to 6.8 enhanced secretagogue-induced zymogen activation and injury, but did not affect secretion. For cerulein, this sensitization was seen over a range of concentrations (0.01-100.00 nmol/L). However, reduced pHe alone had no effect on zymogen activation, amylase secretion, or cell injury. We have reported that zymogen activation is mediated by the vacuolar ATPase (vATPase), a proton transporter. vATPase inhibition, using concanamycin (100 nmol/L), blocked the low pHe effects on zymogen activation. An acute acid load given in vivo enhanced cerulein-induced (50 mu g/kg) trypsinogen activation and pancreatic edema. CONCLUSION: These studies suggest that acid challenge sensitizes the pancreatic acinar cell to secretagogue-induced zymogen activation and injury and may increase the risk for the development and severity of acute pancreatitis.