Mishra Vivek, Patel Krutika, Trivedi Ram N, Noel Pawan, Durgampudi Chandra, Acharya Chathur, Holmes John A, Narla Sonya, Singh Vijay P
Mayo Clinic, Scottsdale, AZ, USA.
Mayo Clinic, Scottsdale, AZ, USA.
Pancreatology. 2014 Nov-Dec;14(6):459-64. doi: 10.1016/j.pan.2014.06.006. Epub 2014 Jul 3.
Multiple deleterious signaling cascades are simultaneously activated in acute pancreatitis (AP), which may limit the success of pharmacologic approaches targeting a single step. We explored whether cooling acinar cells slows distinct steps initiated from a stimulus causing pancreatitis simultaneously, and the temperature range over which inhibition of such deleterious signaling occurs.
Caerulein (100 nM) induced trypsinogen activation (TGA), CXCL1, CXCL2 mRNA levels, cell injury were studied at 37 °C, 34 °C, 31 °C, 29 °C and 25 °C in acinar cells. Trypsin, cathepsin B activities and cathepsin B mediated TGA were studied at 37 °C, 23 °C and 4 °C.
There was >80% reduction in TGA, CXCL1 and CXCL2 mRNA levels at 29 °C, and in cell injury at 34 °C, compared to those at 37 °C. Trypsin activity, cathepsin B activity and cathepsin B mediated TGA at 23 °C were respectively, 53%, 64% and 26% of that at 37 °C. Acinar cooling to 31 °C reduced LDH leakage even when cooling was initiated an hour after caerulein stimulation at 37 °C.
Hypothermia synergistically and simultaneously slows parallel and distinct signaling steps initiated by caerulein, thereby reducing TGA, upregulation of inflammatory mediators and acinar injury.
在急性胰腺炎（AP）中，多个有害信号级联反应会同时被激活，这可能会限制针对单个步骤的药物治疗方法的成效。我们探究了冷却腺泡细胞是否会同时减缓由引发胰腺炎的刺激所启动的不同步骤，以及发生这种有害信号抑制作用的温度范围。
在37℃、34℃、31℃、29℃和25℃下，研究蛙皮素（100 nM）诱导的腺泡细胞中胰蛋白酶原激活（TGA）、CXCL1、CXCL2 mRNA水平及细胞损伤情况。在37℃、23℃和4℃下，研究胰蛋白酶、组织蛋白酶B活性及组织蛋白酶B介导的TGA。
与37℃时相比，29℃时TGA、CXCL1和CXCL2 mRNA水平降低了80%以上，34℃时细胞损伤减少。23℃时胰蛋白酶活性、组织蛋白酶B活性及组织蛋白酶B介导的TGA分别为37℃时的53%、64%和26%。即使在37℃用蛙皮素刺激1小时后开始冷却，将腺泡冷却至31℃也能减少乳酸脱氢酶泄漏。
低温协同并同时减缓了由蛙皮素引发的平行且不同的信号步骤，从而减少了TGA、炎症介质的上调及腺泡损伤。
