Intra-acinar trypsinogen activation mediates early stages of pancreatic injury but not inflammation in mice with acute pancreatitis.
Intra-acinar trypsinogen activation mediates early stages of pancreatic injury but not inflammation in mice with acute pancreatitis.
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DOI：
10.1053/j.gastro.2011.08.033
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发表时间：
2011-12
期刊：
影响因子：
29.4
通讯作者：
Saluja AK
中科院分区：
文献类型：
--
作者：
Dawra R;Sah RP;Dudeja V;Rishi L;Talukdar R;Garg P;Saluja AK
胰酶原激活在急性胰腺炎(AP)发病机制中的作用尚不清楚。我们培育并鉴定了编码胰蛋白酶原7基因突变的小鼠(T7；T−/−小鼠)，这种小鼠与人类阳离子胰蛋白酶原相关。在用雨蛙素诱导AP的过程中，研究了胰酶原在这些小鼠中的病理激活作用。比较Tκ和野生型AP小鼠的腺泡细胞死亡、组织损伤、腺泡内转录因子NF-−/−B的早期激活以及局部和全身炎症反应。T7基因缺失使总胰酶原含量降低60%，阳离子胰酶原完全丧失，但不影响生理功能。T-−/−小鼠缺乏胰蛋白酶原的病理性激活，这种激活发生在AP进展早期的腺泡细胞内。T−/−小鼠缺乏胰酶原激活导致几乎完全抑制了体外的腺泡细胞死亡，并在AP进展期间减少了50%的腺泡坏死。然而，T−/−小鼠在AP进展过程中有类似程度的局部和全身炎症，以及类似的腺泡内核因子-κB激活水平-先前表明，在胰腺炎早期阶段，这种激活与胰蛋白酶原激活同时发生。T7在小鼠急性胰腺炎的发病过程中被激活。胰腺腺泡内胰酶原激活导致胰腺炎早期的腺泡死亡，这是AP胰腺损伤的50%原因。然而，AP的局部和全身性炎症的进展不需要胰蛋白酶原激活。核因子-κB在腺泡细胞早期被激活，独立于胰酶原激活，可能与AP的进展有关。
The role of trypsinogen activation in pathogenesis of acute pancreatitis (AP) has not been clearly established. We generated and characterized mice with disruption in the gene that encodes trypsinogen7 (T7; T−/− mice), the mouse correlate of human cationic trypsinogen. The effects of pathologic activation of trypsinogen were studied in these mice, during induction of AP with caerulein. Acinar cell death, tissue damage, early intra-acinar activation of the transcription factor NF-κB, and local and systemic inflammation were compared between T−/− and wild-type mice with AP. Deletion of T7 reduced the total trypsinogen content by 60%, and resulted in total loss of cationic trypsinogen, but did not affect physiologic function. T−/− mice lacked pathologic activation of trypsinogen, which occurs within acinar cells early during AP progression. Absence of trypsinogen activation in T−/− mice led to near complete inhibition of acinar cell death in vitro and a 50% reduction in acinar necrosis during AP progression. However, T−/− mice had similar degrees of local and systemic inflammation during AP progression, as well as comparable intra-acinar levels of NF-κB activation—which was previously shown to occur concurrently with trypsinogen activation during early stages of pancreatitis. T7 is activated during pathogenesis of AP in mice. Intra-acinar trypsinogen activation leads to acinar death during early stages of pancreatitis, which is responsible for 50% of the pancreatic damage in AP. However, progression of local and systemic inflammation in AP does not require trypsinogen activation. NF-κB is activated early in acinar cells, independently of trypsinogen activation, and might be responsible for progression of AP.
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影响因子：
15.9
作者：
Halangk, W;Lerch, MM;Deussing, J
通讯作者：
Deussing, J
影响因子：
12.6
作者：
Gorelick, Fred S.;Thrower, Edwin
通讯作者：
Thrower, Edwin
DOI：
10.1152/ajpgi.00315.2001
发表时间：
2002-02-01
影响因子：
4.5
作者：
Halangk, W;Krüger, B;Lerch, MM
通讯作者：
Lerch, MM
DOI：
10.1152/ajpgi.1998.275.5.g1010
发表时间：
1998-11-01
影响因子：
4.5
作者：
Grady, T;MaH'Moud, M;Gorelick, FS
通讯作者：
Gorelick, FS
DOI：
10.1006/bbrc.2000.4120
发表时间：
2001-01-12
影响因子：
3.1
作者：
Hietaranta, AJ;Saluja, AK;Steer, ML
通讯作者：
Steer, ML